Early Switch From Intravenous To Oral Antibiotic Therapy in Patients With Cancer Who Have Low-Risk Neutropenic Sepsis: The Easi-Switch RCT

Journals Library
Health Technology Assessment

Volume 28 • Issue 14 • March 2024
ISSN 2046-4924
Early switch from intravenous to oral

antibiotic therapy in patients with cancer
who have low-risk neutropenic sepsis:
the EASI-SWITCH RCT
Vicky Coyle, Caroline Forde, Richard Adams, Ashley Agus, Rosemary Barnes, Ian Chau,
Mike Clarke, Annmarie Doran, Margaret Grayson, Danny McAuley, Cliona McDowell,
Glenn Phair, Ruth Plummer, Dawn Storey, Anne Thomas, Richard Wilson and Ronan McMullan
DOI 10.3310/RGTP7112
a
Early switch from intravenous to oral antibiotic
therapy in patients with cancer who have low-
risk neutropenic sepsis: the EASI-SWITCH RCT
Vicky Coyle ,1* Caroline Forde ,1 Richard Adams ,2

Ashley Agus ,3 Rosemary Barnes ,4 Ian Chau ,5
Mike Clarke ,6 Annmarie Doran ,3 Margaret Grayson ,7
Danny McAuley ,8 Cliona McDowell ,3 Glenn Phair ,3
Ruth Plummer ,9 Dawn Storey ,10 Anne Thomas ,11
Richard Wilson 12 and Ronan McMullan 8
1
Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
2
Centre for Trials Research – Cancer Division, Cardiff University, Cardiff, UK
3
Northern Ireland Clinical Trials Unit, Belfast Health and Social Care Trust, Belfast, UK
4
School of Medicine, Cardiff University, Cardiff, UK
5
Department of Medicine, Royal Marsden Hospital, Surrey, UK
6
Centre for Public Health, Queens University Belfast, Belfast, UK
7
Northern Ireland Cancer Research Consumer Forum, Belfast Health and Social Care
Trust, Belfast, UK
8
Wellcome-Wolfson Institute for Experimental Medicine, Queens University Belfast,
Belfast, UK
9
Translational and Clinical Research Institute, Newcastle University, Newcastle upon
Tyne, UK
10
The Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, UK
11
Leicester Cancer Research Centre, University of Leicester, Leicester, UK
12
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Corresponding author
*
Disclosure of interests
Full disclosure of interests: Completed ICMJE forms for all authors, including all related interests, are
available in the toolkit on the NIHR Journals Library report publication page at https://doi.org/10.3310/
RGTP7112.
Primary conflicts of interest: Vicky Coyle reports a Cancer Research UK Doctoral Fellowship research
grant that part-supported this submitted work. She also reports research grants from Cancer Research
UK and Astex Pharmaceuticals (UK) as well as personal fees and non-financial support from Servier
Laboratories (France) for attending educational meetings, all unrelated to the submitted work. Richard
Adams reports research grants from AstraZeneca PLC (UK) and Merck Sharp & Dohme Ltd (MSD, UK) as
well as personal fees from Bayer Healthcare Pharmaceuticals LLC (Germany), Amgen Inc. (USA) and
Servier Laboratories and non-financial support for attending meetings from Amgen Inc., Servier
Laboratories and Merck Serono (Switzerland), all unrelated to the submitted work. Ashley Agus reports
membership of the NIHR HTA Programme General Funding Committee. Ian Chau reports grants or
contracts from Janssen-Cilag and Eli Lilly and Company. He also reports personal fees from Eli Lilly and
Company (USA), AstraZeneca PLC, MSD, Merck Serono, Bristol Meyers Squibb Inc. (USA), Bayer
Healthcare Pharmaceuticals LLC, Roche AG (Switzerland), OncXerna (China), Pierre Fabre
Pharmaceuticals Inc. (France), Boehringer Ingelheim (Germany), Incyte Inc. (USA), Astellas Pharma
(Japan), GlaxoSmithKline Ltd (UK), SOTIO (Czech Republic), Eisai (Japan), Five Prime Therapeutics, Inc.
(USA), Symphogen (Denmark) and Servier Laboratories. Mike Clarke reports membership of the NIHR
CRSU Funding Board, NIHR HTA Funding Teleconference Members, NIRH HTA Prioritisation Committee
B Methods Group and NIHR HTA General Committee. Daniel McAuley reports research grants from
NIHR, Innovate UK, Medical Research Council (MRC), Novavax Inc. (USA), the Northern Ireland HSC
R&D Division, and the Wellcome Trust as well as personal fees from Bayer Healthcare Pharmaceuticals
LLC, GlaxoSmithKline Ltd (UK), Boehringer Ingelheim (Germany), Novartis AG (Switzerland) and Eli Lilly
and Company (USA); he also reports non-financial support for attending meetings from Vir
Biotechnology Inc. (USA) and Faron Pharmaceuticals (Finland). He also reports spousal personal fees
from Insmed, Inc. and the California Institute for Regenerative Medicine. Apart from NIHR funding for
this trial, all others listed are unrelated to the submitted work. He is co-director of research for the
Intensive Care Society (UK) and Programme Director of the NIHR/MRC Efficacy & Mechanisms
Evaluation (EME) Programme. He also reports membership of the EME Strategy Advisory Committee,
the EME Funding Committee, the EME Funding Committee Sub-Group: Remit and Competitiveness and
former membership of the NIHR/UKRI COVID-19 reviewing committee and the HTA General
Committee and Commissioning Committees. Ronan McMullan reports research grants from the NIHR
HTA Programme, NIHR EME Programme, Wellcome Trust, NI Chest, Heart & Stroke Association and
Randox Laboratories Ltd (UK), as well as personal fees and non-financial support for attending meetings
from Gilead Sciences Europe Ltd (UK), all unrelated to the submitted work. He is also a member of the
NIHR HTA Programme Prioritisation Committee B. Ruth Plummer reports membership of the NIHR EME
Funding Committee. Caroline Forde, Rosemary Barnes, Annmarie Doran, Margaret Grayson, Cliona
McDowell, Glenn Phair, Dawn Storey, Anne Thomas and Richard Wilson report no competing interests.
Published March 2024

DOI: 10.3310/RGTP7112
This report should be referenced as follows:
Coyle V, Forde C, Adams R, Agus A, Barnes R, Chau I, et al. Early switch from intravenous to
oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis: the
EASI-SWITCH RCT. Health Technol Assess 2024;28(14). https://doi.org/10.3310/RGTP7112
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Copyright © 2024 Coyle et al. This work was produced by Coyle et al. under the terms of a commissioning contract issued by
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DOI: 10.3310/RGTP7112 Health Technology Assessment 2024 Vol. 28 No. 14
Abstract
Early switch from intravenous to oral antibiotic therapy in

patients with cancer who have low-risk neutropenic sepsis:
the EASI-SWITCH RCT
Vicky Coyle ,1* Caroline Forde ,1 Richard Adams ,2 Ashley Agus ,3

Rosemary Barnes ,4 Ian Chau ,5 Mike Clarke ,6 Annmarie Doran ,3
Margaret Grayson ,7 Danny McAuley ,8 Cliona McDowell ,3
Glenn Phair ,3 Ruth Plummer ,9 Dawn Storey ,10 Anne Thomas ,11
Richard Wilson 12 and Ronan McMullan 8
1
Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
2
Centre for Trials Research – Cancer Division, Cardiff University, Cardiff, UK
3
Northern Ireland Clinical Trials Unit, Belfast Health and Social Care Trust, Belfast, UK
4
School of Medicine, Cardiff University, Cardiff, UK
5
Department of Medicine, Royal Marsden Hospital, Surrey, UK
6
Centre for Public Health, Queens University Belfast, Belfast, UK
7
Northern Ireland Cancer Research Consumer Forum, Belfast Health and Social Care Trust, Belfast, UK
8
Wellcome-Wolfson Institute for Experimental Medicine, Queens University Belfast, Belfast, UK
9
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
10
The Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, UK
11
Leicester Cancer Research Centre, University of Leicester, Leicester, UK
12
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
Corresponding author v.coyle@qub.ac.uk

*
Background: Neutropenic sepsis is a common complication of systemic anticancer treatment. There is

variation in practice in timing of switch to oral antibiotics after commencement of empirical intravenous
antibiotic therapy.
Objectives: To establish the clinical and cost effectiveness of early switch to oral antibiotics in patients
with neutropenic sepsis at low risk of infective complications.
Design: A randomised, multicentre, open-label, allocation concealed, non-inferiority trial to establish
the clinical and cost effectiveness of early oral switch in comparison to standard care.
Setting: Nineteen UK oncology centres.
Participants: Patients aged 16 years and over receiving systemic anticancer therapy with fever (≥ 38°C),
or symptoms and signs of sepsis, and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with
a Multinational Association for Supportive Care in Cancer score of ≥ 21 and receiving intravenous
piperacillin/tazobactam or meropenem for < 24 hours were eligible. Patients with acute leukaemia or
stem cell transplant were excluded.
Intervention: Early switch to oral ciprofloxacin (750 mg twice daily) and co-amoxiclav (625 mg three
times daily) within 12–24 hours of starting intravenous antibiotics to complete 5 days treatment in total.
Control was standard care, that is, continuation of intravenous antibiotics for at least 48 hours with
ongoing treatment at physician discretion.
Copyright © 2024 Coyle et al. This work was produced by Coyle et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care.
This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction vii
and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original
author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.
Abstract
Main outcome measures: Treatment failure, a composite measure assessed at day 14 based on the
following criteria: fever persistence or recurrence within 72 hours of starting intravenous antibiotics;
escalation from protocolised antibiotics; critical care support or death.
Results: The study was closed early due to under-recruitment with 129 patients recruited; hence, a
definitive conclusion regarding non-inferiority cannot be made. Sixty-five patients were randomised to
the early switch arm and 64 to the standard care arm with subsequent intention-to-treat and per-
protocol analyses including 125 (intervention n = 61 and control n = 64) and 113 (intervention n = 53
and control n = 60) patients, respectively. In the intention-to-treat population the treatment failure rates
were 14.1% in the control group and 24.6% in the intervention group, difference = 10.5% (95%
confidence interval 0.11 to 0.22). In the per-protocol population the treatment failure rates were 13.3%
and 17.7% in control and intervention groups, respectively; difference = 3.7% (95% confidence interval
0.04 to 0.148). Treatment failure predominantly consisted of persistence or recurrence of fever and/or
physician-directed escalation from protocolised antibiotics with no critical care admissions or deaths.
The median length of stay was shorter in the intervention group and adverse events reported were
similar in both groups. Patients, particularly those with care-giving responsibilities, expressed a
preference for early switch. However, differences in health-related quality of life and health resource use
were small and not statistically significant.
Conclusions: Non-inferiority for early oral switch could not be proven due to trial under-recruitment.
The findings suggest this may be an acceptable treatment strategy for some patients who can adhere to
such a treatment regimen and would prefer a potentially reduced duration of hospitalisation while
accepting increased risk of treatment failure resulting in re-admission. Further research should explore
tools for patient stratification for low-risk de-escalation or ambulatory pathways including use of
biomarkers and/or point-of-care rapid microbiological testing as an adjunct to clinical decision-making
tools. This could include application to shorter-duration antimicrobial therapy in line with other
antimicrobial stewardship studies.
Trial registration: This trial is registered as ISRCTN84288963.
Funding: This award was funded by the National Institute for Health and Care Research (NIHR)
Health Technology Assessment programme (NIHR award ref: 13/140/05) and is published in full in
Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further
award information.
viii
NIHR Journals Library www.journalslibrary.nihr.ac.uk

Contents
List of tables xiii
List of figures xv
List of abbreviations xvii
Plain language summary xix
Scientific summary xxi
Chapter 1 Introduction 1
Neutropenic sepsis 1
Empirical management of NS 1
Risk stratification 2
Oral antibiotic therapy as treatment 3
Outpatient management of low-risk NS 3
Rationale for the trial 4
Acute oncology service development 4
Chapter 2 Methods 5
Trial design 5
Trial objectives 5
Primary objective 5
Secondary objectives 5
Research hypotheses 6
Study conduct 6
Ethics, regulatory and research and development approvals 6
Sponsorship 6
Trial management 6
Trial set-up 7
Patient information and consent 7
Screening and randomisation procedures 7
Trial treatment 8
Standard care arm 8
Intervention arm 8
Other treatments 8
Patient population 9
Inclusion criteria 9
Exclusion criteria 9
Co-enrolment 9
Withdrawal of consent 9
Data management 10
Trial database 10
Data quality 10
Data collection 10
Adverse event reporting 10
Serious adverse event 12
Suspected unexpected serious adverse reaction 13
Serious breaches 13
This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction ix
Contents
Protocol amendments 13
July 2016 13
August 2016 13
April 2017 13
June 2018 13
Embedded pilot study 14
Statistical analysis plan 15
Non-inferiority design and non-inferiority margin 15
Sample size 15
Review of study design post-pilot phase and revision of sample size 15
Statistical methods 15
Subgroup analyses 16
Survey design and delivery 16
Site interviews 16
Patient and public involvement 17
Chapter 3 Pilot study results and review of study design 19

Pilot study aim 19
Recruitment rates 19
Initial pilot phase (February to July 2016) 19
Review of eligibility criteria 21
Extended pilot phase I (December 2016 to February 2017) 22
Extended pilot phase II (April 2017 to November 2017) 23
Summary of pilot phase recruitment 24
Adherence to the protocol-specified treatment 24
Separation between trial arms 24
Summary of embedded pilot study results 24
Determining continued importance of the research question 25
Review of assumptions underpinning study design 28
Review of the non-inferiority margin 28
Review of statistical analysis plan 30
Progression to main trial 30
Chapter 4 Main trial progression 31

Screening and recruitment post pilot phase 31
Identification of barriers to recruitment 31
Semistructured interview feedback from key site personnel 32
Investigator survey of barriers to recruitment 34
Additional strategies to enhance recruitment 37
Main trial progress 38
Chapter 5 Clinical effectiveness of early oral switch 39

Recruitment 39
Consolidated Standards of Reporting Trials flow diagram 39
Baseline characteristics 41
Treatment after trial entry 42
Protocol deviations 43
Treatment outcomes 43
Primary outcome 43
Secondary outcomes 45
Subgroup analyses 47
Safety 47
Adverse events 47

Chapter 6 Health economic and patient preference analyses 51

Background 51
Methods 51
Sensitivity analyses 52
Non-health outcomes 52
Results 52
Cost–utility analysis 52
Sensitivity analyses (cost–utility analysis) 56
Cost-effectiveness analysis 57
Sensitivity analyses (cost-effectiveness analysis) 61
Patient preferences 62
Conclusion 64
Chapter 7 Discussion 67
Aim of the study 67
Main findings and interpretation of results 67
Conclusion 69
Implications for future research 69
Acknowledgements 71
References 75
Appendix 1 PPI survey on revision of the EASI-SWITCH trial non-inferiority margin 81
Appendix 2 UK clinician survey 85
Appendix 3 Trial sites and recruitment 87
Appendix 4 Semistructured interview guide for EASI-SWITCH investigators regarding

barriers to recruitment 89
Appendix 5 Reasons for study screening failure 91
Appendix 6 Unit costs of hospital services and study drugs 93
Appendix 7 Patient preference questionnaire 95
Appendix 8 Health economics analyses using all available data 99
This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction xi
List of tables
TABLE 1 Multinational Association of Supportive Care in Cancer risk index 2
TABLE 2 Schedule of assessments 11
TABLE 3 Summary of progress of the embedded pilot study 19
TABLE 4 Summary of initial pilot phase 20
TABLE 5 Reasons for participant exclusion at sites 1 and 2 20
TABLE 6 Summary of difficulties encountered with the original trial eligibility criteria
used during the initial pilot phase 21
TABLE 7 Adjustments to eligibility criteria following the initial pilot phase 22
TABLE 8 Summary of extended pilot phase (I) (December 2016 to February 2017) 23
TABLE 9 Recruitment activity in the extended pilot phase (II) (April 17 to November 17) 23
TABLE 10 Common reasons cited by survey respondents preventing early discharge

of uncomplicated low-risk patients (before 48 hours of hospitalisation) 27
TABLE 11 Reasons for site non-participation in the EASI-SWITCH trial (n = 15 sites) 31
TABLE 12 Summary of recruitment activity 32
TABLE 13 Summary of barriers to recruitment encountered in the EASI-SWITCH trial,

as reported by interviewed clinicians (n = 23) 33
TABLE 14 Most frequent barriers to recruitment as reported in the electronic survey

(n = 40 survey responses) 35
TABLE 15 Survey respondents’ impression of listed potential barriers to recruitment

in relation to their experience of the EASI-SWITCH trial (n = 40 survey responses) 36
TABLE 16 Recruitment by site 39
TABLE 17 Baseline characteristics 41
TABLE 18 Protocol deviations 43
TABLE 19 Analyses for the primary outcome in the ITT and PP populations 44
TABLE 20 Constituents of the composite primary outcome measure leading to

patients reaching the treatment failure end point in the ITT population 45
TABLE 21 Constituents of the composite primary outcome measure leading to

patients reaching the treatment failure end point in the PP population 46
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List of tables
TABLE 22 Secondary outcome measures 46
TABLE 23 Subgroup analyses 47
TABLE 24 Adverse events by treatment group 48
TABLE 25 Hospital service use by group with complete cost and QALY data 53
TABLE 26 Cost (£UK) of hospital service use by group inpatients with complete
cost and QALY data 53
TABLE 27 Health-related quality-of-life scores by group (patients with complete

cost and QALY data) 54
TABLE 28 Results of the cost–utility analyses at 14 days (1000 bootstrap samples) 54
TABLE 29 Incremental net benefit at various willingness-to-pay thresholds per

QALY gained 56
TABLE 30 Hospital resource use by group in patients (complete cost and treatment
failure data) 58
TABLE 31 Cost of hospital service use by group in patients (complete cost and
treatment failure data) 59
TABLE 32 Results of the cost-effectiveness analyses at 14 days (1000 bootstrap

samples) 60
TABLE 33 Incremental net benefit at various willingness-to-pay thresholds per

treatment failure avoided 61
TABLE 34 Patient satisfaction and experience, by group 63
TABLE 35 Patient preferences and risk-based decision-making, by group 64
TABLE 36 Home-based factors, by group 64
TABLE 37 List of trial sites and numbers of patients recruited 87
TABLE 38 Unit costs of hospital services and study drugs 93
TABLE 39 Health-related quality-of-life scores by group using all available data 99
TABLE 40 Hospital resource use by group using all available data 100
TABLE 41 Cost of hospital service use by group (all available data) 101
xiv

List of figures
FIGURE 1 Summary of recruitment activity at the end of the pilot phase
(February 2016 to November 2017): total recruitment of 42 patients 24
FIGURE 2 Cumulative actual recruitment vs. predicted recruitment for the

EASI-SWITCH trial (April 2017 to November 2019 inclusive) 32
FIGURE 3 CONSORT diagram 40
FIGURE 4 Forest plot of differences (90% CI) by analyses performed 44
FIGURE 5 Cost-effectiveness plane for the primary cost–utility analysis showing

1000 bootstrapped replications of mean incremental costs and QALY gain and the
willingness-to-pay threshold of £20,000/QALY 55
FIGURE 6 Cost-effectiveness acceptability curves showing the probability of

intervention being cost-effective compared to standard care for the primary and
sensitivity analyses using QALYs as the outcome 56
FIGURE 7 Cost-effectiveness acceptability curve showing the probability of

intervention being cost-effective compared to standard care using the net monetary
benefit method 57
FIGURE 8 Cost-effectiveness plane for the primary cost-effectiveness analysis

showing 1000 bootstrapped replications of mean incremental costs and treatment
failures avoided 60
FIGURE 9 Cost-effectiveness acceptability curves showing the probability of

intervention being cost-effective compared to standard care for the primary and
sensitivity analyses, using treatment failure rate as the outcome 61
FIGURE 10 Cost-effectiveness acceptability curve showing the probability of

intervention being cost-effective compared to standard care using the net monetary
benefit method 62
This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction xv
List of abbreviations
(G)CSF (granulocyte) colony- ITT intention-to-treat
stimulating factor i.v. intravenous
AE adverse event MASCC Multinational
ALT alanine aminotransferase Association for
Supportive Care in Cancer
AR adverse reaction
NICE National Institute for
ASCO American Society of
Health and Care Excellence
Clinical Oncology
NICTU Northern Ireland
AST aspartate aminotransferase
Clinical Trials Unit
BHSCT Belfast Health and
NIHR National Institute for
Social Care Trust
Health and Care Research
CEA cost-effectiveness analysis
NMB net monetary benefit
CEAC cost-effectiveness
NS neutropenic sepsis
acceptability curves
PI principal investigator
CI confidence interval
PP per-protocol
CISNE clinical index of stable
febrile neutropenia PPI patient and public
involvement
CRF case report form
QALY quality-adjusted life-year
CUA cost–utility analysis
R&D research and development
DMEC data monitoring and
ethics committee RD risk difference
EQ-5D-5L EuroQoL-5 Dimensions, RN research nurse
five-level version SACT systemic anticancer therapy
ESMO European Society for SAE serious adverse event
Medical Oncology
SAR serious adverse reaction
GCP good clinical practice
SUSAR suspected
GDG guideline development unexpected serious
group adverse reaction
GEE generalised estimating SPC summary of product
equations characteristics
HRQoL health-related quality of life TMG trial management group
HTA Health Technology TSC trial steering committee
Assessment
UKONS United Kingdom
ICER incremental cost- Oncology Nursing Society
effectiveness ratio
ULN upper limit of normal
IMP investigational
medicinal product WTP willingness-to-pay
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Plain language summary

The background
Neutropenic sepsis, or infection with a low white blood cell count, can occur following cancer treatment.
Usually patients receive treatment with intravenous antibiotics (antibiotics delivered into a vein) for two
or more days. Patients at low risk of complications from their infection may be able to have a shorter
period of intravenous antibiotics benefitting both patients and the NHS.
What did we do?
The trial compared whether changing from intravenous to oral antibiotics (antibiotics taken by mouth as
tablets or liquid) 12–24 hours after starting antibiotic treatment (‘early switch’) is as effective as usual
care. Patients could take part if they had started intravenous antibiotics for low-risk neutropenic sepsis.
Patients were randomly allocated to ‘early switch’ or to usual care.
The main outcome measured was treatment failure. Treatment failure happened if fever persisted or
recurred despite antibiotics, if patients needed to change antibiotics, if they needed to be re-admitted to
hospital or needed to be admitted to intensive care within 14 days or died.
What did we find?
We had originally intended that 628 patients would take part, but after review of the design of the study
the number needed to take part was revised to 230. We were not able to complete the trial as planned
as unfortunately only 129 patients took part. As the trial was smaller than expected we were not able to
draw conclusions as to whether ‘early switch’ is no less effective than usual care. Our findings suggest
that ‘early switch’ might result in a shorter time in hospital initially; however, treatment failure was more
likely to occur, meaning some patients had to return to hospital for further antibiotics. There were no
differences in side effects and no serious complications from treatment or treatment failure (such as
intensive care admission or death) among the 65 patients in the ‘early switch’ group. Patients were
satisfied with ‘early switch’.
What does this all mean?
Early switch may be a treatment option for some patients with low-risk neutropenic sepsis who would
prefer a shorter duration of hospital admission but accept a risk of needing hospital re-admission.
This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction xix
Scientific summary
Background
Neutropenic sepsis (NS) is a potentially life-threatening complication of treatment with systemic

anticancer therapy (SACT). Many consensus guidelines, including the UK National Institute for Health
and Care Excellence (NICE) guidance, recommend switching from intravenous (i.v.) to oral antibiotics
after 48 hours of therapy, with evidence lacking to support an earlier switch in those patients at low risk
of infective complications. The early switch to oral antibiotic therapy in patients with low-risk NS (EASI-
SWITCH) trial was developed in response to a commissioned call by National Institute for Health and
Care Research (NIHR) to address this evidence gap.
Objectives
To establish the clinical and cost effectiveness of early switch to oral antibiotics (within 12–24 hours of
starting antibiotics) in patients with NS at low risk of infective complications. The primary objective was
to assess whether early switch was non-inferior to standard care (continuation of i.v. antibiotics for at
least 48 hours) in terms of treatment failure at day 14. The secondary objectives were to assess the
effects of early oral switch on quality of life, length of hospital admission, re-admission to hospital,
changes to subsequent planned SACT and death within 28 days in addition to an assessment of cost-
effectiveness and patient preference for these treatment strategies at day 14.
Study design
A pragmatic, randomised, open-label, multicentre non-inferiority trial was designed to compare early
oral switch to standard care i.v. antibiotics. Participants were randomised with randomly permuted
blocks 1 : 1 to intervention and standard care. Allocation concealment was maintained through use of an
automated system with access to the randomisation sequence restricted to the trial statistician.
Participants and clinical or research team members were not blinded to allocated treatment due to both
the pragmatic nature of the study and patient representatives’ advice that outcome assessors would be
likely to be made aware by participants of their allocated treatment. An embedded pilot study was
included to test the assumptions related to recruitment, adherence and separation between treatment
arms underpinning the study design.
The initial sample size was 628 patients based on a stringent approach to trial design in accordance with
a typical Phase 3 efficacy study with a line of sight to therapeutic licensing and a non-inferiority margin
suggested by consensus guidelines. On review after study initiation, the stringency of this design was
felt to be less relevant to a treatment strategy involving agents already routinely used and/or licensed
for use in NS and the low-risk nature of this patient population where treatment failure is not associated
with serious adverse outcomes such as critical care admission or death. The revised target sample size
was 230 patients. This was based on an assumed 15% treatment failure rate in the standard care arm
and a 15% non-inferiority margin, at 90% power [one-sided 95% confidence interval (CI)] requiring 98
patients per group. Allowing for a 5% dropout rate and 10% crossover from control to intervention the
target was 115 participants per group (230 in total). To conclude non-inferiority of the intervention, the
primary analysis was required to demonstrate non-inferiority in both the intention-to-treat (ITT) and
per-protocol (PP) analyses.
This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction xxi
Scientific summary
Methods
Patients aged 16 years and over receiving SACT with fever (≥ 38°C), or symptoms and signs of sepsis,
and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with a Multinational Association
for Supportive Care in Cancer (MASCC) score of ≥ 21 and receiving i.v. piperacillin/tazobactam or
meropenem for < 24 hours were eligible. Patients with acute leukaemia or stem cell transplant were
excluded. Participants were recruited from 19 sites across the UK.
Patients were randomised on a 1 : 1 basis to (1) early switch to oral ciprofloxacin (750 mg twice daily)
and co-amoxiclav (625 mg three times daily) within 12–24 hours of starting antibiotics and completing
5 days treatment in total or to (2) continuation of i.v. antibiotics for at least 48 hours with ongoing
treatment at physician discretion. Patients were discharged by their treating physician in accordance
with their routine clinical practice. A patient diary was used to record any further temperatures and oral
antibiotic compliance. Follow-up at day 14 determined whether the primary outcome measure of
treatment failure was met and health-related quality of life (HRQoL) and patient preference
questionnaires were completed. At day 28, survival status and the effect of NS on any subsequent cycle
of anticancer treatment were assessed.
Outcome measures
Primary outcome measure

Treatment failure at day 14, defined using a composite measure comprising:
• persistence, recurrence or new onset of fever (temperature ≥ 38°C) after 72 hours of starting i.v.
antibiotic treatment
• physician-directed escalation from protocol antibiotic treatment
• re-admission to hospital (related to infection or antibiotic treatment)
• critical care admission
• death.
Secondary outcome measures
• Short-term change in HRQoL, using EuroQoL-5 Dimensions, five-level version (EQ-5D-5L) as the
measurement tool, at baseline and 14 days.
• Cost-effectiveness, based on the cost per treatment failure avoided at 14 days and a cost–utility
analysis (CUA) estimating the cost per quality-adjusted life-year (QALY) at 14 days.
• Time to resolution of fever from initial i.v. antibiotic administration.
• Adverse events (AEs) related to antibiotics.
• Hospital discharge and total length of hospital stay.
• Re-admission to hospital.
• Death within 28 days.
• Adjustment to the subsequent scheduled cycle of chemotherapy.
• Patient preferences for antibiotic treatment strategy assessed at day 14.
Results
The embedded pilot phase of the study highlighted challenges in recruitment and study delivery but no
concerns regarding treatment adherence or separation between treatment arms. Despite revisions to the
study design and eligibility criteria, and taking account of the lower than anticipated incidence of NS,
recruitment remained challenging and appeared to plateau as the study progressed. While logistical aspects
such as the number of potential patients and the short time window for enrolment continued to impact on
xxii

recruitment, review of standard care practice in NS management suggested increasing variation in equipoise
between trial arms as clinicians shifted towards early or upfront oral antibiotics as the trial progressed.
The study was closed early due to under-recruitment with 129 patients recruited. Sixty-five patients
were randomised to the early switch (intervention arm) and 64 to the standard care (control) arm with
subsequent ITT and PP analyses including 125 patients (intervention n = 61 and control n = 64) and 113
(intervention n = 53 and control n = 60), respectively. In the ITT population, the treatment failure rates
were 14.1% in the control and 24.6% in the intervention group, respectively; difference = 10.5% (95%
CI 0.11 to 0.22). In the PP population, the treatment failure rates were 13.3% and 17.7% in control and
intervention groups, respectively; difference = 3.7% (95% CI 0.04 to 0.148). The criteria for non-
inferiority were not met in the ITT analysis but were met in the PP analysis; however, given the under-
recruitment, no definitive conclusion regarding non-inferiority can be made and the discordant results
between ITT and PP analyses add to the uncertainty in interpreting these data.
The main constituents of the composite primary outcome measure accounting for treatment failure
were persistence/recurrence of fever and/or physician-directed escalation from the protocolised
antibiotic regimen. None of the treatment failure events recorded in either arm were attributable to the
need for critical care support or death before day 14. There were no apparent differences between the
two trial arms for time to fever resolution, re-admission to hospital to day 28, survival to day 28 or
changes to the originally intended SACT regimen. AEs were as anticipated for the agents used and
reported at similar rates between treatment arms.
A within-trial economic evaluation was performed to assess the cost effectiveness of early switch to oral
antibiotics. This included a cost-effectiveness analysis (CEA) consistent with the primary outcome measure
to estimate the cost per treatment failure avoided at day 14 and a CUA to estimate the cost per QALY at
day 14. The primary measure used in these analyses, the QALY, was estimated from the EQ-5D-5L
questionnaire. A bespoke Patient Follow-up Questionnaire at day 14 was used to collect information on
non-health outcome measures important to patients. Overall, early oral switch appears to be a cost-
effective approach within existing NHS care pathways and leads to improvements in global HRQoL. The
majority of patients were content with the treatment they received, regardless of the group they were
randomised to. Notably, patients had a much higher acceptance of the possibility of treatment failure in
order to enable early discharge for their primary admission than might be anticipated by clinicians.
Conclusions
Non-inferiority for early oral switch could not be proven. The findings suggest this may be a an
acceptable treatment strategy for some patients who can adhere to such a treatment regimen and would
prefer a potentially reduced duration of hospitalisation while accepting a potentially increased risk of
treatment failure resulting in re-admission.
Trial registration
This trial is registered as ISRCTN84288963.
Funding
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology
Assessment programme (NIHR award ref: 13/140/05) and is published in full in Health Technology
Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.
This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction xxiii
Chapter 1 Introduction
T his chapter contains some text reproduced from the study protocol ‘Early switch from intravenous
to oral antibiotic therapy in patients with cancer who have low risk neutropenic sepsis (the EASI-
SWITCH trial): study protocol for a randomised controlled trial’ published in Trials (2020). https://doi.
org/10.1186/s13063-020-04241-1.1
Neutropenic sepsis
Neutropenic sepsis (NS) is a long-recognised and common complication of systemic anticancer

treatment (SACT).2 The term broadly refers to a significant inflammatory response to a presumed
bacterial infection, in a person with or without fever and a low blood neutrophil count.3 A low neutrophil
count occurs commonly following SACT with a trajectory that varies depending on type and timing
of SACT, typically reaching a nadir around 7 days post SACT then recovering over 2–3 weeks.4 There
is significant variation in the definition of neutropenia and sepsis, with a lack of comparative data to
guide threshold-setting for neutrophil count or fever in patients with potential NS.3,5–15 Based on the
available data, the National Institute for Health and Care Excellence (NICE) Guideline Development
Group (GDG) concluded using a threshold of 0.5 × 109/l for neutrophil count and ≥ 38°C for temperature
for diagnosis of NS reflected an acceptable trade-off between over- and under-treatment of what could
be a potentially fatal infection.3 However, in the NHS, NS care pathways commonly use a temperature
threshold of ≥ 38°C and an absolute neutrophil count threshold of either ≤ 0.5 × 109/l or < 1.0 × 109/l
and falling/expected to fall.
Robust predictors of NS risk are lacking in patients with cancer receiving SACT. It seems that NS is more
common soon after treatment is initiated (within the first two cycles)16 and following administration of
anthracycline or taxane-containing regimens in treatment of early-stage breast cancer. Other factors
associated with risk of developing NS include age, performance status and a diagnosis of blood cancer
rather than solid tumour.17,18
Despite widespread adoption of prophylactic colony-stimulating factors (CSF) and fluoroquinolone

antibiotics for patients at high risk of septic complications, NS remains potentially life-threatening, with
an in-hospital mortality rate of approximately 9.5%19 and, in the setting of severe sepsis or septic shock,
as high as 50%.20 NS deaths recorded by the Office of National Statistics more than doubled in England
and Wales between 2001 and 2010 to approximately two deaths per day (716 deaths in 2010),3 with
significant increases in chemotherapy use likely contributing.21
Significant patient morbidity can also occur through hospitalisation, with a strong desire not to
be hospitalised during treatment cited as a common barrier to patients promptly seeking help for
symptoms.22 An episode of NS can also result in dose delays and reductions to patients’ planned SACT,
potentially compromising treatment efficacy in certain tumour types and settings.3,23–25 There are
associated financial implications on healthcare systems managing NS episodes, with hospital, antibiotic,
diagnostic and additional therapeutic costs involved resulting in an estimated average cost per inpatient
admission in the NHS ranging from approximately £257226 to £3163.27
Empirical management of NS
Neutropenic sepsis continues to be viewed as a time-critical medical emergency with widespread

agreement that early recognition and prompt administration of broad-spectrum empirical antibiotics
are essential to successful treatment.3,21,28,29 However, there is much less consensus on optimal
patient management thereafter, including when to switch from intravenous (i.v.) to oral antibiotics,
This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction 1
Introduction
and duration of antibiotic treatment and hospital admission. Widely variable practice has been noted
among cancer centres in the UK.30 A review of 51 English and Welsh centres, prior to the introduction
of a national UK NS clinical guideline, highlighted the heterogeneity that existed in almost all aspects
of NS management, commenting that there was ‘surprisingly little agreement’ and ‘dramatic variations’
in clinical practice. These findings were consistent with previously published audits of both adult and
paediatric haemato-oncology practice.6,31,32
The NICE GDG recommended use of empirical beta-lactam monotherapy (piperacillin/tazobactam) as

immediate treatment in patients with suspected NS in the absence of local microbiological indications to
use an alternative agent or combination therapy (such as addition of an aminoglycoside) based on local
resistance patterns.3 Evidence supporting a specific duration of treatment was found to be lacking by
the Group but the principle of switch to oral antibiotics following risk assessment after 48 hours of i.v.
antibiotic therapy could be considered. While current European guidelines suggest that following initial
assessment, including prompt institution of empirical broad-spectrum antibiotics, patients identified as
low risk may be suitable for inpatient oral antibiotic treatment, the authors noted clinician preference
was often to continue i.v. treatment for at least 48 hours and then consider a change to oral antibiotics if
fever resolves.28
Risk stratification
A spectrum of NS severity exists, encompassing a heterogeneous group of patients with variable risk of
septic complications such as organ failure, need for critical care support and death.33
At the low-risk end of the spectrum, there are patients who do not demonstrate clear clinical or
microbiological evidence of proven infection, have uncomplicated hospital admissions and are at low risk
of developing septic complications. These patients potentially receive overtreatment, with the associated
distress of hospitalisation and additional burden to the healthcare system.34
Risk stratification tools have therefore been developed in an attempt to identify patients predicted to be
at low risk of an adverse outcome. The Multinational Association of Supportive Care in Cancer (MASCC)
score (Table 1) is the most widely validated risk score for SACT-induced NS.3,28,29,33
TABLE 1 Multinational Association of Supportive Care in Cancer risk index35
Characteristic Weight
Burden of febrile neutropenia: no or mild symptomsa 5
Burden of febrile neutropenia: moderate symptomsa 3
No hypotension (systolic BP > 90 mmHg) 5
No chronic obstructive pulmonary disease 4
Solid tumour or no previous fungal infection 4
No dehydration requiring parenteral fluids 3
Outpatient status 3
Age < 60 years 2
a Points attributable to the variable ‘burden of febrile neutropenia’ are not cumulative. The maximum theoretical score is
26. A score of ≥ 21 suggests a low risk of a serious medical complication, including organ failure, critical care support or
death.

In the original validation set, a risk index score of 21 or greater out of 26 identified low-risk patients with
a positive predictive value of 91%, a sensitivity of 71% and a specificity of 68%. A low rate of adverse
outcomes (6% serious medical complication, 1% mortality) was observed in patients with a risk index
score ≥ 21 compared with 49% in those with a risk score of < 21.35
Oral antibiotic therapy as treatment
A UK single-centre prospective randomised controlled trial (RCT) investigated the effectiveness of

oral antibiotics (ciprofloxacin and co-amoxiclav) with early hospital discharge for patients with low-risk
NS in comparison to standard i.v. antibiotics (tazobacam-piperacillin and gentamicin) with hospital
admission. One hundred and twenty-six NS episodes from 102 patients were evaluated for the ‘success
and safety’ primary end point, which comprised: lysis of fever, resolution of symptoms and signs,
absence of modification of antibiotic regimen, absence of recurrence within 7 days and occurrence of
serious complications or deaths. Treatment success was 90% in the i.v. arm and 84.8% in the oral arm.
Re-admission was required in five episodes (7.6%) and deemed unrelated to the episode of NS in one.
It was recognised that these results were obtained within a single specialist centre but that the findings
supported undertaking a multicentre RCT evaluating oral antibiotics and early discharge.36
A Cochrane review37 of oral versus i.v. antibiotics for NS, evaluating 22 trials comprising 3142
neutropenic episodes in 2372 patients, concluded that it is not likely that significant differences exist
in treatment failure or mortality rates between oral antibiotic and i.v. antibiotic strategies. There was a
trend towards more adverse events (AEs) in patients receiving oral antibiotics, typically gastrointestinal
events, which did not necessitate treatment discontinuation. The majority of studies did not utilise any
formal risk stratification tools but excluded high-risk patients with acute leukaemia, haemodynamic
instability, evidence of organ failure or localising signs of infection.
The Cochrane review therefore broadly supported the early use of oral antibiotics in low-risk NS, but it
was noted most trials were small in sample size, often single-centre and with methodological concerns
and so a robust recommendation for upfront or early oral antibiotic therapy could not be made. It was
suggested that ‘the combination of a quinolone and a second drug active against Gram-positive bacteria
(for example ampicillin-clavulanate) seems prudent’.37 This group also recommended that this therapeutic
approach should be formally evaluated in patients with low-risk NS. The NICE GDG also considered
oral antibiotic therapies but were unable to make a specific recommendation given variation in local
microbiological resistance patterns and variation in use of prophylactic antibiotics.3
Outpatient management of low-risk NS
The NICE GDG reviewed the evidence for inpatient versus outpatient management of NS and
concluded outpatient management can be considered for selected low-risk patients, taking into account
their individual clinical and social circumstances.3 Although the metaregression undertaken by the GDG
suggested early discharge (before 24 hours) may be associated with increased likelihood of re-admission
or therapy change, the quality of evidence supporting outpatient management was low to moderate.
The available data were limited by a lack of reporting of key outcomes such as critical care admission
or clinically documented infection and a very low event rate for adverse outcomes including death.3
Similarly, there is negligible literature relating to impact on quality of life for different models of care,
including immediate use of oral antibiotics and non-admission to hospital, with a single study suggesting
role function improved more for inpatients than home care patients but that emotional function
declined with hospital admission.38 It was therefore proposed that if a short period of hospital admission
was found to be safe and effective for selected patients with NS, it could provide considerable
improvements in quality of life and health resource usage.
Introduction
Rationale for the trial
NICE therefore recommended that a randomised trial should be undertaken to evaluate the
effectiveness of switching from i.v. to oral antibiotics within the first 24 hours of treatment in patients
receiving i.v. antibiotics for NS. The early switch to oral antibiotic therapy in patients with low-risk NS
(EASI-SWITCH) trial was developed in response to this recommendation and a commissioned call from
the UK National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA)
programme to address this evidence gap. It aimed to establish the clinical and cost effectiveness of an
early switch to oral antibiotics 12–24 hours after i.v. antibiotic treatment commences in low-risk cancer
patients with NS.
Acute oncology service development
While prospective RCTs evaluating upfront or early oral antibiotics remain lacking from publication of the
NICE guidance, there have been significant service developments in response to acute care pressures
and increasing demands due to increases in cancer incidence and available treatments with the aim of
developing novel models of care for meeting cancer patients’ complex needs.39 Ambulatory care has
been introduced in acute medical and elderly care NHS settings with growing interest in developing care
pathways in cancer services in recent years. This has included management of low-risk NS although it
has only been implemented by a limited number of UK cancer centres.40,41 Some have reported results
from longitudinal patient series. Marshall et al.42 reported a series of 100 patients from a large UK tertiary
cancer centre over a 2-year period with NS who were assessed and given a first dose of i.v. antibiotics
then managed on an ambulatory low-risk NS pathway. Patients were stratified using MASCC score
and National Early Warning Score (NEWS) score and following observation for at least 4 hours were
discharged for outpatient follow-up (repeat clinical assessment and routine bloods) within 48 hours.42
Six of the 100 patients (8.8%) required re-admission within 7 days, typically with positive blood cultures,
but none required critical care support. Brunner et al.43 reported a low-risk NS ambulatory care pathway
case series from another UK centre. One hundred and twenty-three patients presented with NS over a
2-year period, 41% of whom were deemed low risk based on MASCC score. Of these, 24 were managed
on the ambulatory care pathway with a first dose of i.v. antibiotic and discharge with oral antibiotics and
proactive telephone follow-up. A further 24 patients were admitted but had early discharge. Again, no
serious complications occurred and the re-admission rate was 10%. However, despite the investment in
establishing the ambulatory care pathway, approximately 80% of patients with NS were still admitted.
Similarly, other international centres have reported real-world data where only a minority of patients are
managed on ambulatory pathways or considered for same-day discharge.44 For example, in a large US
emergency department (ED) only 5% of NS patients were discharged home, with most low-risk patients
admitted for inpatient antibiotics.45 A subsequent large-scale review of approximately 350,000 US ED
visits with NS confirmed this finding, with 94% of visits resulting in hospitalisation.46 Cost analysis data
from real-world data sets are also lacking.

Chapter 2 Methods
org/10.1186/s13063-020-04241-1.1
Trial design
EASI-SWITCH was a UK prospective Phase 3, randomised, open-label, non-inferiority trial to evaluate

whether early switch to oral antibiotics is non-inferior to standard care in adult patients with cancer with
NS at low risk of complications.
The main aim was to determine the clinical effectiveness of early switch to oral antibiotics 12 to
24 hours after commencement of empirical i.v. antibiotics compared to standard care, which comprises
continuation of i.v. treatment for at least 48 hours, based on treatment failure rate. Treatment failure
was defined by a composite measure incorporating a number of important clinical outcomes assessed at
day 14 of follow-up.
The trial included an embedded pilot study across four UK sites in order to test the recruitment and
adherence assumptions which had informed the trial design.
Trial objectives
Primary objective
To determine whether early switch to oral antibiotic therapy is non-inferior to standard care therapy in
terms of treatment failure measured at day 14.
Treatment failure was defined as a composite measure incorporating the following important
treatment outcomes:
1. persistence, recurrence or new onset of fever (temperature ≥ 38°C) after 72 hours of starting i.v.
antibiotic treatment
2. physician-directed escalation from protocol antibiotic treatment
3. re-admission to hospital (related to infection or antibiotic treatment)
4. critical care admission
5. death.
Secondary objectives
To assess the effect of early switch to oral antibiotics on:
1. short-term change in health-related quality of life (HRQoL), using EuroQoL-5 Dimensions, five-level
version (EQ-5D-5L) as the measurement tool, at baseline and 14 days
2. cost-effectiveness, based on the cost per treatment failure avoided at 14 days and a cost–utility
analysis (CUA) estimating the cost per QALY at 14 days
3. time to resolution of fever from initial i.v. antibiotic administration
4. AEs related to antibiotics
5. hospital discharge and total length of hospital stay
6. re-admission to hospital within 28 days
Methods
7. death within 28 days

8. adjustment to the subsequent scheduled cycle of chemotherapy within 28 days
9. patient preferences for antibiotic treatment assessed at day 14.
Research hypotheses
1. Early oral switch (within 12–24 hours after commencing i.v. antibiotic therapy) in cancer patients
with low-risk NS is non-inferior to standard care (continuation of i.v. antibiotic therapy for at least
48 hours).
2. The incremental cost effectiveness of early oral switch is significant compared to standard care.
3. AEs are comparable between the two study arms.
4. Patients’ preference will be for early oral switch.
Study conduct
Ethics, regulatory and research and development approvals

The trial was approved by the Medicines Healthcare and Regulatory Agency (MHRA) on 31 July 2015.
It was approved by the Northern Island (NI) Research Ethics Committee (REC) on 6 October 2015. At
each participating site, local research and development (R&D) approval was obtained prior to patient
enrolment to the trial. The trial was conducted in accordance with the principles of good clinical practice
(GCP), the requirements and standards set out by the WU Directive 2001/20/EC and the applicable
regulatory requirements in the UK, the Medicines for Human Use (Clinical Trials) Regulations 2001 and
subsequent amendments and the Research Governance Framework.
Sponsorship
EASI-SWITCH was sponsored by the Belfast Health and Social Care Trust (BHSCT).
Trial management
Clinical trial management was undertaken by the Northern Ireland Clinical Trials Unit (NICTU). Additional
trial oversight committees were convened by the trial including a Trial Management Group (TMG), Trial
Steering Committee (TSC) and Data Monitoring and Ethics Committee (DMEC).
The TMG comprised the co-chief investigators, other clinical investigators, the trial manager/co-ordinator,
the trial statistician, the trial health economist, the sponsor pharmacovigilance representative and the
patient and public representative. The TMG met monthly to review site set-up, screening and recruitment,
trial conduct, AEs and any other issues relating to trial conduct. A TMG charter detailed the terms of
reference of the TMG including roles/responsibilities.
The TSC provided oversight for the progress of the trial on behalf of the sponsor and funder. The TSC was
appointed by the NIHR and comprised an independent chair (a microbiologist), an independent oncologist,
an independent statistician, at least one patient/public representative and TMG members. The remit of
the TSC was progression of the trial including recruitment and adherence, the well-being, safety and rights
of trial participants and ensuring trial conduct was appropriate. A TSC charter described the terms of
reference of the TSC including membership and roles/responsibilities.
The DMEC provided independent review of the trial. Its role was to safeguard the rights and safety of
participants, to review trial data related to recruitment, protocol compliance, safety and efficacy and
to recommend to the TSC whether the trial should continue or not based on ethical or safety reasons.
DMEC appointments were approved by NIHR and included an independent chair (an oncologist), an
independent clinician, an independent statistician and a patient/public representative. DMEC reports
were provided by the trial statistician to include recruitment, AE and outcome data along with any other

information requested by the Committee. These reports were confidential and not shared with the trial
investigators. A DMEC charter described the terms of reference of the DMEC including memberships
and roles/responsibilities.
Trial set-up
In total 19 sites in hospitals and cancer centres across the four UK nations were opened to patient
recruitment. A list of these sites can be found in the Acknowledgements. Potential sites were asked
to complete an eligibility questionnaire that assessed clinical trial experience and local capability and
capacity for the study. Local antimicrobial guidelines and treatment care pathways for NS were also
requested from sites at this stage to identify and address any potential issues with protocol compliance.
Prior to sites opening to recruitment a face-to-face site initiation visit was undertaken by trial team
members to provide training on trial procedures to local research team members. Additional training,
where needed, was provided by teleconference. The trial team maintained regular communication with
sites by e-mail and teleconferencing to provide any ongoing training needed, answer any queries arising
at site and support sites in identifying and resolving barriers to recruitment.
Patient information and consent
Potentially eligible patients were those who had commenced treatment with i.v. antibiotics for NS.
Patients were identified at each study site daily through local acute admission/handover processes
dependent on the unscheduled care admission pathways at site. Patients meeting these criteria were
discussed with their treating physician on that day prior to enrolment to confirm their agreement to
patient participation. This also provided an opportunity to confirm that their treating physician would
be willing to follow the treatment strategy outlined in either arm of the trial. Patients were approached
by a member of the research team and a patient information sheet was provided. Patients were given
time to review the patient information sheet although this time period was < 24 hours given the acute
care setting and timing of the intervention.
As enrolment was occurring at ward level and patients had already been initiated on treatment, patients
being approached were clinically stable and viewed as competent to give informed consent in this
setting. Patients who were unable to give informed consent, for any reason, were not recruited. Patients
who indicated they were unwilling or unable to make a decision within the 24-hour time period were
not recruited. Regulatory approvals were obtained for patient-facing materials additional to the patient
information sheet to be used at site to make patients aware of the trial. These included a summary
information sheet about the trial that could be included in the standard SACT patient education
materials about NS and a poster to be displayed in SACT clinics and treatment units. All of these
materials were prepared in collaboration with the trial patient representatives.
Informed consent for participation was sought from patients by appropriately trained research nurses
(RNs) and medically trained investigators at site supported by the site principal investigator (PI) and local
infrastructure. If patients required any further clarification about the risks and benefits of participation,
this was provided by other research team members or an independent senior physician (one nominated
in advance at each trial site). The PI (or designee) taking informed consent was required to have
completed GCP training, be suitably qualified and experienced and be delegated this duty by the PI on
the delegation log.
Screening and randomisation procedures
Electronic trial screening and recruitment logs, submitted by sites to the clinical trial unit (CTU) on a
monthly basis, aimed to capture all patients who received a patient information sheet and whether
Methods
they proceeded to consent and randomisation. Research teams were asked to provide a reason for
non-participation if patients were not recruited.
After informed consent was obtained and eligibility was confirmed, participants were allocated to
intervention or standard care groups using an automated randomisation system (sealed envelopes).
Blocked randomisation with randomly permuted block sizes was used and a 1 : 1 allocation ratio.
There were no factors for stratification. Access to the randomisation sequence was restricted and
not accessible to site staff who enrolled patients or assigned interventions. Only the allocation of the
intervention was blinded. As this was a pragmatic trial, it was felt that blinding clinical teams, researchers
and trial participants to the intervention would limit the ability of the trial to measure the impact of the
intervention on routine care pathways. Additional support from this approach came from our patient
and public involvement (PPI) representatives, who viewed that participants would be highly likely to
reveal their treatment allocation during discussion with healthcare providers and outcome assessors,
making it unlikely these groups could remain blinded.
Trial treatment
Patients eligible to participate were aged over 16 years, receiving SACT for a cancer diagnosis and were
receiving standard-dose i.v. piperacillin/tazobactam or meropenem as initial antibiotic treatment for
suspected NS for < 24 hours. Patients were only permitted to be enrolled in the trial on one occasion
in line with consensus guidelines.47 All protocolised antibiotics were considered to be investigational
medicinal products (IMPs) for the purpose of the trial: co-amoxiclav 500 mg/125 mg film coated tablets;
ciprofloxacin 250 mg, 500 mg, 750 mg film coated tablets; meropenem 1 g powder for solution for
injection or infusion and tazocin 4 g/0.5 g powder for solution for infusion.
Standard care arm

Participants in the standard care group were allocated to continue current treatment with i.v. antibiotics
for a minimum of 48 hours. This was selected based on the NICE guidance recommendations.3 Subsequent
antibiotic management was at the discretion of the treating physician, who could switch to oral antibiotics
or stop antibiotics at any point thereafter, reflecting the variation encountered in routine clinical practice.30
Intervention arm
Participants randomised to the intervention group switched from i.v. antibiotic treatment within
12–24 hours after starting treatment, to co-amoxiclav 625 mg three times daily and ciprofloxacin
750 mg twice daily, to complete at least 5 days antibiotic treatment in total. The combination of a
quinolone and a second drug active against Gram-positive bacteria (e.g. co-amoxiclav) was based on the
conclusions of the Cochrane review.37
Other treatments
Any other treatments or investigations that patients required were carried out in accordance with
standard care. It was recognised that escalation from protocol-specified antibiotic treatment might be
required in the event of clinical deterioration, progression of the presumed infection, a microbiological
indication based on microbiological culture results or an adverse reaction (AR) to the prescribed
antibiotics. A change from protocol-specified antibiotics, including additional antibiotic treatment other
than the study drugs, or persistent/recurrent fever (> 38°C) after 72 hours was within the definition of
treatment failure, with such participants reaching the trial’s primary end point.
Patients were discharged home from hospital once their treating physician was content to do so, with
a patient diary to record any further temperatures and oral antibiotic compliance. Due to the pragmatic
nature of the trial, specific discharge criteria were not protocolised, but it was assumed the patient’s
overall clinical condition and psychosocial circumstances would be considered by the treating clinician in
line with their normal clinical practice.

Patient population
Patients commenced on i.v. antibiotics within 24 hours after starting treatment for low-risk NS were
recruited from sites across England, Scotland, Wales and NI, comprising both large cancer centres and
cancer units, to ensure that the sample is broadly representative of patients developing NS in the UK.
Inclusion criteria
1. Age over 16 years.

2. Receiving SACT for a diagnosis of cancer.
3. Started on empirical i.v. piperacillin/tazobactam or meropenem, for suspected NS, for < 24 hours.
4. Absolute neutrophil count ≤ 1.0 × 109/l with either a temperature of at least 38°C or other signs or
symptoms consistent with clinically significant sepsis, for example hypothermia. Self-measurement
at home or earlier hospital assessment of temperature is acceptable provided this is documented in
medical notes and is within 24 hours prior to i.v. antibiotic administration.
5. Expected duration of neutropenia < 7 days.
6. Low risk of complications using a validated risk score (MASCC score ≥ 21).
7. Able to maintain adequate oral intake and take oral medication.
8. Adequate hepatic [aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
< 5 × upper limit of normal (ULN)] and renal function (serum creatinine < 3 × ULN) within the
24 hours prior to randomisation.
9. Physician in charge of care willing to follow either the intervention or standard care protocol per
randomisation, at enrolment, including not treating with CSF. Prophylactic CSF is not an exclusion
criterion.
Exclusion criteria
1. Underlying diagnosis of acute leukaemia or haematopoietic stem cell transplant.

2. Hypotension (systolic pressure < 90 mmHg on > 1 measurement) within the 24 hours prior to
randomisation.
3. Prior allergy, serious AR or contraindication to any study drug.
4. Enrolled in this trial with prior episode of NS.
5. Previously documented as being colonised with an organism resistant to a study drug regimen, for
example MRSA.
6. Localising signs of severe infection (pneumonia, soft-tissue infection, central-venous access device
infection, presence of purulent collection).
7. Patients unable to provide informed consent.
8. Pregnant women, women who have not yet reached the menopause (no menses for ≥ 12 months
without an alternative medical cause) who test positive for pregnancy, are unwilling to take a
pregnancy test prior to trial entry or are unwilling to undertake adequate precautions to prevent
pregnancy for the duration of the trial.
9. Breastfeeding women.
Co-enrolment
Patients who were enrolled in other Phase I IMP studies and other antimicrobial IMP studies were
excluded. Patients enrolled in other Phase II–IV IMP or observational studies were eligible for enrolment
in this study at the PI’s discretion and when the burden on participants was not considered to be onerous.
Withdrawal of consent
Participants were able to withdraw consent to participate in the trial at any time. If the participant
withdrew consent during protocolised treatment, no further treatment within the trial was given and the
Methods
clinician responsible for their care determined the safest and most appropriate continued management
plan. A withdrawal of consent form identified which parts of the trial the patient wished to withdraw
from: protocol-specified antibiotic therapy; future data collection (all data collected or data collected at
day 14 and/or day 28 follow-up). Participants could be withdrawn from the study at the discretion of the
investigator if any safety concerns arose.
Data management
Trial database
The EASI-SWITCH trial database is an electronic clinical trial database (MACRO) held by the NICTU. Trial
data were entered on to a web-based case report form (CRF) with imposed rules for data entry with valid
responses and linkage of dates and trial identification numbers by trained and delegated site personnel.
Data were processed in accordance with the trial Data Management Plan and CTU Standard Operating
Procedures. Data queries were ‘raised’ electronically via MACRO where clarification was needed for data
entries or to complete missing data and staff at site ‘responded’ electronically to queries and amended
database entries where applicable. A final review for missing or inconsistent data was carried out by the
trial statistician with subsequent opportunity for query resolution / data completion prior to the database
lock for end of trial analyses. All essential documentation and trial records were stored securely with
access restricted to authorised staff only.
Data quality
Data management within the CTU was governed by Standard Operating Procedures to ensure
standardisation and compliance with International Conference of Harmonisation Good Clinical Practice
(ICH-GCP) guidance and regulatory requirements. NICTU provided site staff training in data collection
and CRF completion. On-site monitoring visits during the trial checked accuracy of CRF entries against
source documents in addition to protocol and trial procedure adherence. Discrepancy reports were
generated after data entry to identify inconsistent or out-of-range data and protocol deviations based
on data validation checks programmed into the clinical trial database.
Data collection
Data were collected by delegated research team members. Each participant was allocated a unique
Participant Study Number at randomisation, alongside their initials for identification for the duration of
the trial. Data were collected from the time of trial entry until day 28 (± 1 day) in accordance with the
schedule of assessments shown in Table 2. Baseline data collection occurred in the hospital setting. Primary
and secondary outcome data were collected via a review of patient medical notes (including laboratory
results), submission of participant questionnaires, patient diary, GP records and telephone calls with
patients. Participants discharged before day 14 were asked to complete a diary noting administration of oral
antibiotics, any new medications and a temperature diary (if required) until day 14. Questionnaires were
administered face-to-face or via telephone (if discharged or no scheduled outpatient visit) at day 14 (± 1 day).
Adverse event reporting
Directly observed or patient-reported AEs that were not related to underlying medical conditions were
recorded by the site PI or designee. AEs clearly related to SACT administration (such as peripheral
neuropathy) were not required to be recorded; however, if an AE could be due to SACT, NS or antibiotic
therapy (such as fever or gastrointestinal symptoms), then it was required to be recorded. Initially the AE
reporting period for the trial was from enrolment until 28 days after randomisation. This was amended
subsequently to 14 days from enrolment until 14 days after randomisation in recognition that antibiotic
AEs generally occurred within this time frame and that patients were typically receiving a further course
of SACT within the 14–28 day window, resulting in AEs that were more likely to be SACT-related or a new
episode of NS rather than related to the episode of NS that had resulted in trial entry or antibiotic therapy.
10

TABLE 2 Schedule of assessments
t-24 hours Day 0 Study visits and procedures
Pre-consent Pre- Day Day Day Day

Time point (standard care) randomisation Randomisation 1–2 3–5 6–14 28
Pre-consent eligibility screening
Eligibility screening as appro- ✗

priate (per standard care) for
example full blood count, blood
culturea
Informed consent
Informed consent obtained ✗
Pre-randomisation eligibility and assessments
Eligibility screening as appro- ✗

priate (non-standard care) for
example pregnancy test, MASCC
score, max temp ≤ 24 hours prior
to randomisation.
EQ-5D-5L ✗
Randomisation
Standard care antibiotic ✗ ✗ ✗ ✗ ✗

administrationb
Intervention (early switch) ✗ ✗ ✗ ✗ ✗

antibiotic administrationb
Send GP letter ✗
Baseline assessments to be recorded on CRF after eligibility is confirmed
Demographics ✗
Vital signs (HR, RR and BP) ✗
Medical historyc ✗
Symptoms indicative of mild ✗

localised infection
Cancer assessmentd ✗
SACT administered prior to ✗

presentatione
Relevant microbiological results ✗ ✗ ✗ ✗ ✗
Hospital admission details ✗
Concomitant medications ✗ ✗ ✗ ✗ ✗
Daily data collection
Antibiotic regimenf ✗ ✗ ✗ ✗ ✗ ✗
Highest daily temperatureg ✗ ✗ ✗ ✗ ✗ ✗
Protocol compliance
Adherence to protocol specified ✗ ✗

intervention
continued
Methods
TABLE 2 Schedule of assessments (continued)
t-24 hours Day 0 Study visits and procedures
Pre-consent Pre- Day Day Day Day

Time point (standard care) randomisation Randomisation 1–2 3–5 6–14 28
Patient follow-up
EQ-5D-5L ✗
Patient follow-up questionnaire ✗
Follow-up contact ✗ ✗
Survival status ✗ ✗
New medications ✗
Changes to next planned SACT ✗
Hospital discharge/re-admission/ ✗ ✗ ✗ ✗ ✗
critical care admission details
Recording and reporting of AEs ✗ ✗ ✗ ✗ ✗
a Date taken, positive or negative, organism(s).

b Intravenous antibiotics starting before informed consent.
c As a minimum AST or ALT and serum creatinine will be documented and reviewed for eligibility. When available the
following standard care blood results should also be recorded – Hb, platelets, CRP, albumin, lactate.
d Cancer type, treatment intent (radical, adjunctive, palliative), line of treatment (1st, 2nd or 3rd).
e Date, regimen and cycle number.
f Route, dose (strength and frequency), antibiotic name.
g Highest daily temperature while inpatient or temperature recorded if unwell as an outpatient.
IV antibiotics will commence prior to informed consent.
The PI (or designee) was required to make an assessment of expectedness of any AE deemed possibly,
probably or definitely related to any of the trial IMPs based on the relevant Summary of Product
Characteristics (SPCs).
AEs related to IMP exposure were deemed ARs. ARs were classified as expected (consistent with IMP
side effects listed in the SPC) or unexpected (not consistent with the SPC).
Serious adverse event

In the trial, a serious adverse event (SAE) was defined as any AE that:
• resulted in death
• was life-threatening
• required hospitalisation or prolongation of existing hospitalisation
• resulted in persistent or significant disability or incapacity
• consisted of a congenital anomaly or birth defect
• was any other important medical event(s) that carried a real, not hypothetical, risk of one of the
outcomes above.
All deaths that occurred within 28 days of randomisation were recorded and reported as a SAE
regardless of the nature of the event (even if due to progressive cancer). PIs were required to report
SAEs to NICTU using the trial-specific SAE form within 24 hours after becoming aware of the event.
Treatment failure due to persistence, recurrence or new occurrence of fever after 72 hours of antibiotic
commencement and/or clinician-directed escalation of protocolised antibiotic therapy during the first
14 days was captured as part of the primary outcome measure. This was only reported as an AE when
categorised as a SAE.
12

Suspected unexpected serious adverse reaction

Adverse reactions that were unexpected (not consistent with the relevant SPC) and met the criteria for
seriousness were deemed suspected unexpected serious adverse reactions (SUSARs) and required expedited
safety reporting. NICTU reporting procedures report SUSARs to relevant competent authorities within 7–15
calendar days in accordance with UK regulations.
Serious breaches
A serious breach was defined as an occurrence which represented a deviation from the trial protocol that
was likely to result in significant effect on the safety of a trial participant or the scientific value of the trial.
The PI (or designee) was responsible for direct reporting of serious breaches to the trial sponsor with
onward reporting to the relevant competent authorities in accordance with UK regulations.
Protocol amendments
All amendments to the trial protocol, patient information sheet, informed consent form and other key
documents were submitted to the relevant regulatory authorities for approval prior to implementation.
Local research and development approval was also obtained at each site. Version 2 of the trial protocol
was the protocol approved for use as trial commencement and subsequent substantial protocol
amendments are summarised below.
July 2016
Version 3 of the protocol was submitted to the regulatory authorities. This incorporated changes to the
eligibility criteria in order to align better with the NICE guidance and routine practice in the NHS setting.
The NICE guidance stated ‘Diagnose neutropenic sepsis in patients having anticancer treatment whose
neutrophil count is 0.5 × 109 per litre or lower and who have either: a temperature higher than 38°C
or other signs or symptoms consistent with clinically significant sepsis’. On initial design, the trial had
only incorporated the objective definitions (i.e. temperature and neutrophil count) because of possible
difficulty in defining ‘signs or symptoms consistent with clinically significant sepsis’ for a trial population.
This protocol amendment permitted recruitment of patients with either:
1. a neutrophil count of ≤ 0.5 × 109 per litre who have either a temperature of at least 38°C or other signs
or symptoms consistent with clinically significant sepsis (to align fully with the NICE guidance); or
2. a neutrophil count of < 1.0 × 109 per litre, and falling or expected to fall, who have a temperature of
at least 38°C (to reflect usual NHS practice). Given the pragmatic nature of the trial this amendment
was felt to allow a more realistic evaluation of the intervention in routine care.
August 2016
Versions 4 and 5 of the protocol incorporated an extension to the pilot phase of the study including the
addition of up to four new sites, the resultant change in the overall study duration and clarification of
eligibility criteria and outcome measure definitions. The key change within these amendments was the
extension of the embedded pilot study to 12 months to assess the impact of the change in eligibility
criteria on recruitment, which had been lower than anticipated after the trial commenced.
April 2017
Protocol version 7 was submitted to the regulatory authorities (protocol version 6 was a non-substantial
amendment). The purpose of this amendment was to clarify use of non-protocolised antibiotics and
reporting of AEs.
June 2018
Protocol version 8 was submitted to the regulatory authorities. This incorporated revisions to the
study design following review of the pilot study and discussions with the research team, trial sites, trial
Methods
oversight committees. While the extended pilot study did meet the pre-specified recruitment target for
study continuation, the trial team and oversight committees concluded that it would not be possible to
recruit the originally planned sample size of 628 patients within a meaningful time frame to ensure the
results remained relevant to clinical practice. Both the trial team and oversight committees continued
to view the research question as important and relevant to current practice; opinion sought from the
oncology clinical community and PPI representatives nationally also supported this view. The DMEC
confirmed in November 2017 that there were no concerns regarding treatment adherence, separation
between treatment groups or the observed treatment failure rate. Therefore, the assumptions that had
underpinned the original trial design remained valid but, in retrospect, the choice of non-inferiority
margin and statistical analysis may have been too stringent for a pragmatic trial where the risk of
treatment failure was unlikely to result in serious risk to patients (in particular critical care admission
or death). Following extensive stakeholder discussion and consideration of alternative assumptions for
sample size recalculation, the sample size was recalculated using a 15% non-inferiority margin as this
was felt to maintain an acceptable trade-off between the possibility and consequences of treatment
failure for this low-risk patient population. This amendment included a sample size recalculation that
comprised both a widening of the non inferiority margin from 10% to 15% and a change in the one-
sided confidence interval (CI) from 97.5 % to 95%. This was recommended by the TSC independent
statistician and following discussion with the wider TSC felt to be reasonable given the original 97.5% CI
had been based on regulatory agency recommendations for licensing studies of new treatments which
require a greater degree of certainty than was felt warranted for a pragmatic trial testing antibiotics
already licensed or within routine clinical use for the same indication. This amendment also included an
increase in the total number of study sites and an extension to the project duration.
Embedded pilot study
The trial contained an embedded pilot study involving four UK sites to test the recruitment and
adherence assumptions underpinning the study design. Progression to the full study was based on the
following criteria:
1. Recruitment rate:
a. progression without major modification if at least 75% of target reached

b. progression with addition of further trial sites if between 50% and 75% of target reached
c. progression unlikely if < 50% of target reached – discussion with trial oversight committees and
funder required.
2. Adherence to protocol-specified intervention:
a. progression without major modification if at least 75% adherence in both trial arms
b. if adherence was between 50% and 75% of target, progression would be supported by a de-
tailed analysis of the process and decision-points that led to non-adherence and a recognised
strategy to address this identified
c. progression unlikely if < 50% adherence in either arm.
3. Separation:
a. separation in terms of the timing of antibiotic switch of at least 24 hours between the trial
arms to enable progression was required.
The four-site pilot study was expected to run for 6 months between February and July 2016.
Recruitment was < 50% target threshold for progression and the study was halted to review progress
and proposals to address under-recruitment. This review identified the stringent eligibility criteria
14

as a barrier to recruitment and not reflective of the routine management of patients with suspected
NS. A protocol amendment (July 2016, described above) was submitted to address this. Recruitment
was resumed with a 3-month extension to the pilot study (December 2016 to February 2017)
with an improvement in recruitment rates (11 patients of an anticipated 13.5 recruited). On the
recommendation of the HTA Programme Director, a larger pilot phase extension followed from April
until November 2017. Progression with addition of new sites continued from this point until the end
of the study.
Statistical analysis plan
Non-inferiority design and non-inferiority margin

A non-inferiority design was felt to be appropriate as it was not anticipated that early switch to oral
antibiotics would offer superior treatment efficacy to standard care (i.v. antibiotics for at least 48 hours
based on NICE guidance). It would also enable the evaluation of an intervention of broadly comparable
efficacy to standard care based on available literature but with potential for reduced cost and improved
quality of life.
It was estimated that the treatment failure rate in the control arm would be 15% based on data from three
studies with patient populations most comparable to the proposed EASI-SWITCH population. Selecting
the non-inferiority margin, the maximum clinically acceptable extent of non-inferiority, was challenging due
to the limited evidence available to help guide this selection. A 10% non-inferiority margin was originally
chosen to reflect the recommendations of a published expert consensus in NS antibiotic trials but this did
not take into consideration risk stratification.47 Input from patient representatives was also considered,
but it is important to note that feedback initially came predominantly from our PPI co-applicant rather
than a wider range of patient representatives, who felt if an extra 10% failed an early switch, in addition to
the expected 15% treatment failures that occur with standard care, the advantage of 75% of early switch
patients having successful treatment outweighed this.
Sample size
The original target sample size for the trial was 628 patients. This was based on the assumed 15%
treatment failure rate in the standard care arm and a 10% non-inferiority margin, at 90% power
(one-sided 97.5% CI), which would require 269 patients per arm. A dropout rate of up to 5% was also
accounted for based on previously reported NS trial data and a crossover rate of up to 10% from the
control to the intervention arm, giving 314 patients per arm (628 in total).
Review of study design post-pilot phase and revision of sample size

As outlined above, a protocol amendment related to review of the study design following the
embedded pilot phase was submitted in June 2018. This included a review of the assumptions that had
underpinned the original trial design, including the rationale for the choice of non-inferiority margin and
statistical analyses. As previously described, extensive discussion took place with stakeholders including
the research team, trial oversight committees, funder, sponsor and clinicians and PPI representatives
nationally, in relation to the study design. The consequent revisions to the study design had implications
for the sample size, which was recalculated using the same treatment failure rate in the standard care
group (15%), power (90%), dropout rate (5%) and crossover rate from control to intervention (10%) while
widening the non-inferiority margin from 10% to 15% and using a one-sided 95% CI. This gave a revised
sample size of 230 patients.
Statistical methods
The primary analysis was conducted on both the per-protocol (PP) population and the intention-to-treat
(ITT) population. Given the potential risk of bias arising from either of these analyses alone within a
non-inferiority trial, it was pre-specified that non-inferiority of the intervention would only be proven if
demonstrated in both the PP and ITT groups.
Methods
Analyses were one-sided and at a significance level of 0.05. The difference in treatment failure rate
(one-sided 95% confidence limit) was compared to the non-inferiority margin of 15%. As this was
a non-inferiority trial, the null hypothesis was that the degree of inferiority of the intervention to
the control was greater than the non-inferiority margin of 15%. The alternative hypothesis was
therefore that the intervention was inferior to the control by less than the non-inferiority margin of
15%. Therefore, non-inferiority would be established by showing that the upper limit of a 90% CI for
Intervention – Control is < 15%.
A secondary comparison of the primary and other binary outcomes between the two groups was
investigated using logistic regression, adjusting for covariates (such as extent of neutropenia).
Comparison of continuous outcomes between the two groups was investigated using independent
t-tests or Mann–Whitney. Statistical diagnostic methods were used to check for violations of the
assumptions, and transformations were performed where required.
Baseline characteristics, follow-up measurements and safety data were described using appropriate
descriptive summary measures depending on the scale of measurement and distribution.
Subgroup analyses
Exploratory subgroup analyses were pre-specified using 99% CI. Logistic regression was used with
interaction terms (treatment group by subgroup) for the following subgroups:
1. tumour type (solid tumour vs. lymphoma)

2. neutrophil count at randomisation (≤ 0.5 × 109/l vs. > 0.5 × 109/l < 1.0 × 109/l)
3. maximum temperature on the day of presentation (< 38°C vs. ≥ 38°C).
An additional post hoc subgroup analysis was requested for those patients who had a positive blood
culture versus those who did not at baseline.
Survey design and delivery
A series of surveys were undertaken to obtain stakeholder feedback on important questions relating to
the trial. All electronic surveys were conducted using the SurveyMonkey tool (www.surveymonkey.co.uk).
Ethical approval was not required for these projects as they sought only to define clinicians’ current standard
of care and were categorised as service evaluation rather than research according to UK Health Research
Authority definitions. All were designed pragmatically for data collection and to encourage responses.
They were piloted informally by clinical and PPI colleagues at the lead site prior to wider dissemination to
improve clarity and understanding but did not undergo formal reliability or validity testing. Participation was
voluntary, with potential responders assured that no site or personal information would be publicly shared.
Onward e-mail circulation to appropriate colleagues was encouraged to maximise responses, accepting this
makes estimation of response rates challenging. At least one e-mail reminder was sent also to encourage
responses, with all surveys open for completion for at least 8 weeks in total.
The analyses of the survey responses are presented descriptively, with percentages rounded to
the nearest 1%. If the survey contained questions where respondents had the opportunity to leave
comments, these are presented thematically, with representative illustrative quotes.
Site interviews
To understand factors impacting trial recruitment at sites, a series of purposeful semistructured interviews
with key personnel at each site, including PIs and lead RNs, were conducted by the trial Clinical Research
Fellow over a 2-month period (April to May 2018). Qualitative research has previously been demonstrated
16

as one of the most helpful tools in identifying and overcoming barriers to recruitment.48,49 The aim of
the interviews was to explore clinician’s experience of recruiting and delivering the trial at their site and
identify barriers to recruitment.
An initial e-mail invitation describing the nature and purpose of the interviews was sent to all PIs
and lead RNs at all 12 open sites in March 2018. Participation was voluntary, and participants were
reassured that no individual or site-specific information would be identified in summary reports.
Interviews could be conducted either face to face or via telephone depending on participant preference.
On receipt of a positive response, an interview was arranged and all were conducted in April and May
2018. Verbal consent was confirmed at the commencement of each interview. A short interview guide
was prepared based on broad themes that had already emerged from previous discussions about
the trial’s progress and difficulty recruiting. Participants were first asked in an open-ended question
to simply comment on their experience recruiting to the trial and then highlight any challenges
encountered. If not already discussed, they were then prompted to provide feedback on the trial’s
screening and recruitment processes, including eligibility criteria. They were also prompted to comment
on any issues encountered with local support for the study, research capacity, participant follow-up
and data collection. Finally, interviewees were asked to highlight any strategies they felt had facilitated
recruitment at their individual site. Interviews ranged from 15 to 50 minutes in length.
With the participant’s permission field notes were taken during the interview to capture key responses.
A summary of the main findings was then verbally confirmed by the participant at the end of each
interview to ensure content validation. Data saturation (i.e. no new information raised in later
interviews) was reached during the interviews.
Thematic analysis of the qualitative data was then undertaken50 to generate a summary list of reported
barriers to trial recruitment. The field notes for each interview were first scrutinised individually and
organised into themes relating to barriers to recruitment. This systematic process was repeated for all
interviews and then combined to produce a final group analysis summary list. Post analysis of the data,
the co-chief investigators reviewed the data for completeness, reporting coherence between the data
and reported themes to ensure robustness of the interpretation of the data.
Patient and public involvement
The trial has benefitted from having an experienced PPI member in the team, Mrs Margaret Grayson,
from study conception to completion. The trial was developed in response to a commissioned call,
meaning the main research question was pre-defined; however, input from the Northern Ireland
Cancer Research Consumer Forum (NICRCF) via Mrs Grayson was that this was an important research
question of value to patients where potential overtreatment and prolonged hospital admission may
negatively impact upon quality of life. From this position, Mrs Grayson contributed to the trial design
with particular input in the following areas: (1) helping to define the composite outcome measure and
define secondary outcome measures important to patients and the health service; (2) defining the non-
inferiority margin to incorporate patients’ views on acceptable trade-offs for treatment de-escalation;
and (3) providing the patient viewpoint on the most appropriate method to obtain day 14 outcome data
balancing the need for data quality with burden on patients. Additional support was given by the readers
panel of the NICRCF at this stage through development and review of the trial protocol, the patient
information sheet, the informed consent form and other patient-facing materials, for example brief
summary flyers and posters for sites to use in SACT treatment units to make patients aware of the trial.
As the trial progressed, there was ongoing input from Mrs Grayson through both her membership of the
TSC and participation in the TMG. Her input was critical when the overall study design was reviewed
during the course of the trial, co-ordinating PPI opinion on the proposed changes and contributing to
the final amended design. Through her linkages with the NICRCF and nationally (with the Independent
Methods
Cancer Patient Voice group) she sought opinion on the ongoing importance of the research question
and whether there was support for continuation of the trial with changes to the study design. As part
of this process, she co-developed with the study team a PPI survey outlining proposed changes to the
study design with particular focus on whether additional uncertainty around treatment effectiveness
arising from a change in the non-inferiority margin and sample size would be acceptable to patients.
She then collated responses, reporting to the study team the support of the majority of respondents
and providing written and verbal communication with the funder in decision-making about these
proposed changes.
The trial was also supported by additional independent PPI representation on the TSC and DMEC. Input
from these representatives in review of trial data and progress was critical at decision-making points
relating to trial progression and potential amendments to study procedures. Dissemination of results is
an ongoing area of activity for all of the PPI team trial team members.
18

Chapter 3 Pilot study results and review of

study design
org/10.1186/s13063-020-04241-1.1
Pilot study aim
The aim of the internal pilot study was to carefully evaluate the recruitment and adherence assumptions
underpinning the main study design. The main parameters of interest were:
• recruitment rates
• adherence to the protocol-specified treatment
• separation in terms of timing of the antibiotic switch between the two arms.
These criteria were set to guide trial progress and inform the procedures to be utilised in the delivery of
the main trial.
Recruitment rates
A target recruitment rate of 1.7 patients per site per month was set based on historical published data30
and service evaluation data from two of the pilot sites. Progression of the trial without modification
beyond the embedded pilot study was contingent upon at least 75% of this recruitment target being
met. It was otherwise pre-specified that progression would continue with the addition of further trial
sites if 50–75% of this target was met but that progression at a recruitment rate lower than 50% of
this target rate would require review of the trial and discussion with oversight committees, funder
and sponsor for trial progression. The embedded pilot study was intended to last 6 months with 4
participating sites but was extended to 17 months and 10 sites in total, as summarised in Table 3.
Initial pilot phase (February to July 2016)
The internal four site pilot study was expected to run for 6 months. It commenced on the 17 February
2016, when Site 1 opened and completed on the 21 July 2016. Progress is summarised in Table 4.
TABLE 3 Summary of progress of the embedded pilot study
Recruitment Expected Actual Cumulative trial

Dates Sites target recruitment recruitment recruitment
Initial pilot February to 4 pilot sites 1.7 patients/ 22 7 7

phase July 2016 (6 months) month/site
Extended pilot December 2016 to 4 pilot sites 1.7 patients/ 13.5 11 18

phase (I) February 2017 (3 months) month/site
Extended pilot April to November 2017 10 1 patient/ 49 24 42

phase (II) (8 months) 4 pilot sites month/site
6 additional
sites
Pilot study results and review of study design
TABLE 4 Summary of initial pilot phase
Duration of Recruitment rate

Number recruitment Expected Actual (patients/site/
Site Date open screened (months) recruitment recruitment month)
1 17 February 2016 32 5 7 1 0.2
2 14 March 2016 26 4 6 2 0.5
3 4 May 2016 5 3 4 1 0.3
4 31 March 2016 6 4 5 3 0.75
Total 22 7
Recruitment of 31 patients was originally projected if all four sites had been open to recruitment for the
full 6 months. This was based on a recruitment rate of 1.7 patients per month per site, allowing for a 50%
reduction in recruitment at each site during the first 3 months as sites became established. However, delays
encountered at site level resulted in only one of the four sites being open for the full 6 month period. Taking
this into account recruitment of 22 patients was anticipated, but only 7 were recruited. In view of this, the
study was halted to enable review of screening and recruitment activity and recruitment target.
The original accrual target was based on historically published NS surveys and audit data from two
sites, suggesting approximately 20 patients were admitted per month with NS in 2011 and 2013. This
was consistent with the NICE guidance,3 which suggested active specialist units admitted at least 20
patients with NS per month. Allowing for exclusion of high-risk patients (approximately 30%51) and trial
ineligibility it was assumed that 10 patients per month at each site would be eligible and recruitment of
two of these appeared an achievable target.
On review of screening and recruitment logs the number of NS admissions was lower than expected. This
was consistent with updated audit data from sites and may reflect changes in standard care relating to
growing use of targeted therapies and immunotherapies in place of cytotoxic chemotherapy and continued
improvements in the care of patients with suspected sepsis, including NS. However, even within this it was
clear that the majority of patients screened for study entry were considered ineligible, as highlighted by
activity at Sites 1 and 2 in the previous table where 1 of 32 patients and 2 of 26 patients were screened
and recruited, respectively. The reasons for exclusion are summarised in Table 5; as expected around 30%
of patients were high risk based on MASCC score, but for the remainder it seemed that the eligibility
criteria did not reflect the patient population receiving treatment for NS in routine care pathways.
From discussion with the clinical and research teams at study sites, specific issues with the trial eligibility
criteria mainly related to the stringent requirements for fever, neutropenia, use of other antimicrobials
and organ function, summarised in Table 6.
TABLE 5 Reasons for participant exclusion at sites 1 and 2
Principal reason for exclusion Site 1 (n) Site 2 (n)
High risk (MASCC score < 21) 9 7
Pyrexial but absolute neutrophil count (ANC) between 4 5

0.5 and 1.0 × 109/l
ANC between 0.5 and 1.0 × 109/l 9 6

Apyrexial but other signs and symptoms
Penicillin allergy 6 3
Recent prophylactic ciprofloxacin/other oral antibiotics 2 3
Total number of patients excluded 30 24
20

TABLE 6 Summary of difficulties encountered with the original trial eligibility criteria used during the initial pilot phase
Eligibility criteria Impact on recruitment
1. Neutrophil criteria • Although NICE defines neutropenia as < 0.5 × 109/l, at three of the four pilot sites,
similar to other centres, patients with a neutrophil count of < 1.0 × 1 09/l rather than
< 0.5 × 109/l were routinely commenced on empirical treatment for NS.
2. Fever criteria • Number of scenarios encountered where patients treated for low-risk NS did not meet
the fever criteria (hospital-documented temperature of > 38°C for the trial):
– hospital-documented temperature of 38°C but no recordings > 38°C as paracetamol
had been administered
– self-reported pyrexia at home but apyrexial on presentation and no further fever in
hospital
– low-grade temperature at home/hospital for example 37.8°C, paracetamol admin-
istered and other signs or symptoms suggestive of infection or sepsis
– no home/hospital-documented fever but other signs/symptoms suggestive of
infection or sepsis
– hypothermia recorded and other signs/symptoms suggestive of localising infection
or sepsis.
3. Prophylactic antibiotics • Patients receiving fluoroquinolone/penicillin antibiotics in preceding 14 days originally

and recent antibiotic use excluded.
• Two patients at Site 1 who were otherwise eligible had just received several planned
days of prophylactic ciprofloxacin (500 mg BD) as part of their SACT regimen and were
therefore excluded. It was felt co-amoxiclav and ciprofloaxcin would have been appro-
priate antibiotic treatment.
• Recognised that other patient groups may be excluded on the basis of recent antibiot-
ic use, who similarly would not be managed as higher-risk patients in routine clinical
practice. This included patients who had completed antibiotics for an unrelated issue
up to 2 weeks prior and potentially before commencement of their current SACT cycle,
as well as patients who may have only just commenced an oral antibiotic from their GP
before spiking a fever and being referred to hospital.
4. Organ function • Conservative estimates set for organ function including hepatic function, which result-
ed in the upper limit for liver function being lower that those advised in the reference
safety information for all of the antibiotics and more cautious than what is employed in
routine practice.
5. Hypotension • Hypotension incorporated into patients’ MASCC scores but also an independent trial
exclusion criterion, as it is felt to represent potentially haemodynamically unstable
patients, unsuitable for early oral antibiotic treatment.
• Numerous approaches to defining hypotension, some of which take into account pa-
tients’ baseline blood pressure, but it was felt initially this information may not always
be readily available.
• It was evident, however, that an isolated systolic blood pressure measurement of
< 90 mmHg on a single measurement may not represent concerning hypotension, par-
ticularly in for example, otherwise fit, young breast cancer patients with a low baseline
blood pressure.
Review of eligibility criteria

It was therefore concerning from screening data that the trial population was not going to fully reflect the
patient population being managed as low-risk NS, with a significant proportion of patients commenced on
NS care pathways who did not meet the study eligibility criteria, negatively affecting recruitment. Moreover,
as this was intended to be a pragmatic trial within the setting of standard care therapies (all agents used
within the trial were already licensed for treatment of NS or used within routine care for this indication), it
was also felt important that the trial was not restrictive around organ dysfunction beyond the parameters of
standard care.
On initial trial design, the fever and neutrophil thresholds had been aligned with the objective elements
of the NICE definitions of NS with the rationale that it might be difficult to define the non-objective
elements of the NICE definition in which a diagnosis of NS may be appropriate in patients without
documented fever but with other ‘signs or symptoms consistent with clinically significant sepsis’. It was
clear this excluded a significant number of patients commencing treatment for NS.
Adjustments to the eligibility criteria were therefore proposed focused on ensuring they were less
stringent and more pragmatic, as summarised in Table 7. These adjustments would widen the pool of
eligible patients and ensure the trial population more accurately reflected patients being commenced
on NS pathways in standard clinical practice, providing a more realistic evaluation of the intervention in
routine care.
With the adjusted eligibility criteria, a further 15 patients at Site 1 and 14 patients at Site 2 would have
been potentially suitable during this 6 month pilot phase. It was therefore expected the revised eligibility
criteria would increase the number of eligible patients to 1–2 patients per site per month. A 6-month
extension to the pilot phase was proposed to assess the impact of the adjusted eligibility criteria
on recruitment.
Extended pilot phase I (December 2016 to February 2017)
A 3-month, four-site extension to the pilot study was delivered from 1 December 2016 to 28 February
2017, using the adjusted eligibility criteria, summarised in Table 8.
The expected recruitment rate was 1.7 patients per site per month, with again a 50% reduction
permitted for the first 3 months of site opening. With recruitment on hold from 21 July 2016 until
1 December 2016 there was significant loss of momentum at sites, which was difficult to recover
and combined with local site capacity issues resulted in a very short window of potential recruitment
at two sites. Consequently, both of these sites failed to recruit during this extension phase, despite
having been active in screening and recruitment during the first phase of the pilot study. The other
two sites achieved an average monthly recruitment between the two sites of 1.8 patients per month,
similar to the predicted recruitment rate, with review of screening data suggesting a positive impact
TABLE 7 Adjustments to eligibility criteria following the initial pilot phase
Original eligibility criteria

(Version 2.0, 30 July 2015) Adjusted eligibility criteria (Version 3.0, 14 July 2016)
Absolute neutrophil count < 0.5 × 109/l Absolute neutrophil count ≤ 1.0 × 109/l with either
– a temperature of at least 38°C
Fever > 38°C – or other signs or symptoms consistent with clinically significant
sepsis for example hypothermia.
Self-measurement at home or hospital assessment acceptable

provided this is documented in the medical notes and within 24 hours
of i.v. antibiotic administration
Received i.v. piperacillin/tazobactam or mero- Systemic antibiotic administered prior to randomisation is not a
penem for < 24 hours reason for exclusion
Patients who have been started on additional antimicrobial drugs
(e.g. gentamicin or teicoplanin) are eligible provided the physician in
charge of their care is willing to stop this additional antimicrobial at
the time of enrolment
Adequate hepatic (AST and/or ALT < 2.5 × ULN) Adequate hepatic (AST and/or ALT < 5 × ULN) function within
function within 24 hours prior to randomisation 24 hours prior to randomisation
Physician in charge of care willing to follow Highlighted that prophylactic use of CSF is not an exclusion criterion
either the intervention or standard care protocol
per randomisation at enrolment, including not
treating with CSF
Hypotension (systolic pressure < 90 mmHg) Hypotension (systolic pressure < 90 mmHg on greater than one
within 24 hours of randomisation measurement) within 24 hours of randomisation
Treatment with fluoroquinolone or penicillin No longer an exclusion criterion

antibiotics in preceding 14 days
22

TABLE 8 Summary of extended pilot phase (I) (December 2016 to February 2017)
Number Duration of Target Total Recruitment rate

Site Date open screened recruitment (months) recruitment recruitment (patients/site/month)
1 1 December 2016 10 3 5 8 2.7
2 3 January 2017 0 2 3.5 0 0
3 1 December 2016 3 3 5 3 1.0
4 1 February 2017 1 1 0 0 0
Total 13.5 11 0.9
of the adjusted eligibility criteria on recruitment. It was, however, again noted that the number of NS
admissions remained lower than historical data, with an average of six admissions per month.
Extended pilot phase II (April 2017 to November 2017)
Due to the longer than anticipated pilot phase, under-recruitment was now inevitable if the project
timeline was not modified, even if the number of recruiting sites for the main trial was expanded
significantly from 12 to 20. To maximise the potential for successful completion of the trial, with the
research question as fully addressed as possible, the preferred option was to increase the number of
recruiting sites to 20 and extend the project timeline by approximately 1 year. To mitigate risk, it was
agreed first to further extend the pilot phase until November 2017, aiming to open an additional seven
sites during this period. This would allow an assessment of the potential recruitment at a broader
selection of sites. A revised recruitment target was set of one patient per month per site to account for
the lower frequency of neutropenic admissions.
A further 8 month period of recruitment to the pilot phase of the trial occurred between April and
November 2017. Six additional sites were opened during this phase and a summary of recruitment by
site is shown in Table 9. Even with the revised recruitment target of one patient per site per month, only
50% of the expected recruitment was met, with 24 patients recruited compared with the predicted 49
(average monthly recruitment rate across all sites was 0.4 patients).
TABLE 9 Recruitment activity in the extended pilot phase (II) (April 17 to November 17)
Site Start date Target recruitment Total recruitment Recruitment rate (patients/site/month)
1 17 February 2016 8 11 1.4
2 14 March 2016 8 1 0.1
3 4 May 2016 8 2 0.3
4 31 March 2016 8 6 0.8
5 22 June 2017 4 1 0.1
6 17 July 2017 4 0 0
7 26 June 2017 5 3 0.4
9 18 September 2017 2 0 0
10 28 September 2017 2 0 0
11 13 November 2017 0 0 0
Total 49 24 0.4
Summary of pilot phase recruitment
By 30 November 2017, there had been 17 months of active recruitment to the study, with as planned
10 sites open to recruitment and an eleventh due to open shortly. Forty-two patients had been
recruited compared with a revised target of 68 patients as summarised in Figure 1.
Adherence to the protocol-specified treatment
Adherence to the protocol-specified intervention was assessed by whether patients switched to

co-amoxiclav and ciprofloxacin, 12–24 hours after starting i.v. meropenem or piperacillin tazobactam
i.v. therapy for at least 5 days total treatment. Adherence to the standard care arm required receipt
of at least 48 hours of i.v. piperacillin/tazobactam or meropenem. The pre-specified threshold for
adherence of 75% in both arms was achieved with adherence 86% and 83% in the intervention and
control arms, respectively.
Separation between trial arms
The final criteria for trial progression was evidence of adequate separation in terms of the timing of
antibiotic switch of at least 24 hours between the trial arms. The time on i.v. antibiotics was calculated
for each patient and then the mean calculated for each trial arm and the difference between the two
arms assessed. The mean duration of i.v. antibiotics was 19 hours in the intervention arm and 48 hours
in the control arm; hence, mean separation in terms of timing of antibiotic switch was acceptable at
29 hours.
Summary of embedded pilot study results
The internal pilot phase of the EASI-SWITCH trial demonstrated that while recruitment was challenging
there were no other concerns relating to treatment failure, protocol adherence or safety concerns.
Based on recruitment between April and November 2017, it was likely that on average each site would
only be able to recruit one patient every 2 months. The pilot phase had demonstrated that recruitment
to the original proposed sample size of 628 patients for the main trial was not going to be achievable.
Recruitment had originally been scheduled to complete at the end of December 2018. With 10 sites
open and recruiting on average one patient every 2 months, based on current recruitment activity total
recruitment was estimated to complete at approximately 100 patients. This would result in a significantly
80
70
60
Actual cumulative total
50
Initial cumulative target total
40 (1.7 patient/site/month)
30 Revised cumulative target total
(1 patient/site/month)
20
10
0
Jan-16 May-16 Sep-16 Jan-17 May-17 Sep-17
FIGURE 1 Summary of recruitment activity at the end of the pilot phase (February 2016 to November 2017): total
recruitment of 42 patients.
24

underpowered study, with results unlikely to have any significant impact and the evidence gap for
an early oral switch identified by NICE remaining unanswered. It was clear important assumptions
underpinning the trial design would have to be urgently reviewed to decide about whether to progress
beyond the pilot phase to main trial delivery.
Determining continued importance of the research question
In view of the recruitment difficulties and the longer than anticipated pilot phase, an updated
understanding of how low-risk NS patients were currently being managed across the UK was critical to
assess the continued importance of the research question and assess whether there remained equipoise
between the trial arms.
Between January and June 2018, NS management policies were reviewed and a survey of practice
was undertaken nationally. Local NS policies from throughout the UK were sought via an e-mail
request distributed to acute oncology nurse specialists within United Kingdom Oncology Nursing
Society (UKONS) and EASI-SWITCH team members. Policies were reviewed for compliance with NICE
recommendations, with particular focus on those advocated as key priorities for implementation in the
guideline and their approach to low-risk management.
It is likely that a wide range of factors, including awareness of guidance, personal treatment preferences
and clinical experience, will influence individual compliance with local policies when delivering NS care.
A complementary electronic survey aimed to more fully reflect clinicians’ daily clinical practice, attitudes
and preferences when managing NS. The survey link was disseminated via the UKONS, Royal College
of Pathologists’ electronic newsletter and the clinicians involved in the EASI-SWITCH trial with onward
dissemination to colleagues encouraged. In the survey, respondents were encouraged to reflect on their
individual routine practice, rather than what their local institution’s NS policy or national guidelines
might recommend.
A review of standard practice, completed for NICE in 2012, suggested approximately a third of 51
English and Welsh centres surveyed included the option of empirical oral antibiotics for lower-risk adult
patients, with the intention of immediate discharge or earlier discharge compared with i.v. inpatient
antibiotics.3 It was unknown if this remained the status quo in the years following the publication
of NICE guidance, with no national data available regarding centres’ standard approach to low-risk
NS patients.
An updated understanding of management of low-risk NS patients was essential to assess whether

there remained equipoise between the trial arms. If clinical practice had already largely shifted towards
the intervention arm of EASI-SWITCH, there may be less impetus to continue to dedicate patient
time and resources towards the trial. An updated audit of paediatric NS policies in 2015 had shown
a lack of adherence, however, to NICE guidance, with continued variability in diagnostic criteria and
management.52 The impact of the NICE recommendations on adult NS management was unknown and it
was unclear whether the publication reduced variation in practice for adult cancer patients.
A total of 53 adult NS policies were returned and reviewed: six cancer network policies and 47 acute
trust policies, with representation from all four UK nations. As the request for policies was often
forwarded to colleagues within a healthcare trust, it was not possible to determine an overall response
rate. Most policies (94%) provided advice for both oncology and haematology patients. All policies,
which were dated, had been updated post 2012, with no policy obviously issued before the NICE
guidance was published and 57% specifically referenced that guideline.
A total of 235 responses were received from the electronic survey of individual practice. After excluding
those containing only demographic data or minimal responses, there were 217 evaluable surveys. Again,
there was representation from all four nations, with 69% of respondents based in England. The majority
(72%) worked in oncology (predominantly as oncology consultants, acute oncology specialist nurses
and advanced nurse practitioners), 23% worked in haematology and the remaining 5% were consultants
mainly based in EDs or acute or general medicine. Forty-three per cent worked in university hospitals
or regional cancer centres, 52% worked in acute hospitals with SACT day case units on site, and the
remaining 5% worked in smaller acute hospitals which did not deliver SACT.
Of major interest was understanding current practice regarding routine risk stratification and any specific
low-risk protocols or practices. The policies varied in their adoption of the NICE recommendations focused
on assessing patients’ risk of septic complications and in decision-making about when, or if, to switch to
oral antibiotics and about hospital discharge.
When practice was reviewed in 2012 by the NICE GDG, approximately a third of adult policies included
the option of empirical oral antibiotics for lower-risk patients, with the intention of immediate discharge
or earlier discharge compared with i.v. inpatient antibiotics (NICE30). In contrast, approximately half of
current polices (53%) encourage identification of low-risk patients, with potential discharge on oral
antibiotics within 48 hours after hospital admission. Almost half the policies (45%) suggest stratification
based on MASCC score. Risk stratification is often only performed by senior oncology/haematology
doctors or acute oncology specialists, if available.
Only 40% of clinicians reported routinely risk-stratifying patients within 24 hours of presentation. The
MASCC score was most commonly used (by 70%), with the remaining 30% of clinicians using a local
institutional risk-scoring system, a Modified Early Warning Score (EWS; Subbe et al.53) or the Clinical
Index of Stable Febrile Neutropenia (CISNE; Carmona-Bayonas et al.54).
A wide range of approaches to early oral antibiotics and outpatient management are described in policies
and by clinicians. Only 9% of policies clearly describe the option of starting empirical oral antibiotics for
low-risk patients from the outset and most of these admit patients for 24–48 hours before discharge.
Similarly, only a small number of survey respondents (5%) suggested they would start upfront oral
antibiotics rather than i.v. antibiotics initially for low-risk patients. A further three haematology consultants
suggested this would be considered for patients with difficult i.v. access or who were in the terminal
phase of illness. Most policies do not define a period of observation following the start of oral antibiotics,
although 13% of policies specify at least a 24-hour admission to hospital. The most common ‘low-risk’ oral
antibiotic regimen is co-amoxiclav (625 mg three times daily) and ciprofloxacin, (either 500 mg or 750 mg
twice daily; 16 of 20 policies specifying a regimen) for 5 to 10 days in duration.
A number of the policies referred to the extensive additional clinical criteria that the American Society
of Clinical Oncology (ASCO) suggest should exclude patients from outpatient management, including
ensuring patients do not live alone, they have access to a telephone and transport and can return to
hospital promptly.7,29
NICE commented in 2012 that the criteria for considering either stopping or switching from i.v. to oral
antibiotics greatly varied. This work showed continuing variation in ongoing inpatient management of
uncomplicated NS. Sixty-eight per cent of policies provided advice about when it might be suitable
to switch from i.v. to oral antibiotics, in addition to guidance about early oral antibiotics. The majority
(57%) recommend considering a switch from i.v. to oral antibiotics at 48 hours. The European Society
for Medical Oncology (ESMO) guideline offers further advice about a range of factors to consider at
48 hours for switching to oral antibiotics and duration of treatment, which have been incorporated into
many policies.28 This includes whether the patient is still febrile and the neutrophil count is > 0.5 × 109/l.
One hundred and sixty-three survey respondents provided some indication as to when they would
routinely switch low-risk uncomplicated patients to oral antibiotics and discharge home. These
questions were not answered by clinicians who treat with oral antibiotics from the outset. Thirty-seven
26

per cent reported switching to oral antibiotics typically within 24 hours of admission, 44% within or
at 48 hours and 20% after 48 hours of admission. Various standard times to discharge after switching
patients to oral antibiotics were also reported, ranging from immediate discharge in 27% to after at least
24 hours of observation in 53%.
It was evident that clinicians generally do not recalculate MASCC scores after admission. They confirmed,
however, that the most important criteria, apart from initial risk scores, for determining when to switch
to oral antibiotics are duration of apyrexia (70%) and if symptoms are improving (62%). Over half the
respondents consider the patient’s neutrophil count (56%) and availability of microbiology results (52%) as
important. Fewer consider the duration of i.v. antibiotics the patient received (31%) and expected duration
of neutropenia (12%).
Survey respondents highlighted common reasons preventing early discharge of low-risk patients
before 48 hours of hospitalisation (see Table 10), most commonly a clinically well patient experiencing
ongoing fever.
It would therefore seem that despite the introduction of NICE guidance risk stratification is not routine
practice for many NHS centres or clinicians. A small number of specialist teams are prescribing upfront
oral antibiotics for low-risk patients, but this practice appears limited. There has been some increase in
the number of policies which include the option of discharging low-risk patients on oral antibiotics before
48 hours but approximately half of policies still advise initial i.v. antibiotics and subsequent oral switch
after 48 hours or later. Even more clinicians, approximately two-thirds, in their routine practice choose to
switch from i.v. to oral antibiotics at 48 hours or later. It is therefore evident that for at least half of centres
and clinicians surveyed routine practice is in accordance with the standard care arm in the EASI-SWITCH
trial. There has not yet been widespread adoption of risk stratification tools or routine early oral antibiotics
in low-risk patients. A number of factors appear to have slowed progress, including the limited evidence
base highlighted in the NICE guidance and in some cases dissatisfaction with current risk stratification
tools, which has resulted in centre, clinician and patient hesitance about early oral switch approaches.
The majority of policies encourage initial investigations and empirical antibiotic regimens that accurately
reflect NICE recommendations and therefore the initial management approach assumed in the EASI-
SWITCH trial. Eighty-five per cent of polices promote initial beta-lactam monotherapy, compared to
only 36% in NICE’s 2012 review. There has been a general reduction in the routine use of empirical
aminoglycosides and glycopeptides for patients with central lines: 13% of current policies include
gentamicin as part of an empirical dual antibiotic regimen, compared with 63% in 2012. Four of the
current policies suggest initial doses of gentamicin but that these only be continued if there are signs
of severe sepsis or for haematology patients. Local organism antibiotic resistance patterns are likely to
TABLE 10 Common reasons cited by survey respondents preventing early discharge of uncomplicated low-risk patients
(before 48 hours of hospitalisation)
Reason preventing early discharge % (n)
Patients are clinically well but have ongoing fever 47 (103)
Patients have other clinical issues keeping them in hospital, for example, other anticancer treatment toxicities 45 (97)
Patients do not feel clinically improved 33 (71)
Clinicians are not keen for discharge 33 (71)
The centre does not have an agreed protocol for early discharge of low-risk patients 30 (66)
The centre does not have an agreed pathway for follow-up of low-risk patients discharged early 26 (56)
Patients’ initial microbiology results are not available, for example, blood cultures 24 (52)
Patients or carers are not keen for discharge 16 (35)
be a contributing factor for those policies where gentamicin is routinely administered to all patients and
is permitted under NICE guidance. Only 4% of current policies suggest empiric use of glycopeptides if
a central line is present but a line infection not suspected, compared to 15% in 2012. Clinical practice
therefore supported the standard care i.v. antibiotics being utilised in the EASI-SWITCH trial.
Finally, comparing diagnostic thresholds to the NICE guidance, only 19% of policies and 24% of survey
respondents define neutropenia as a neutrophil count of ≤ 0.5 × 109/l as suggested by NICE, with most
employing a broader definition. While there has been a reduction in policies simply defining neutropenia
as < 1.0 × 109/l (51% compared with approximately 70% of adult policies in 2012) this is offset by
those that include patients whose neutrophil count is < 1 × 109/l and expected to fall. More policies
now encourage starting empirical treatment in patients who have had a single temperature ≥ 38°C
(78% compared with 50% in 2012), in keeping with NICE criteria. Similarly, a patient presenting with
a single temperature of 38°C or above would meet the temperature criteria used by 96% of clinicians
and just over a third (36%) of these clinicians would start empirical treatment if lower temperature
thresholds were recorded (e.g. single/sustained temperature of ≥ 37.5°C/≥ 37.7°C). The importance of
considering NS in patients who are generally unwell, irrespective of their temperature, was stressed in
the majority of policies, including prompts for signs and symptoms such as rigors, altered mental state
and haemodynamic instability. Overall the review of current policy and practice supported the proposed
adjustments to the eligibility criteria to the trial.
Review of assumptions underpinning study design
The review of current NS practice confirmed the continued importance of the research question
nationally and the potential impact the trial could have on routine NS management in the UK. A careful
review of the assumptions underpinning the original trial design and sample size calculation was
therefore undertaken to determine whether the delivery of a smaller study could still have a meaningful
clinical impact.
On initial design, the trial was powered at 90% and with a one-sided 97.5% CI, to detect non-inferiority
of the early antibiotic intervention within a margin of 10%, assuming a 15% treatment failure rate in the
standard care arm. This would require 269 patients per group. Allowing for a 5% dropout rate and up to
10% crossover from control to intervention, 314 participants would be required for each group, resulting
in an overall target sample size of 628 patients.
The assumed 15% treatment failure rate for patients receiving standard care was derived from the three
studies thought to best reflect the proposed control arm in relation to the populations included and
duration of i.v. antibiotic treatment administered.36,55,56
The pilot results raised no concerns regarding treatment adherence, separation between the treatment
arms or the observed treatment failure rates in each arm. It was therefore presumed that the
assumptions relating to those sample size parameters remain valid but, in retrospect, the choice of
non-inferiority margin and statistical analysis may have been too stringent for a pragmatic trial where
treatments were being used within their licensed indications or established clinical practice and where
the risk of treatment failure was unlikely to result in serious risk to patients (in particular critical care
admission or death).
Review of the non-inferiority margin

Selecting the non-inferiority margin was challenging due to the limited evidence available to help guide
this selection. The rationale for the originally selected 10% margin was based on:
1. A historical consensus guideline advocating the use of a 10% margin in trials of antibiotic treatment
among patients with NS.47
28

2. Advice from the trial’s PPI co-applicant and representatives that this was an acceptable trade-off,
for the potential overall gain in quality of life expected within this margin of uncertainty for clinical
effectiveness.
It is important to note the consensus recommendation for a 10% margin relates to the overall NS
population, with no consideration for stratification by risk of septic complications. This approach may
be over-simplistic given the significant differences in clinical outcomes in low- and high-risk patients.
The EASI-SWITCH target population are patients at low risk of septic complications, selected through
their MASCC score and additional study eligibility criteria. Treatment failure in this population, as
highlighted in two Cochrane reviews, therefore typically results in persistence or recurrence of fever,
leading to prolongation of admission or re-admission for further i.v. antibiotic treatment. There has
been no association noted between mortality and oral antibiotic treatment in low-risk patients.37,57
This contrasts sharply with patients classified at high risk of complications at presentation, where
treatment failure is likely to have more significant consequences and potentially result in organ failure,
critical care admission or even death.
It was therefore felt appropriate to explore the acceptability of a larger non-inferiority margin
considering the low-risk patient population, as this could maintain an acceptable trade-off between
the possibility and consequences of treatment failure versus the potential quality of life and economic
benefits associated with early switch. Therefore, the opinions of PPI and clinician stakeholders was
sought on whether a review of design including widening of the non-inferiority margin would remain
acceptable for assessment of the primary outcome.
1. Patient and public opinion
Input was sought from a range of PPI representatives. A summary of the study design and progress,
including the rationale and implications for reviewing the sample size and specifically the non-inferiority
margin, was prepared and distributed via e-mail to the membership of two PPI forums (see Appendix 1):
(1) the Northern Ireland Cancer Research Consumer Forum, which has a range of patient and carer
members from across Northern Ireland who work in partnership with cancer researchers; and (2) the
Independent Cancer Patient Voice (ICPV), a national independent patient advocate group.
Respondents were requested to reply via e-mail as to whether they supported the proposed change in
non-inferiority margin or not, with additional comments also welcome. Consent was obtained from all
respondents for their comments to be made publicly available.
Twenty-one survey replies from patient and public representatives were received, with the majority
of these supportive of increasing the non-inferiority margin from 10% to 15% (n = 19). Additional
comments from seven of these respondents along with comments from one uncertain respondent
and one who was not supportive are detailed in Appendix 1. Respondents’ comments demonstrated a
good understanding of the key issues. They highlighted that earlier discharge if feasible is an important
quality-of-life issue for many patients. The concerns raised about patients having adequate support at
home and being able to be re-admitted quickly again if required, as well as the small risk of an adverse
clinical outcome, are extremely appropriate.
2. UK clinicians’ opinion
Opinion was also sought from clinicians nationally regarding the proposed widening of the non-inferiority
margin. A short description of the trial, key study design considerations and feedback to date on the
proposed revisions from PPI representatives was summarised for clinicians. Again, respondents were asked
a simple yes/no question, with additional comments welcome (see Appendix 2). Trial co-investigators and
site PIs disseminated the survey via e-mail throughout their clinical networks. Attendees at a Scottish
Clinical Trials showcase meeting (January 2018) were also surveyed using a paper copy of the questionnaire.
Almost all clinicians who provided feedback were supportive of widening the non-inferiority margin
from 10% to 15% and continuing the study. In total, 50 responses were received from 39 consultants,
9 clinical fellows/speciality trainees and 2 RNs, with representation from the four UK nations. All but
one of the respondents were supportive of the revision. Anonymised clinician comments in support of
widening the non-inferiority are detailed in Appendix 2, and typically highlighted the continued validity
of the research question and the potential impact upon practice. Notably, clinicians within centres that
consider early/upfront oral antibiotics were supportive of continuation of a smaller achievable study;
although this would involve altering the current standard of care in these centres, this would be an
acceptable approach for the proposed time period given the potential to generate results that could
make a compelling argument for further acute oncology service development. The cost-effectiveness
analysis to be undertaken within the study was also perceived to be important, with the potential to
show a reduction in length of stay cited in support of study continuation.
Additionally, the EASI-SWITCH trial is part of the National Cancer Research Institute’s Colorectal Cancer
Clinical Studies Group (CSG) portfolio; hence, the proposed change to study design was presented
at the Adjuvant and Advanced Disease CSG Subgroup meeting in January 2018. Membership of this
group includes UK-wide representation from oncology (nine consultant medical oncologists) and other
disciplines, including a statistician and clinical trials unit director. This group was also unanimously
supportive of the proposed revision to the non-inferiority margin.
3. Trial Oversight Committees’ opinion
The EASI-SWITCH DMEC and TSC (met 22 November 2017 and 1 December 2017, respectively) both
supported this approach and recommended continuing the study with a revised non-inferiority margin.
The TSC were influenced in particular by the continued importance of the research question to the NHS
and the strong support from PPI respondents when making their recommendation.
Review of statistical analysis plan

The TSC independent statistician also recommended review of the selected CI. The original choice of a one-
sided 97.5% CI was based on recommendations by regulatory agencies for trials of novel therapies that have
not been licensed for a specific clinical setting. This recommendation is focused on the provision of evidence
for decisions about the licensing of drugs. This requires a greater degree of certainty than decisions about a
strategic progression within the current use and licensed indication of an established treatment, which is the
case with EASI-SWITCH. International recommendations for NS clinical trials also emphasise that the use of
95% CIs is acceptable.47 There is obviously no expectation that the intervention will have superior efficacy to
standard care, which is why a one-sided CI has been selected from the outset. Therefore, a one-sided 95% CI
was felt appropriate for the EASI-SWITCH primary analysis and was unlikely to be detrimental to the impact
of the trial’s findings.
The revised sample size calculation with a 15% non-inferiority margin and one-sided 95% CI requires
230 patients with retention of 90% power, a 5% dropout rate and a 10% crossover rate from control
to intervention.
Progression to main trial
In addition to this stakeholder support, the study sponsor and HTA programme director were also
supportive of continuation with the proposed revisions in study design. Based on the recruitment during
the pilot phase, the revised target recruitment rate was 0.5 patients per site per month. Accrual of the
revised sample size of 230 based on this target would be achieved by increasing the number of trial
sites (to a total of 20) and the duration of recruitment to allow for the halt during the pilot phase and its
subsequent prolongation.
30

Chapter 4 Main trial progression

Screening and recruitment post pilot phase
The internal pilot phase of EASI-SWITCH highlighted lower than anticipated recruitment rates, even
with the revision of eligibility criteria and associated positive impact on recruitment. Further revision
to study design was deemed acceptable to the trial stakeholders with the aim of delivering a clinically
meaningful study. On review of updated audit data from two study sites, it was clear there was a
sustained downward trend in NS admissions, consequently a revised recruitment target of 0.5 patients
per site per month was set with an accompanying increase in number of recruiting sites to 20.
Post pilot phase, the EASI-SWITCH trial continued recruitment for another 24 months. In total, 19 out
of a planned 20 sites opened to recruitment, which were a combination of cancer centres and units.
This included 14 sites in England, 3 in Northern Ireland, 1 in Scotland and 1 in Wales (see Appendix 3,
Table 37). In April and May 2019, 4 sites requested closure due to inactivity, leaving 15 active sites at
the time of trial closure.
Identification of interested and appropriate sites was challenging. A range of methods were employed
to promote the trial including the NIHR clinical research networks, relevant professional groups and
national meetings. NIHR regulations around TSC and DMEC independence precluded participation
of some interested sites because of associations with TSC and DMEC members. Table 11 summarises
reasons for site non-participation.
In total, 827 patients were screened for trial entry. The main reasons for exclusion (in order of frequency)
were patients not fulfilling the diagnostic criteria of NS, a diagnosis of acute leukaemia, deemed at high
risk of complications using the MASCC score (score < 21), history of penicillin (or other IMP) allergy, the
physician in charge was not willing to support entry into either trial arm or not treat with CSFs, signs of
severe localising infection present or the patient had already received > 24 hours of i.v. antibiotics. In
total, 129 participants were recruited out of the target sample size of 230. In November 2019, the TSC
recommended trial closure due to under-recruitment. A summary of recruitment activity across the trial
phases is provided in Table 12 and Figure 2.
Identification of barriers to recruitment
In view of the lower than anticipated target population, there was a need to understand the barriers
to recruitment experienced by sites as the trial progressed and identify potential solutions in order to
maximise the likelihood of successful trial delivery. This was particularly important in recognition of the
narrow window of opportunity for patients to be recruited, whereby screening and recruitment both had
to occur within 24 hours of commencing i.v. antibiotics for NS.
TABLE 11 Reasons for site non-participation in the EASI-SWITCH trial (n = 15 sites)
Reason for site non-participation N=
Research team resource capacity 3
Clinical team resource capacity 5
Standard care more aligned with the intervention arm of EASI-SWITCH 3
Standard care in conflict with CSF use 4
Main trial progression
TABLE 12 Summary of recruitment activity
Phase Pilot phase Main trial
February December 16 April to December 17 to

Dates to July 16 to February 17 November 17 November 19
Months 1–6 7–9 10–18 19–45
Total number open 4 4 10 10–19 (15 sites

sites active November 19)
Cumulative number 70 97 154 813

of patients screened
Cumulative 7 18 42 129
recruitment
To understand factors impacting recruitment at sites, two approaches were taken as the trial progressed
post pilot phase. These were (1) semistructured interviews with key site personnel and (2) an investigator
survey of barriers to recruitment.
Semistructured interview feedback from key site personnel

A series of semistructured interviews with site PIs and lead RNs were conducted (April 2018) to explore
clinician’s experience of recruiting and delivering the trial at their site (see Appendix 4).
All clinicians who were invited to take part via e-mail agreed to participate with representation from
all 12 sites open to recruitment, including 12 PIs and 11 RNs (one open site had no RN in post due to
illness). A summary list of reported barriers to trial recruitment is presented in Table 13.
The most common barrier consistently noted by all sites unsurprisingly was the lower than anticipated
number of patients being admitted with NS and therefore reduced pool of potentially eligible patients. It
was noted at several sites that some patients required repeated hospitalisation with NS and other SACT-
related toxicities during treatment, further reducing the number of potentially eligible patients.
Logistical issues at the site were more frequently identified as barriers compared to individual clinician
barriers. It was noted that this trial, as an acute oncology trial across multiple tumour types, differed
from the majority of oncology/haematology trials in their research portfolio, where patients were
identified and managed as outpatients by tumour site-specific research teams, meaning the daily
250
200 Actual cumulative total

Predicted total recruitment
per month until
150 December 2017
(1 patient/site/month)
Revised predicted total
100 recruitment
from January 2018
(0.5 patient/site/month)
50
0
Apr-17 Aug-17 Dec-17 Apr-18 Aug-18 Dec-18 Apr-19 Aug-19
FIGURE 2 Cumulative actual recruitment vs. predicted recruitment for the EASI-SWITCH trial (April 2017 to November
2019 inclusive). Total recruitment of 129 patients (November 2019). With the adjusted recruitment rate of 0.5 patients per
site per month from January 2018 predicted recruitment was 216 patients by November 2019, based on the number of
open sites.
32

TABLE 13 Summary of barriers to recruitment encountered in the EASI-SWITCH trial, as reported by interviewed
clinicians (n = 23)
Investigator
Trial design Site Clinician Patient
• Eligibility criteria. • Reduced NS admissions. • Importance of the • Time to consider

• Confirmation of eligibility • Resource capacity. research question and participation.
required to be performed • Patient identification involving inpatients in • Previous SACT and
by a medically qualified processes. research. toxicity history.
professional. • Resource planning – • Motivation and commit- • Symptom burden.
• Prescription of allocated availability of staff; time ment to the study. • Preference for one study
treatment by a medically and workload required at • Experience discussing arm.
qualified professional. short notice. the study intervention. • Social circumstances.
• Competing research • Preference for one study • Education, literacy and
interests. arm. language.
• Communication and
co-ordination with study
team members.
requirement for screening and patient identification could be challenging. Recruitment was also more
challenging if the RNs were solely responsible for screening with minimal engagement or support from
front-line clinical staff. The unpredictable nature of NS admissions and the requirement to be available at
short notice made it difficult to plan workload.
Clinical and research team members’ interest in the study and the perceived importance of the trial and the
research question it is trying to address were cited as an important barrier. While enthusiasm was often
noted to be high when the trial opened, long periods of actively screening but not recruiting impacted morale
and general willingness to continue to actively screen, refer and recruit patients. Maintaining prioritisation
and interest in the study was reported as challenging with short-term clinical staff, for example, rotating
junior medical staff or changes in inpatient nursing staff. Research teams therefore needed to regularly
promote the trial and train new staff. Specialist registrars or clinical fellows, if available at sites, were noted
to be well placed to help with consent, confirm eligibility and institute the allocated management plan but
needed responsive site training and delegation to be available given typically short-term rotations.
The experience and confidence of the team member first introducing the study to patients was
also noted to be important. RNs in particular noted recruitment was easiest when experienced and
enthusiastic senior clinicians, for example senior acute oncology nurse specialists, consultants or
clinical fellows, promptly reviewed patients post admission and considered their suitability for the trial,
introducing trial participation as a treatment option from the outset for patients. Several RNs highlighted
their limited experience reviewing inpatients, including patients with NS.
Three of the 12 sites (predominantly PIs) also importantly noted a preference by some clinicians for
the intervention arm compared with standard care. All of the these sites prior to trial opening had
utilised MASCC scoring and had a specific low-risk policy in place. They had, however, been supportive
of the trial being undertaken and agreeable to recruit patients. Undoubtedly, some of the low-risk
NS admissions have been treated with an approach similar to the intervention arm, rather than being
offered the EASI-SWITCH trial. One site described how ‘bed pressures’ had resulted in some patients
being managed with what they perceived to be an intermediate approach between the intervention and
standard care trial arms. Conversely, some RNs indicated that certain clinicians were less supportive of
certain groups of patients participating, whom they viewed as ‘higher risk’. This included certain tumour
types, for example haematology and sarcoma patients or patients presenting with severe neutropenia
(ANC < 0.1 × 109/l), despite there being no clear evidence to support this approach.
While barriers related to trial design were infrequently cited, these related to the inability to recruit
penicillin-allergic patients and the sponsor requirement for confirmation of eligibility and prescription of
protocolised therapy by a medical professional. Otherwise, it appeared that the previous revisions to the
eligibility criteria had facilitated recruitment and the trial population was now reflective of the low-risk NS
population seen in routine practice. While patient follow-up was viewed favourably, it was noted that the
28-day follow-up could be difficult to achieve if patients had received a further cycle of SACT within this
period, particularly if toxicities related to this were experienced and/or re-admission with a new episode
of NS or other SACT toxicity occurred, as this tended to impact patients’ recall of the NS episode related
to the preceding cycle of treatment. Reporting of AEs beyond the day 14 primary outcome measure was
felt to be not clinically relevant to the episode of NS in view of this and, along with capturing concomitant
medications which could be multiple in this patient population, was a potential burden.
Site staff felt that the trial was well received by the majority of patients but, as anticipated, the short
time to consider participation and consult with family or friends was the most common barrier for
patients. Otherwise, patients’ previous experiences with SACT toxicity (and unscheduled care
admissions arising from this) and symptom burden were also relevant – previous experiences, other
toxicities, lack of improvement in symptoms from initial admission and difficulty coping with existing
burden of information and uncertainty from an individual patient’s cancer care plan even prior to
considering trial entry were all considered barriers to recruitment.
Overall, the interviews provided a clearer, in-depth understanding of the perspectives of key site
personnel trying to recruit patients to the EASI-SWITCH trial. With equal representation from all sites,
selection and non-respondent bias was avoided. It was evident a range of barriers to recruitment were
present at several levels at trial design, site, individual clinician and patient levels, some of which could
potentially be addressed.
Investigator survey of barriers to recruitment

As accrual to the trial continued to be challenging a further assessment of the key barriers to
recruitment was undertaken in March 2019, through an electronic anonymous survey of personnel
involved in trial recruitment. It aimed to assess whether the barriers identified from the interviews
(April 2018) remained the most important and relevant to those currently trying to deliver the study,
almost 1 year later. An online survey of recruitment experience was deemed the best strategy in order to
obtain feedback from a wider range of personnel involved in the trial’s delivery and potentially identify
additional factors through use of anonymised responses.
Forty complete responses were obtained with representation from all active sites except one (i.e. 15 of 16
open sites). Forty-eight per cent were RNs, 18% were site PIs and 33% were subinvestigators; 90% had
been involved in the trial since it opened and 83% had been actively involved in recruiting participants.
Table 14 details the factors identified as barriers to recruitment by 30% or more of respondents. They
are listed in order of their weighted score, providing an indication as to which barriers were felt most
significant. The percentage of respondents who considered it a barrier at all (from somewhat to highly
significant) is also provided.
The most commonly reported barriers of reduced NS admissions, the unscheduled patient
population and short window for recruitment, were the same as those that had been identified in the
semistructured interviews:
I think that we have a motivated team who are keen to recruit but we have very few numbers actually
coming into our oncology assessment unit and ED with neutropenic sepsis (far smaller numbers than I
had realised).
Difficulty in recognising potential participants in the time frame.
A small number have been missed due to lack of availability of research nurses within the time frame.
34

TABLE 14 Most frequent barriers to recruitment as reported in the electronic survey (n = 40 survey responses)
Ranked in order Per cent of responses

of weighted score Identified barrier identifying this barrier (n)
1 Number of NS admissions to sites 75 (30)
2 Potential participants are unscheduled 68 (27)

admissions
3 Eligibility criteria for patients to 73 (29)

participate
4 Having to consent and randomise within 63 (25)

24 hours of i.v. antibiotics commencing
5 The acceptability of the trial to patients 58 (23)
6 Identification of suitable patients 58 (23)
7 Other clinicians prefer standard care 50 (20)
8 Expected recruitment rate for your site 43 (17)
9 Patients prefer standard care 43 (17)
10 Other clinicians prefer the intervention 38 (15)
11 Other patients prefer the intervention 38 (15)
12 The acceptability of the trial to other 45 (18)

clinicians
13 Engagement and enthusiasm of other 43 (17)

potential recruiters at your site
14 Locally available resources and 40 (16)

infrastructure to support the trial
15 The clinician being surveyed prefer the 30 (12)

intervention
16 Administration burden and workload 30 (12)

involved in recruiting a patient
The trial’s eligibility criteria were also highly ranked as a barrier, more prominently than had emerged
in the interviews. Apart from inability to recruit penicillin-allergic patients, this probably refers to CSFs
being prohibited once on study. There is expert national and international consensus that this is not an
indicated intervention in low-risk patients but nevertheless remains common practice. While survey
respondents continued to express their enthusiasm and commitment to the trial it is interesting that
the lack of engagement and enthusiasm of other colleagues was felt to be more significant at this stage
of the trial than previously had been reported through the interviews. Table 15 summarises the results
reported for all of the listed barriers categorised according to the ORCA key recruitment domains.
In general, the electronic survey further supported the multiple barriers that had emerged from the
semistructured interviews, confirming that they were ongoing issues, which continued to impact
recruitment. No new barriers were identified that had not previously been present. The variation
in equipoise between the trial arms experienced by different clinicians and patients was, however,
more prominently described in the survey than in the interviews. While the interviews had alluded to
preferences for the intervention or standard care arms, it was clearer from the survey that there could
in fact be significant preferences from investigators, clinical colleagues and patients for one arm over
the other, impacting recruitment. Thirty per cent of survey respondents were inclined to prefer the
intervention (early antibiotic switch), whereas clinical colleagues could prefer either standard care (cited
by 49% respondents) or the intervention arm (cited by 38% respondents), hindering recruitment. Similarly,
TABLE 15 Survey respondents’ impression of listed potential barriers to recruitment in relation to their experience of the
EASI-SWITCH trial (n = 40 survey responses)
Trial design and Recruitment

pre-trial planning Trial conduct information needs Recruiter differences
Eligibility criteria Number of NS Training needs of other Engagement and

for patients to admissions (76%) researchers involved in enthusiasm of other
participate (73%) the study (19%) potential recruiters (43%)
24-hour window Potential participants are Training respondent Which recruiter approaches
for recruitment and unscheduled inpatients (68%) received on the study the potential patient about
randomisation (62%) protocol (8%) the trial (22%)
The acceptability of the Identification of suitable Participant information Communication and

trial to patients (57%) patients (57%) sheet and consent support between research
form (8%) team and front-line clinical
staff (22%)
Other clinicians prefer Locally available resources and Your engagement

standard care (49%) infrastructure to support the and enthusiasm for the
trial (41%) trial (8%)
The acceptability of Administration burden and Communication and

the trial to other workload involved in recruiting a support within the research
clinicians (46%) patient (30%) team (5%)
Expected recruitment Organisational or institution

rate for your site (43%) support for the trial (24%)
Patients prefer Clarity of the trial protocol (22%)

standard care (43%)
Other clinicians prefer Data collection required for the

the intervention (38%) case report form (19%)
Patients prefer the Delegation of the individual

intervention (38%) recruitment tasks between
research team members (16%)
You prefer the
intervention (30%)
Priority of the trial Consent process involved

outcomes to other for the trial (16%)
clinicians (27%)
Priority of the Follow-up required for the

trial outcomes to study, including questionnaires
patients (22%)
The acceptability Recruitment updates from the

of the trial to the clinical trials unit regarding trial
respondent (16%) progress (8%)
Priority of the trial Data monitoring and

outcomes to the management from the clinical
respondent (14%) trials unit (5%)
Respondent prefers
standard care (14%)
Notes
≥ 50% of respondents identified factor as barrier to recruitment.
≥ 30–49% of respondents identified factor as barrier to recruitment.
≤ 29% of respondents identified factor as barrier to recruitment.
36

some patients’ strong preference for standard care (cited by 43% respondents) and others for the early oral
intervention (cited by 38% respondents) had the potential to prevent trial recruitment:
The only barrier has been eligible patients declining entry to the study as their preference was inpatient
antibiotic treatment.
Sometimes patients have turned down the study because they did not want a 50:50 chance of having to
stay in on i.v. for 48 hrs if low risk.
The electronic survey was a quicker and easier strategy to obtain feedback about recruitment from
a wider range of responders with different roles across different sites with variable recruitment
performances. The ORCA recruitment domains provided a framework to guide the survey’s questions
and ensure key barriers were not missed, although not all listed factors were overly applicable, and
some benefitted from tailoring to the individual EASI-SWITCH setting. The survey importantly avoided
interviewer bias and allowed respondents to express their views freely and anonymously. As a result
of this a greater understanding of the variation in preference for one trial arm across the study was
obtained. Despite a good response rate, potential limitations of the survey were obviously respondent
non-response, selective responder bias and misinterpretation of questions.
Additional strategies to enhance recruitment
As the trial progressed and recruitment failed to meet expectations, a pragmatic shift in recruitment
strategies occurred, with additional approaches added to try and address the modifiable barriers
identified. As previously discussed, revision of eligibility criteria was made during and after the pilot
phase to ensure the study was pragmatic and reflected the patient population routinely treated for
NS. Further minor adjustments were made based on investigator interview feedback in May 2018,
including: (1) recruitment of patients given additional systemic antibiotics at the time of presentation
(such as a single dose of gentamicin) provided it was clinically appropriate to discontinue these at the
time of enrolment, to include patients presenting to non-specialist units; (2) addition of suspension
oral antibiotics to protocolised antibiotic therapy for patients unable to swallow tablets; (3) clarification
of use of short-acting CSF to include patients who had a course of short-acting prophylactic CSFs
prescribed as part of their SACT regimen but continuing to exclude those commenced on CSF as
treatment for the presenting episode of NS.
In response to feedback about clinical workload, AE reporting was simplified, reducing the reporting
period from 28 days to 14 days, with reporting of AEs beyond the 14-day primary outcome follow-up
felt unlikely to add anything additional, in terms of understanding AEs related to the early switch
antibiotic intervention. Shortening the reporting period was felt to benefit research teams, as it was not
uncommon for patients to be re-admitted to hospital again within the current 28-day reporting period,
once they had received a further cycle of chemotherapy. These hospital admissions were unrelated to
the patient’s EASI-SWITCH episode and treatment but required research teams to report them as a
serious AE within 24 hours of becoming aware. By shortening the reporting period to just the primary
follow-up period of interest, it was hoped it would allow teams to prioritise time for recruiting new
patients by reducing the intensity of patient follow-up required.
In the electronic survey distributed in March 2019, investigators were also asked to share any strategies
they had found useful at their site in facilitating recruitment, so they could be shared with other sites.
All comments related to optimising awareness of the trial, with clinical staff first assessing and managing
new admissions and trying to create a suitable pool of staff who could provide consistent screening of
patients and perform research-related tasks.
Main trial progress
While revisions to the eligibility criteria and trial design appeared to have a positive impact on
recruitment initially, it is apparent from the recruitment graph in Figure 2 that, by the end of 2018,
recruitment was consistently falling behind target and appeared to be plateauing thereafter, suggesting
achieving even a smaller study in a timely manner would be challenging. Consequently, the DMEC
recommended study closure on grounds of under-recruitment in November 2019. Despite clinician
and researcher support for the study, persistent challenges to recruitment in relation to the numbers of
potential patients and the challenges of identifying and enrolling patients within a narrow time window
following admission remained. It is also possible that as time progressed, the variation in equipoise
between trial arms demonstrated in the investigators’ survey (March 2019) in comparison to the site
team interviews (April 2018) became more prominent and was potentially accompanied by changes in
clinicians’ treatment approaches.
38

Chapter 5 Clinical effectiveness of early

oral switch
T his chapter contains some text reproduced from ‘Early switch to oral antibiotic therapy in patients
with low risk neutropenic sepsis (EASI-SWITCH): a randomized non-inferiority trial’ published in
Clinical Microbiology and Infection (2023). https://doi:10.1016/j.cmi.2023.07.021.58
Recruitment
One hundred and twenty-nine patients were enrolled in EASI-SWITCH when trial closure was recommended
by the DMEC in November 2019. In total, 827 patients were screened for study entry; the most common
reasons for screen failure are described in the previous chapter and listed in Appendix 5. Recruitment
numbers by site are summarised in Table 16 with a list of sites provided in Appendix 3, Table 37.
Consolidated Standards of Reporting Trials flow diagram
In total, 129 patients were randomised from 19 sites. Sixty-five patients were randomised to the early
switch intervention and 64 to the standard care control arm (see Figure 3, CONSORT diagram). Of these,
125 patients were included in the primary ITT analysis (comprising 61 patients allocated to intervention
and the 64 patients allocated to control). Four patients were excluded (all allocated to intervention) for
the following reasons: one patient was randomised in error, one withdrew from continued participation
and two patients were lost to follow-up. Twelve patients included in the primary ITT analysis were
TABLE 16 Recruitment by site
Site Total number of patients recruited (%)
s01 50 (38.8)
s02 4 (3.1)
s03 15 (11.6)
s04 13 (10.1)
s05 2 (1.6)
s06 5 (3.9)
s07 5 (3.9)
s09 9 (7.0)
s10 1 (0.8)
s11 7 (5.4)
s12 7 (5.4)
s13 3 (2.3)
s15 1 (0.8)
s16 4 (3.1)
s17 2 (1.6)
s19 1 (0.8)
Clinical effectiveness of early oral switch
Assessed for eligibility

n = 827
Excluded (n = 698)
• Did not meet eligibility criteria, n = 581
• Unable to provide informed
consent, n = 6
• Other, n = 111
Randomised
n = 129
Allocated to early oral switch intervention, n = 65 Allocated to standard care, n = 64

• Received allocated intervention, n = 55 • Received allocated standard care (≥48 hours i.v.
• Did not receive allocated intervention, n = 8 antibiotic therapy), n = 60
Did not receive allocated intervention, n = 6 • Did not receive allocated intervention, n = 4
˚Randomised in error, n = 1 i.v. antibiotic therapy duration <48 hours, n = 4
˚Withdrew consent, n = 1
˚
Lost to follow-up, n = 2 Lost to follow-up, n = 0

• Data not retrievable at study site, n = 1
• Patient did not return completed diary, n = 1
Included in primary outcome ITT analysis, n = 61 Included in ITT analysis, n = 64

• Excluded, n = 4
Randomised in error, n = 1
˚ Withdrew consent, n = 1
˚ Lost to follow-up, n = 2
˚
Included in primary outcome PP analysis, n = 53 Included in primary outcome PP analysis, n = 60

• Excluded, n = 8 • Excluded, n = 4
Switched to oral antibiotics more than 48 hours
˚ Switched to oral antibiotics less than 12 hours
after starting i.v. antibiotic, n = 1
˚ after starting i.v. antibiotic, n = 4
˚ after starting i.v. antibiotic, n = 2
Received less than 5 days total treatment, n = 2
˚ Treatment interrupted (missed at least 2
˚ consecutive doses of oral antibiotic), n = 1
˚ after starting i.v. antibiotic AND
received less than 5 days total treatment, n = 2
FIGURE 3 CONSORT diagram.
excluded from the PP analysis; consequently, the primary PP population comprised 53 patients in the
intervention group and 60 in the standard care group. The reasons for exclusion of the eight patients
in the intervention group were: premature discontinuation of antibiotic treatment (n = 4), interruption
40

to antibiotic treatment involving at least two consecutive missed doses (n = 2) and insufficient initial
i.v. antibiotic treatment (n = 1). All four excluded patients in the standard care group had received
< 48 hours of i.v. antibiotic treatment.
Baseline characteristics
Table 17 describes the patient, tumour and treatment characteristics in the intervention and control
groups. As anticipated, only a minority of participants had a haematological malignancy (6.2%) in
comparison with solid tumours (93.8%), of which the most common cancer type was breast cancer
(54.6%). The majority of patients were receiving treatment in the neoadjuvant or adjuvant setting
(60.4%) rather than palliative setting (27.9%). In general, baseline characteristics were well balanced
across the intervention and control groups in relation to cancer type, anticancer treatment and
symptoms and signs of infection (including fever, absolute neutrophil count and MASCC score). Use
of prophylactic Granulocyte colony stimulating factor (GCSF) support was noted to be higher in the
standard care arm (34.4%) in comparison to the intervention arm (15.6%).
TABLE 17 Baseline characteristics. Data presented as mean (SD) for continuous data and number (%) for categorical data
Treatment group
Standard care Intervention Total

Baseline characteristics (n = 64) (early switch) (n = 65) (n = 129)
Age (years) 56.2 (15.1) 56.6 (13.4) 56.4 (14.2)
Gender:
Male 21 (32.8%) 20 (30.8%) 41 (31.8%)
Female 43 (67.2%) 45 (69.2%) 88 (68.2%)
Malignancy:
Solid tumour 59 (92.2%) 62 (95.4%) 121 (93.8%)
Haematological 5 (7.8%) 3 (4.6%) 8 (6.2%)
Solid tumour type: n = 59 n = 62 n = 121
Breast 30 (50.9%) 36 (58.1%) 66 (54.6%)
Lung 4 (6.8%) 3 (4.8%) 7 (5.8%)
Gastrointestinal/hepatobiliary 4 (6.8%) 5 (8.1%) 9 (7.4%)
Germ cell 3 (5.1%) 0 (0.0%) 3 (2.5%)
Genitourinary 5 (8.5%) 5 (8.1%) 10 (8.3%)
Head and neck 2 (3.4%) 0 (0.0%) 2 (1.7%)
Gynae 4 (6.8%) 3 (4.8%) 7 (5.8%)
Sarcoma 4 (6.8%) 4 (6.5%) 8 (6.6%)
Other 3 (5.1%) 6 (9.7%) 9 (7.4%)
Haematological malignancy type: n=5 n=3 n=8
Hodgkin lymphoma 4 (80.0%) 2 (66.6%) 6 (75%)
Other 1 (20.0%) 1 (33.3%) 2 (25.0%)
continued
TABLE 17 Baseline characteristics. Data presented as mean (SD) for continuous data and number (%) for
categorical data (continued)
Treatment group
Standard care Intervention Total

Baseline characteristics (n = 64) (early switch) (n = 65) (n = 129)
Cancer treatment intention
Radical 9 (14.1%) 3 (4.6%) 12 (9.3%)
Palliative 16 (25.0%) 20 (30.8%) 36 (27.9%)
Adjuvant/neoadjuvant 38 (59.4%) 30 (61.5%) 78 (60.4%)
Other 1 (1.6%) 2 (3.1%) 3 (2.3%)
Cancer treatment line n = 64 n = 128
1st line 54 (84.4%) 55 (85.9%) 109 (85.2%)
2nd line 7 (10.9%) 7 (10.9%) 14 (10.9%)
3rd line and beyond 3 (4.7%) 2 (3.1%) 5 (3.9%)
Maximum temperature 38.2 (0.6) 38.2 (0.8) 38.2 (0.7)
Absolute neutrophil count 0.3 (0.3) 0.3 (0.3) 0.3 (0.3)
Symptoms of mild local infection
Cough 15 (23.4%) 21 (32.3%) 36 (27.9%)
Sore mouth/throat 29 (45.3%) 22 (33.8%) 55 (39.5%)
Dysuria 3 (4.7%) 5 (7.7%) 8 (6.2%)
Nausea/vomiting 11 (17.2%) 10 (15.4%) 21 (16.3%)
Diarrhoea 10 (15.6%) 9 (13.9%) 19 (14.7%)
Other symptoms 32 (50.0%) 29 (44.6%) 61 (47.3%)
MASCC score 24.0 (1.8) 24.3 (1.8) 24.2 (1.8)
Prophylactic GCSF administered
Yes 22 (34.4%) 10 (15.6%) 32 (25.0%)
No 42 (65.6%) 54 (84.4%) 96 (75.0%)
C-reactive protein (mg/l) 48.6 (49.2) 50.3 (52.7) 49.5 (50.8)
Blood cultures:
Positive 20 (10.9%) 16 (7.6%) 36 (9.1%)
Negative 163 (89.1%) 196 (92.5%) 359 (90.9%)
GCSF, Granulocyte colony stimulating factor
Treatment after trial entry
All patients (n = 64) randomised to the standard care arm commenced allocated study treatment; however,
four patients did not complete allocated treatment, receiving < 48 hours of i.v. antibiotic therapy. Two
patients randomised to the early switch intervention (n = 65) did not proceed to allocated study treatment
due to ineligibility (n = 1) and withdrawal of consent (n = 1). Therefore, 63 patients in the intervention arm
commenced allocated treatment; however, protocolised treatment was not completed in eight patients for
a number of reasons. These included premature switch to oral antibiotics (after < 12 hours of i.v. antibiotic
therapy; n = 1); late switch to oral antibiotics (after 24 hours of i.v. therapy; n = 2); completion of < 5 days
42

antibiotic treatment in total (n = 1) and a combination of late oral switch (after 12 hours) and short duration
(< 5 days) of treatment in total (n = 2).
The mean duration of i.v. antibiotic therapy (and SD) was 54.8 hours (24.2) and 22.6 hours (26.9) in the
standard care and early switch intervention groups, respectively.
No patients in the standard care arm were lost to follow-up for the day 14 primary outcome measure.
Three patients is the intervention arm were lost to follow-up at day 14; however, it was still possible to
determine the primary outcome for one of these patients, who had a treatment failure before the day 14
time point.
In total, of 65 patients allocated to intervention, 61 were included in the primary outcome ITT analysis
and 53 in the PP analysis. Of the 64 patients allocated to standard care, all were included in the ITT
analysis and 60 included in the PP analysis.
Protocol deviations
In total, 93 protocol deviations were reported. The most common reason for these was assessments
taking place outside of schedule (45.2%). These typically related to the timing of study questionnaires
at baseline, day 14 and day 28 of follow-up. This might be anticipated, particularly for the follow-up
questionnaires, given this patient population are likely to have multiple hospital attendances related to
continued SACT or management of complications arising from treatment or their underlying disease.
Protocol deviations by number and type across treatment groups are listed in Table 18.
Treatment outcomes
Primary outcome
Both ITT and PP analyses were conducted for the primary outcome measure of treatment failure. It was
pre-specified that equal weighting would be given to both analyses such that a definitive conclusion of
non-inferiority required both analyses to concur. A one-sided 95% confidence limit placed about the
difference in treatment failure rate was compared to the non-inferiority margin of 15%. Conclusion
of non-inferiority required that the upper bound of the one-sided 95% CI placed about the difference
in treatment failure rates (intervention minus control) should not exceed 15% (see Figure 4). The 95%
one-sided confidence limit was derived from the upper bound of a two-sided 90% CI. The Pearson
TABLE 18 Protocol deviations
Treatment group
Category Standard care Intervention (early switch) Total
Eligibility (%) 1 (2.3) 3 (6.1) 4 (4.3)
IMP issues (%) 3 (6.8) 8 (16.3) 11 (11.8)
Assessment outside schedule (%) 19 (43.2) 23 (46.9) 42 (45.2)
Randomisation (%) 1 (2.3) 0 (0) 1 (1.1)
Opportunistic research blood sampling (%) 5 (11.4) 2 (4.1) 7 (7.5)
Other (%) 15 (34.1) 13 (26.5) 28 (30.1)
Total 44 49 93
Analysis Difference (90% CI)
ITT population 0.105 (–0.010 to 0.221)
PP population 0.036 (–0.075 to 0.148)
–.25 –.15 0 .15 .25

Favours intervention Favours standard care
FIGURE 4 Forest plot of differences (90% CI) by analyses performed.
chi-square test was used to test significance of observed differences between trial arms. Table 19
presents the number (%) and the differences in proportions (95% CI) in relation to the primary outcome
in the ITT and PP analyses.
In the ITT analysis, 9 of the 64 patients (14.1%) in the standard care arm met the primary end point of
treatment failure, compared with 15 of 61 (24.6%) in the early oral switch arm. Based on the pre-specified
15% non-inferiority margin, the risk difference of 10.5% (one-sided 95% CI −1% to 22%; p = 0.14) was
such that the intervention was not found to be non-inferior to standard care in the ITT population.
The result of the PP analysis was not consistent with the ITT analysis. In the PP population, 8 of the
60 patients (13.3%) in the standard care arm met the primary end point of treatment failure, compared
with 9 of 53 (17%) in the early oral switch arm. The risk difference of 3.7% (one-sided 95% CI −7% to
14.8%; p = 0.59) was such that the intervention was found to be non-inferior to standard care in the
PP population.
Non-inferiority for the early switch intervention could not be concluded in the absence of concurrence
of both the ITT and PP analyses and, even if concurrence had been demonstrated, findings would remain
TABLE 19 Analyses for the primary outcome in the ITT and PP populations
Standard care (n = 64) Intervention (n = 61) Risk difference (90% CI) p-value
Treatment failure ITT (N = 125)
Yes 9 (14.1%) 15 (24.6%) 0.11 (−0.01 to 0.22) 0.14
No 55 (85.9%) 46 (75.4%)
Treatment failure PP (N = 113)
Yes 8 (13.3%) 9 (17.0%) 0.04 (−0.07 to 0.148) 0.59
No 52 (86.7%) 44 (83.0%)
44

limited due to relative under-powering of the analyses. The main constituents of the composite primary
outcome measure that accounted for patients reaching the treatment failure end point by day 14 were
persistence/recurrence of fever and/or physician-directed escalation from the protocolised antibiotic
regimen. None of the treatment failure events recorded in either arm were attributable to the need for
critical care support or death before day 14. Tables 20 and 21 present the constituents of the primary
outcome measure in the ITT and PP populations, respectively. The number of patients for whom each
component of the composite outcome measure was available is expressed, by trial arm, for that measure
and the p-value given is from significance testing of observed differences between trial arms using the
Pearson chi-square test.
A post hoc exploratory analysis using generalised estimating equations (GEE) to account for possible
clustering of observations within participating centres produced a risk difference (RD; 95% CI) of
0.106 (−0.032 to 0.244); p = 0.13, indicating no significant difference in risk of treatment failure when
examining study site as a random effect.
Secondary outcomes
Among patients for whom secondary outcome data were available, there was a reduction in median duration
of inpatient admission. Time to fever resolution, re-admission to hospital to day 28, survival to day 28, or
changes to the originally intended SACT regimen appeared similar between the two arms (see Table 22).
TABLE 20 Constituents of the composite primary outcome measure leading to patients reaching the treatment failure end
point in the ITT population
Standard care Intervention Difference

(n = 64) (n = 61) (95% CI) p-value
Treatment failure ITT
Yes 9 (14.1%) 15 (24.6%) 0.105 (−0.010 to 0.221) 0.14
No 55 (85.9%) 46 (75.4%)
Persistence/recurrence of fever n = 62 n = 60
(T ≥ 38°C) after 72 hours
of i.v. antibiotic initiation
Yes 4 (6.5%) 10 (16.7%) 0.102 (−0.010 to 0.215) 0.08
No 58 (93.6%) 50 (83.3%)
Physician-directed escalation from protocol-specified antibiotic treatment
Yes 6 (9.4%) 10 (16.4%) 0.070 (−0.047 to 0.187) 0.24
No 58 (90.6%) 51 (83.6%)
Day 14: CCU admission n = 62
Yes 0 (0.0%) 0 (0.0%)
No 62 (100%) 61 (100%)
Day 14: Re-admission to hospital n = 62
Yes 2 (3.2%) 2 (3.3%) 0.001 (−0.062 to 0.063) 0.99
No 60 (96.8%) 59 (96.7%)
Day 14: Patient survival status
Alive 64 (100%) 61 (100%)
Deceased 0 (0.0%) 0 (0.0%)
TABLE 21 Constituents of the composite primary outcome measure leading to patients reaching the treatment failure end
point in the PP population
Standard care (n = 60) Intervention (n = 53 Difference (95% CI) p-value

Treatment failure
Yes 8 (13.3%) 9 (17.0%) 0.036 (−0.075 to 0.148) 0.59
No 52 (86.7%) 44 (83.0%)
Persistence/recurrence of fever (T ≥ 38°C) after 72 hours of i.v. antibiotic initiation
Yes 4 (6.8%) 6 (11.5%) 0.048 (−0.060 to 0.156) 0.38
No 55 (93.2%) 46 (88.5%)
Physician-directed escalation from protocol-specified antibiotic treatment
Yes 5 (8.4%) 5 (9.4%) 0.011 (−0.094 to 0.116) 0.84
No 55 (91.7%) 48 (90.6%)
Day 14: CCU admission n = 58
Yes 0 (0.0%) 0 (0.0%)
No 58 (100%) 53 (100%)
Day 14: Re-admission to hospital n = 58
Yes 2 (3.5%) 2 (3.8%) 0.003 (−0.066 to 0.073) 0.93
No 56 (96.6%) 51 (96.2%)
Day 14: Patient survival status
Alive 60 (100%) 53 (100%)
Deceased 0 (0.0%) 0 (0.0%)
TABLE 22 Secondary outcome measures
Standard Care (n = 64) Intervention (n = 65) p-value

Day 14: time to fever resolution from initial i.v. n = 36 n = 37 0.52
antibiotic administration (hours)a
25.6 (8.5, 46.0) 18.5 (9.5, 39.6)
Day 28: Re-admission to hospital n = 64 n = 61
(related to infection or antibiotic treatment)
Yes 6 (9.4%) 11 (18.0%) 0.16
No 58 (90.6%) 50 (82.0%)
Day 28: Change in subsequent planned SACT n = 61 n = 59
Yes 22 (36.1%) 22 (37.3%) 0.89
No 39 (63.9%) 37 (62.7%)
Day 28: Patient survival statusb n = 62 n = 61
Alive 61 (98.4%) 58 (95.1%) 0.30
Deceased 1 (1.6%) 3 (4.9%)
Duration of inpatient admission (days) a
n = 58 n = 52 0.002
3 (2,4) 2 (2,3)
a Median and interquartile range presented and p-value from Wilcoxon rank-sum test.
b p-value from Pearson chi-square test.
Note
Frequency and percentage presented for treatment arms.
46

Subgroup analyses
Subgroup analyses were pre-planned in the ITT population in the following subgroups: (1) tumour type
(solid tumour vs. haematological malignancy); (2) neutrophil count at randomisation (≤ 0.5 × 109/l vs.
> 0.5 × 109/l) and (3) maximum temperature on the day of presentation (< 38°C vs. > 38°C). A post hoc
subgroup analysis based on blood culture results (positive or negative) was also performed. The first
pre-specified analysis was not undertaken due to the small number of patients with haematological
malignancy enrolled in the study. Risk differences and 99% CI from the treatment × subgroup interaction
models are presented in Table 23 for the remaining subgroups for the primary outcome of TFR. The
p-values presented are from a global test for interaction and indicate no significant interactions.
Safety
Adverse events
In total, 106 AEs were observed from randomisation to the day 14 primary outcome measure end point.
Of these, 46 occurred in the intervention arm. As might be anticipated, gastrointestinal disorders were
the most commonly reported AEs, occurring in 33 patients (25.6%), of whom 12 patients were in the
intervention arm.
There were 29 serious AEs, 12 of which occurred in the intervention arm. Of these, one was fatal but
deemed unrelated to protocolised treatment. Eleven SAEs (8.5%) were due to blood and lymphatic
system disorders, which may have reflected complications arising in patients who received a further
cycle of SACT within the study reporting period.
Overall the AE profiles were similar between intervention and control groups. Table 24 summarises the
total number of AEs, ARs, SAEs, serious adverse reactions (SARs) and SUSARs according to the number
of events/patients by treatment group.
TABLE 23 Subgroup analyses
Treatment group
Treatment failure rate n (%) Standard care Intervention RD (99% CI) Interaction p-value
Neutrophil count at randomisation
≤ 0.5 × 109/l (n = 92) 7 (14.6%) 11 (25.0%) 0.10 (−0.11 to 0.32) 0.51
> 0.5 × 109/l (n = 33) 2 (12.5%) 4 (23.5%) 0.11 (−0.23 to 0.45)
Maximum temperature on the day of presentation
< 38°C (n = 41) 3 (13.0%) 4 (22.2%) 0.09 (−0.22 to 0.40) 0.50
≥ 38°C (n = 84) 6 (14.6%) 11 (25.6%) 0.11 (−0.11 to 0.33)
Positive blood culture
No (n = 99) 7 (13.7%) 11 (22.9%) 0.09 (−0.11 to 0.29) 0.39
Yes (n = 21) 2 (20.0%) 4 (36.4%) 0.16 (−0.33 to 0.66)
48
TABLE 24 Adverse events by treatment group


Number of events Number of patients
Standard Total Standard care Intervention

Total care Intervention (n = 129) (%) (n = 64) (%) (n = 65) (%) RR (95% CI) p-value
AE/AR, Total number of AEs 106 60 46 56 (43.4) 30 (46.9) 26 (40.0) 0.85 (0.57 to 1.27) 0.48
SAE/SAR and
SUSAR Total number of ARs 40 24 16 23 (17.8) 14 (21.9) 9 (13.9) 0.63 (0.30 to 1.36) 0.26
Total number of SAEs 29 12 17 28 (21.7) 12 (18.8) 16 (24.6) 1.31 (0.68 to 2.55) 0.52
Total number of SARs 1 1 0 1 (0.8) 1 (1.6) 0 (0.0)
Total number of events related to 0 0 0

study drug and unexpected (SUSAR)
AEs Blood and lymphatic system 12 6 6 12 (9.3) 6 (9.4) 6 (9.2) 0.98 (0.34 to 2.89) 1.00
disorders
Gastrointestinal disorders 48 31 17 33 (25.6) 21 (32.8) 12 (18.5) 0.56 (0.30 to 1.05) 0.07
General disorders and administration 15 7 8 14 (10.9) 6 (9.4) 8 (12.3) 1.31 (0.48 to 3.57) 0.78
site conditions
Infections and infestations 6 3 3 6 (4.7) 3 (4.7) 3 (4.6) 0.98 (0.21 to 4.70) 1.00
Investigations 8 5 3 4 (3.1) 2 (3.1) 2 (3.1) 0.98 (0.14 to 6.78) 1.00
Musculoskeletal and connective 1 0 1 1 (0.8) 0 (0.0) 1 (1.5)

tissue disorders
Nervous system disorders 5 2 3 5 (3.9) 2 (3.1) 3 (4.6) 1.48 (0.26 to 8.55) 1.00
Psychiatric disorders 1 0 1 1 (0.8) 0 (0.0) 1 (1.5)
Respiratory, thoracic and mediastinal 4 2 2 3 (2.3) 1 (1.6) 2 (3.1) 1.97 (0.18 to 21.18) 1.00
disorders
Skin and subcutaneous tissue 3 2 1 3 (2.3) 2 (3.1) 1 (1.5) 0.49 (0.05 to 5.30) 0.62
disorders
Vascular disorders 3 2 1 3 (2.3) 2 (3.1) 1 (1.5) 0.49 (0.05 to 5.30) 0.62

This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction
DOI: 10.3310/RGTP7112
TABLE 24 Adverse events by treatment group (continued)
Number of events Number of patients
Standard Total Standard care Intervention

Total care Intervention (n = 129) (%) (n = 64) (%) (n = 65) (%) RR (95% CI) p-value
SAEs Blood and lymphatic system 11 6 5 11 (8.5) 6 (9.4) 5 (7.7) 0.82 (0.26 to 2.55) 0.76
disorders
Gastrointestinal disorders 2 1 1 2 (1.6) 1 (1.6) 1 (1.5) 0.98 (0.06 to 15.4) 1.00
General disorders and administration 9 3 6 9 (7.0) 3 (4.7) 6 (9.2) 1.97 (0.51 to 7.54) 0.49
site conditions
Health Technology Assessment 2024 Vol. 28 No. 14

Infections and infestations 3 2 1 3 (2.3) 2 (3.1) 1 (1.5) 0.49 (0.05 to 5.30) 0.62
Investigations 1 0 1 1 (0.8) 0 (0.0) 1 (1.5)
Nervous system disorders 1 0 1 1 (0.8) 0 (0.0) 1 (1.5)
Psychiatric disorders 1 0 1 1 (0.8) 0 (0.0) 1 (1.5)
Respiratory, thoracic and mediastinal 1 0 1 1 (0.8) 0 (0.0) 1 (1.5)

disorders
49
Chapter 6 Health economic and patient

preference analyses
T his chapter contains some text reproduced from ‘Early switch to oral antibiotic therapy in patients
with low risk neutropenic sepsis (EASI-SWITCH): a randomized non-inferiority trial’ published in
Clinical Microbiology and Infection (2023). https://doi:10.1016/j.cmi.2023.07.021.58
Background
A within-trial economic evaluation was performed to assess the cost-effectiveness of early switch to oral
antibiotics compared with usual care in the treatment of NS in patients with cancer. This included a cost-
effectiveness analysis (CEA) consistent with the primary outcome measure to estimate the cost per treatment
failure avoided at day 14 and a CUA to estimate the cost per QALY at day 14. The primary measure used in
these analyses was the QALY, estimated from the EQ-5D-5L questionnaire administered at baseline and at day
14 of follow-up (either in person or using the validated telephone version). In recognition that the EQ-5D-5L
only measures the potential effect on health of an early switch from i.v. to oral antibiotics and does not reflect
patients’ preferences for non-health effects of the intervention, such as early discharge from hospital, a Patient
Follow-up Questionnaire was used to collect additional information on this.
Methods
As the study treatments are for infection, not cancer, a short-term time horizon reduced the chance of
costs and effects being contaminated by the impact of underlying disease or cancer therapy. A 14-day time
horizon was adopted and the analysis was performed from a hospital perspective. Discounting of costs and
outcomes was not necessary due to the time horizon being < 1 year. Patients’ use of hospital resources was
collected over the study period on the case-report form using data from the day 14 interview and review
of medical records, including treatments and medication received during the primary admission and any
associated re-admissions. Costs were calculated by attaching appropriate unit costs from publicly available
sources59–61 (e.g. Department of Health National Schedule of Reference Costs) and are listed in Appendix 6,
Table 38. The final year of data collection was taken as the cost year (2018/2019).
For the CUA patients’ HRQoLs were measured at baseline and at day 14 of follow-up using the EQ-5D-5L
(either in person or using the validated telephone version) and the 3L mapping function62 was used to
convert responses into a single utility value, as currently recommended by NICE.63 The area-under-the-
curve method was used to estimate patient-specific QALYs accrued over the study duration. For the
cost-effectiveness analysis, treatment failures were categorised as described in the previous chapter.
Since the EQ-5D-5L only measures the potential effect on health of an early switch from i.v. to oral
antibiotics and does not reflect patients’ preferences for non-health effects of the intervention, such as early
discharge from hospital, a Patient Follow-up Questionnaire was used to collect additional information on this.
Following database lock, individual patient data were evaluated to measure costs and QALYs related to
early oral switch and standard care. Descriptive statistics were used to summarise the hospital resource
use, associated costs and outcomes as means with 95% CIs for each group. Significance was judged
where the CIs of differential means excluded zero or p < 0.05. The study was powered for the primary
outcome of treatment failure but not for costs, QALYs or cost effectiveness.
The mean differences in costs, treatment failures and QALYs between groups were estimated and
incremental cost-effectiveness ratios (ICERs) were calculated to estimate the cost per QALY gained
Health economic and patient preference analyses
(CUA) and the cost per treatment failure avoided (CEA) and the non-parametric bootstrapping was
used to resample with replacement the cost and outcome data from the original sample to generate
1000 replicate ICERs. These were then plotted on the cost-effectiveness plane to display their joint
distribution. Cost-effectiveness acceptability curves (CEAC) were constructed from the data by
calculating the proportion of the ICER replicates which would be considered cost-effective at various
thresholds of willingness-to-pay (WTP) for an additional QALY and to avoid a treatment failure. In
general NICE consider interventions with an ICER of < £20,000/QALY to be cost-effective;64 however,
no such threshold exists for treatment failures avoided.
The net monetary benefit (NMB) was also used to aid interpretation. The NMB is a summary statistic
representing the value of an intervention in monetary terms when a WTP threshold for a unit of benefit
is known. A positive NMB indicates the intervention is cost-effective. A range of threshold values were
used for each analysis. All analysis was carried out using Stata 15/IC (StatCorp) for Windows®.
Sensitivity analyses
The following sensitivity analyses were performed:
1. In both the CUA and CEA costs and outcomes were adjusted for baseline age, gender and EQ-5D-5L
score using multiple regression.
2. Where missing data levels were > 5% multiple imputation was used to predict missing values. As the
levels of missing data in the CUA for QALYs were 13% (16% intervention, 9% control), QALY data
points were filled using multiple imputation by chained equations and predictive mean matching to
generate 20 imputed data sets. Treatment group, baseline EQ-5D-5L score, age and gender were
entered into the model as predictors of missing data. Multiple imputation was not required for the
CEA as missing data for treatment failures were under 2%.
3. PP analyses were carried out for both the CUA and CEA, including only patients who received treat-
ment as detailed in the protocol and excluding those who did not.
4. An unplanned sensitivity analysis was conducted to exclude a patient in the CEA who had a prolonged
ICU admission.
Non-health outcomes
A follow-up questionnaire was designed to determine what participants thought about the antibiotic
treatment they received and also to find about their hypothetical preferences for future antibiotic
treatment should they develop NS again (see Appendix 7). The questionnaire contained 14 questions,
including questions to measure agreement towards specific statements (agree/disagree/uncertain),
closed questions about treatment choice and home care, and one open-ended question to gather
rationale for preferred treatment method. The number (%) of patients who agree or disagree with each
statement in the questionnaire is presented and analysed.
Results
One hundred and twenty-six patients were eligible for the economic analysis; 62 in the intervention
group and 64 in the standard care group. The results are presented in two parts: the CUA based on
using the QALY as the outcome using complete data; and the cost effectiveness using treatment failures
avoided, also only using complete data. Results using all available data are included in Appendix 8,
Tables 39–41.
Cost–utility analysis
To maintain the correlation structure of the data the primary CUA analysis only included those
participants with complete cost and QALY data, therefore if EQ-5D-5L data were not collected
at baseline and day 14, or cost data were missing, they were excluded. These data were available
for 110 patients (52 in the intervention group and 58 in the standard care group), with a higher
52

proportion in the intervention arm having missing data (16% vs. 9%). Use of hospital services within
14 days of randomisation, including the primary admission and any subsequent re-admission(s), is
presented in Table 25. The mean length of stay in participants’ primary admission was 0.52 days
longer for standard care, as might have been anticipated from an early oral switch intervention. The
mean length of stay during re-admission was less than half for standard care patients compared to
those in the intervention arm. None of the differences between groups were statistically significant.
The corresponding costs of these services, along with drug costs, are presented in Table 26. The additional
time spent as an inpatient led to a mean difference in cost of £250. The mean cost of study drugs was over
TABLE 25 Hospital service use by group with complete cost and QALY data. Values are number (percentages) of patients
using the service and mean (95% CI) use
Intervention (n = 52) Standard care (n = 58)

Mean difference
Service n (%) Mean (95% CI) n (%) Mean (95% CI) (95% CI)
Primary admission
Ward days 52 (100.00) 2.62 (1.99 to 3.24) 58 (100.00) 3.14 (2.71 to 3.57) −0.52 (−1.26 to 0.22)
Emergency- 2 (3.85) 0.04 (−0.02 to 0.09) 2 (3.45) 0.03 (−0.01 to 0.08) 0.00 (−0.07 to 0.08)
department
attendancea
Re-admission
Ward days 4 (7.69) 0.46 (−0.13 to 1.06) 2 (3.45) 0.19 (−0.08 to 0.46) 0.27 (−0.35 to 0.89)
Emergency- 4 (7.69) 0.08 (0.00 to 0.15) 2 (3.45) 0.03 (−0.01 to 0.08) 0.04 (−0.04 to 0.13)
department visits
Outpatient visits 2 (3.85) 0.04 (−0.02 to 0.09) 2 (3.45) 0.03 (−0.01 to 0.08) 0.00 (−0.07 to 0.08)
a Includes patients starting antibiotics in emergency department.
TABLE 26 Cost (£UK) of hospital service use by group inpatients with complete cost and QALY data. Values are mean
(95% CI) costs
Mean cost £ (95% CI) Mean cost £ (95% CI) Mean difference (95% CI)
Primary admission
Ward days 1250.81 (951.16 to 1550.46) 1500.72 (1294.76 to 1706.67) −249.91 (−603.17 to 103.35)
Emergency- 7.54 (−3.06 to 18.13) 6.76 (−2.73 to 16.24) 0.78 (−13.24 to 14.80)
department attendance
Re-admission
Ward days 220.73 (−63.81 to 505.27) 90.70 (−37.14 to 218.55) 130.03 (−167.57 to 427.63)
Emergency- 15.08 (0.39 to 29.76) 6.76 (−2.73 to 16.24) 8.32 (−8.61 to 25.25)
department visits
Outpatient visits 5.19 (−2.11 to 12.49) 4.66 (−1.88 to 11.19) 0.54 (−9.12 to 10.19)
Medication
Study drug 52.18 (44.00 to 60.35) 83.19 (68.68 to 97.70) −31.01 (−48.00 to −14.02)
Concomitant 13.34 (2.33 to 24.35) 33.40 (2.02 to 64.77) −20.06 (−54.44 to 14.33)
medication
Total 1564.86 (1171.52 to 1958.21) 1726.18 (1453.16 to 1999.19) −161.31 (−626.74 to 304.11)
£30 higher in the standard care arm, due to the lower unit cost of ciprofloxacin and co-amoxiclav, and the
difference was statistically significant. The mean total cost was £1726 in the standard care arm compared
to £1565 for intervention, a mean difference of £161, which was not statistically significant.
Mean HRQoL scores are reported in Table 27. There were no significant differences in baseline or
follow-up scores in EQ-5D-5L or visual analogue scale. Both measures showed increases in both groups
by similar amounts, with the base figure being higher in the intervention arm for each method. The
incremental QALY gain was small and not statistically significant: 0.002 QALYs is equivalent to 0.73 days
in full health per year, but given that the follow-up period was 14 days, any difference would be small.
Although the differences are small, in cases such as this where the intervention is cost-saving and leads
to more positive outcomes the intervention is said to be the dominant strategy (see Table 28). The ICER
is not calculated as it would be a negative and would not convey any meaning.65 Figure 5 demonstrates
the result of the bootstrapped ICERs and the majority of points fall in the south-east quadrant, indicating
that in the majority of cases the intervention is associated with cost savings and QALY gains, albeit small
and not statistically significant. The CEAC in Figure 6 shows at a WTP threshold of £20,000/QALY there
is a 78% probability the intervention is cost-effective compared to standard care. The NMB was positive
TABLE 27 Health-related quality-of-life scores by group (patients with complete cost and QALY data). Values are mean
(95% CI) scores
Variable Mean (95% CI) Mean (95% CI) Difference (95% CI)
EQ-5D-5L utilities
Baseline 0.78 (0.71 to 0.84) 0.74 (0.68 to 0.80) 0.03 (−0.05 to 0.12)
14 days 0.82 (0.77 to 0.87) 0.77 (0.72 to 0.82) 0.05 (−0.03 to 0.12)
EQ-5D VAS
Baseline 65.94 (59.99 to 71.90) 59.31 (53.97 to 64.65) 6.63 (−1.25 to 14.52)
14 days 76.12 (71.13 to 81.10) 69.98 (65.37 to 74.60) 6.13 (−0.58 to 12.84)
QALYs 1 (0.029 to 0.032) 0.029 (0.027 to 0.031) 0.002 (−0.001 to 0.004)
TABLE 28 Results of the cost–utility analyses at 14 days (1000 bootstrap samples)
Mean incremental total health Mean incremental QALY Incremental cost-

service costs (£) (95% CI) gain (95% CI) effectiveness ratioa
Primary analysis −161.31 (−630.59 to 307.96) 0.002 (−0.001 to 0.004) Dominant strategy
(nI = 52, nSC = 58)
Sensitivity analysis – controlling −125.45 (−612.33 to 361.44) 0.001 (−0.000 to 0.002) Dominant strategy
baseline characteristics
(nI = 52, nSC = 58)
Sensitivity analysis – multiple 18.42 (−520.09 to 556.93) 0.001 (−0.001 to 0.004) £11,437.45
imputation of QALY values
(nI = 62, nSC = 64)
PP analysis −319.70 (−795.55 to 156.16) 0.002 (−0.001 to 0.004) Dominant strategy

(nI = 45, nC = 54)
nC, number analysed in standard care arm; nI, number analysed in intervention arm.
a Values not presented for negative ICERs.
54

FIGURE 5 Cost-effectiveness plane for the primary cost–utility analysis showing 1000 bootstrapped replications of mean incremental costs and QALY gain and the willingness-to-pay
0.010
WTP threshold
£20,000/QALY
costly and more effective
costly and more effective

NE: Intervention more
SE: Intervention less

than standard care
than standard care
0.005
Incremental QALYs
-
costly and less effective
NW: Intervention more
SW: Intervention less costly
–0.005
than standard care
and less effective than

standard care
–0.010
£1500
£1250
£1000
£750
£500
£250
£0
–£250
–£500
–£750
–£1000
–£1250
–£1500
threshold of £20,000/QALY.
Incremental costs
100%
90%
80%
Probability that intervention is cost-effective
70%
60%
Primary analysis
Controlled for baseline
50%
Multiple imputation
40% Per protocol
30%
20%
10%
0%
£0 £5000 £10,000 £15,000 £20,000 £25,000 £30,000 £35,000 £40,000 £45,000 £50,000
Willingness to pay per QALY gain (£)
FIGURE 6 Cost-effectiveness acceptability curves showing the probability of intervention being cost-effective compared
to standard care for the primary and sensitivity analyses using QALYs as the outcome.
for all WTP thresholds (see Table 29), indicating the intervention was cost-effective compared to standard
care, while the CEAC constructed (see Figure 7) from this method showed a marginal difference in cost-
effectiveness probability (79%).
Sensitivity analyses (cost–utility analysis)

The results of the sensitivity analyses in the CUA are presented in Table 29. Adjusting for baseline
characteristics (age, gender, baseline EQ-5D-5L score) reduced the size of the difference in costs, but the
intervention arm still exhibited a lower mean cost and positive outcomes, and so remained dominant.
Using multiple imputation to estimate QALY scores for those not completing the EQ-5D-5L at day
14 resulted in the intervention arm’s mean cost being more than £18 higher than standard care and
a slight increase in QALYs. This generated an ICER of £11,437/QALY, and a 54% probability of being
cost-effective at a ceiling ratio of £20,000/QALY, much lower than the primary analysis, which can be
partly attributed to the reversal in total costs. Those receiving the intervention who were missing these
follow-up data were much heavier resource users than their counterparts and due to incomplete data
were not included in the primary analysis.
TABLE 29 Incremental net benefit at various willingness-to-pay thresholds per QALY gained
Willingness to pay per additional QALY Incremental net benefit (mean, 95% CI)
£0 161.31 (−304.11 to 626.74)
£1000 162.83 (−303.16 to 628.81)
£5000 168.87 (−299.51 to 637.25)
£10,000 176.43 (−295.24 to 648.11)
£20,000 191.55 (−287.71 to 670.82)
£50,000 236.91 (−272.52 to 746.34)
56

100%
90%
80%
70%
60%
50% NMB QALY
40%
30%
20%
10%
0%
£0 £5000 £10,000 £15,000 £20,000 £25,000 £30,000 £35,000 £40,000 £45,000 £50,000
Willingness to pay per QALY gain (£)
FIGURE 7 Cost-effectiveness acceptability curve showing the probability of intervention being cost-effective compared to
standard care using the net monetary benefit method.
The PP analysis showed the intervention to once again be the dominant option. The difference in QALYs
remained small but the intervention was shown to be almost £320 less costly than standard care, with
the revised CEAC estimating a 93% probability of the intervention being cost-effective (see Figure 6).
Cost-effectiveness analysis
Complete data were available for 124 patients (98%) for this analysis (100% standard care, 97%
intervention), resulting in a slightly different population to the CUA. Table 30 shows the use of hospital
resources. For those re-admitted to ward, the mean length of stay was more than double for intervention
patients, 0.4 compared to 0.17 days, in part due to two of these patients both remaining hospitalised
for 11 days. Notably in the intervention arm, one patient was transferred to critical care 5 days after
starting antibiotics and was still there at the 14 day follow-up. This patient was excluded from the CUA
as they did not complete the EQ-5D-5L at day 14.
Costs of hospital resources and drugs are illustrated in Table 31. As was the case in the CUA, the
difference in cost of study drug is statistically significant. Total costs were on average £22 higher in the
intervention arm using these data – a difference that was not statistically significant.
In contrast to the CUA, these data have shown the cost to be marginally greater in the intervention
arm, and the outcome to be negative due to higher treatment failure rate (see Table 32), although no
differences were statistically significant. When this occurs the intervention is dominated by standard
care. Figure 8 shows a large percentage of the bootstrapped ICERs in the north-west quadrant with
higher costs and negative outcomes. As before, negative ICERs have not been calculated.
There is no generally accepted WTP threshold for treatment failure avoided but the CEAC (see
Figure 9) shows the probability of being cost-effective at varying amounts: at £1000 it was 36%,
decreasing to 13% at £10,000. The CEAC does not cut the y-axis as some of the joint density includes
cost savings (SE and SW quadrants of Figure 8) and asymptotes to zero because the density does not
involve health gains.66
58

TABLE 30 Hospital resource use by group in patients (complete cost and treatment failure data). Values are number (percentages) of patients using the service and mean (95% CI) use
Service n (%) Mean (95% CI) n (%) Mean (95% CI) Mean difference (95% CI)
Primary admission
Ward days 60 (100.00) 2.78 (2.18 to 3.38) 64 (100.00) 3.17 (2.73 to 3.61) −0.39 (−1.12 to 0.34)
Critical care days 1 (1.67) 0.15 (−0.15 to 0.45) 0 (0) - 0.15 (−0.14 to 0.44)
Emergency department 2 (3.33) 0.03 (−0.01 to 0.08) 2 (3.13) 0.03 (−0.01 to 0.08) 0.00 (−0.06 to 0.07)
Re-admission
Ward days 4 (6.67) 0.40 (−0.11 to 0.91) 2 (3.13) 0.17 (−0.07 to 0.41) 0.23 (−0.32 to 0.78)
Emergency-department visits 4 (6.67) 0.07 (0.00 to 0.13) 2 (3.13) 0.03 (−0.01 to 0.08) 0.04 (−0.04 to 0.11)
DOI: 10.3310/RGTP7112
TABLE 31 Cost of hospital service use by group in patients (complete cost and treatment failure data). Values are mean (95% CI) costs
Primary admission
Ward days 1331.13 (1044.22 to 1618.03) 1516.95 (1307.80 to 1726.10) −185.82 (−534.10 to 162.46)
Critical care 139.98 (−140.12 to 420.07) 0 139.98 (−128.25 to 408.21)
Emergency department 6.53 (−2.63 to 15.70) 6.13 (−2.46 to 14.71) 0.41 (−12.01 to 12.83)
Re-admission
Ward days 191.30 (−54.95 to 437.55) 82.20 (−33.52 to 197.91) 109.10 (−154.78 to 372.98)

Emergency-department visits 13.07 (0.33 to 25.80) 6.13 (−2.46 to 14.71) 6.94 (−8.09 to 21.97)
Medication
Concomitant medication 20.29 (3.54 to 37.05) 40.26 (7.84 to 72.68) −19.97 (−56.83 to 16.89)
Total 1759.08 (1283.51 to 2234.65) 1736.68 (1466.92 to 2006.44) 22.40 (−510.16 to 554.96)
59
TABLE 32 Results of the cost-effectiveness analyses at 14 days (1000 bootstrap samples)
Mean incremental total health Incremental treatment Incremental cost-

Analysis service costs (£) (95% CI) failures avoided (95% CI) effectiveness ratioa
Treatment failure avoided – 22.40 (−508.92 to 553.71) −0.09 (−0.23 to 0.05) Dominated by
primary analysis standard care
(nI = 60, nSC = 64)
Sensitivity analysis – controlling 122.87 (−461.66 to 707.41) −0.10 (−0.25 to 0.04) Dominated by
baseline characteristics standard care
(nI = 60, nSC = 64)
Sensitivity analysis – excluding −131.57 (−579.67 to 316.53) −0.08 (−0.22 to 0.06) £1650.22
patient who had prolonged
ICU admission
(nI = 59, nSC = 64)
PP analysis −149.44 (−694.28 to 395.39) −0.02 (−0.15 to 0.11) £7285.40

(nI = 52, nSC = 60)
nC, number analysed in standard care arm; nI, number analysed in intervention arm.
a Negative ICER values not presented.
£1000
NW: Intervention more
costly and less effective NE: Intervention
£800 more costly and
than standard care
more effective than
£600 standard care
£400
£200
Incremental costs
£0
–£200
–£400
–£600
–£800 SW: Intervention less costly and

less effective than standard care SE: Intervention less
–£1000 costly and more effective
than standard care
–£1200
–0.40 –0.35 –0.30 –0.25 –0.20 –0.15 –0.10 –0.05 0.00 0.05 0.10 0.15
Incremental treatment failures avoided
FIGURE 8 Cost-effectiveness plane for the primary cost-effectiveness analysis showing 1000 bootstrapped replications of
mean incremental costs and treatment failures avoided.
When using NMB at varying thresholds of WTP, the result was positive (meaning the intervention is
cost-effective) for values up to £240/treatment failure avoided, and negative from £250 and above (see
Table 33). The CEAC using NMB data (see Figure 10) showed a 39% probability of the intervention being
cost-effective over standard care at a WTP threshold of £1000/treatment failure avoided.
60

100%
90%
80%
70%
60% TFR analysis

TFR - controlled for baseline
50% TFR - excluding patient with
prolonged ICU admission
40% TFR per protocol
30%
20%
10%
0%
£0 £5000 £10,000 £15,000 £20,000 £25,000 £30,000 £35,000 £40,000 £45,000 £50,000
Willingness to pay per treatment failure avoided (£)
FIGURE 9 Cost-effectiveness acceptability curves showing the probability of intervention being cost-effective compared
to standard care for the primary and sensitivity analyses, using treatment failure rate as the outcome.
TABLE 33 Incremental net benefit at various willingness-to-pay thresholds per treatment failure avoided
Willingness to pay for treatment failure avoided Incremental net benefit (mean, 95% CI)
£0 22.40 (−510.16 to 554.96)
£200 3.86 (−515.83 to 523.55)
£250 −0.78 (−517.43 to 515.88)
£1000 −70.31 (−551.19 to 410.57)
£10,000 −904.68 (−2122.83 to 313.46)
£20,000 −1831.77 (−4384.27 to 720.73)
Sensitivity analyses (cost-effectiveness analysis)

For all sensitivity analyses, there continued to be no statistically significant differences in costs or
outcomes. Baseline characteristics (age, gender, baseline EQ-5D-5L score) were adjusted for using
multiple regression. The overall decision was unchanged: the incremental costs were five times higher
than in the primary analysis, and outcomes were slightly more negative, and so the intervention was
dominated by standard care (as previously presented in Table 32). When the analysis was performed
excluding the patient who had a prolonged ICU admission the results showed although there were more
treatment failures in the intervention arm, it was also now on average £132 less expensive per patient
compared to standard care, giving an ICER of £1650.52 per treatment failure avoided. This turnaround
in mean costs shows how heavily the primary analysis was influenced by this one high resource user. The
adjusted CEAC exhibits increased probability of the intervention being cost-effective at all thresholds; at
a threshold of £1000/treatment failure avoided it increases to 57%.
The PP analysis also showed the intervention arm to be less expensive by almost £150 per patient and
although there were still on average more treatment failures in this arm (0.02), it was less than in the
primary analysis. The probability of the intervention being cost-effective increased to 68% at a threshold
of £1000/treatment failure avoided.
100%
90%
80%
70%
60%
50% NMB TFR
40%
30%
20%
10%
0%
£0 £5000 £10,000 £15,000 £20,000 £25,000 £30,000 £35,000 £40,000 £45,000 £50,000
Willingness to pay per treatment failure avoided (£)
FIGURE 10 Cost-effectiveness acceptability curve showing the probability of intervention being cost-effective compared
to standard care using the net monetary benefit method.
Patient preferences
A total of 114 patients (60 in the standard care group and 54 in the intervention group) provided responses,
with slightly fewer for probability-based questions. The overwhelming majority of patients (95%) in
both arms were satisfied with the care received and level of hospital support, and were happy with their
method of treatment, believing it to be effective (see Table 34). Approximately, 70% of patients in each arm
disagreed that they were concerned their treatment would not work beforehand and a total of 16 patients
were concerned about how treatment for NS would affect family and friends (intervention 15%; standard
care 13%). Of these 16, 88% would be willing to accept the risk of re-admission (15%) for early discharge,
and 81% said they would still accept the risk even if this doubled to 30%, indicating a strong preference to
be discharged as soon as possible.
A greater proportion of those in the intervention arm thought it was important to be discharged 1–2 days
earlier, 59% in comparison to 35% in the control arm (see Table 35). This shows a tendency for patients to
choose the response in keeping with the treatment they actually received. Patients in both arms agreed
it was important not to be re-admitted to hospital although with slightly more in the intervention group
agreeing this (85% vs. 72%). The majority of patients in both groups agreed they would accept some risk of
re-admission in order to be discharged early (72% in the intervention group and 65% in the control group).
When asked which treatment they would choose, 71% of patients in the intervention arm said they would
choose the early switch to oral antibiotics, compared with 46% of standard care patients, again suggesting
allegiance to the treatment received.
When presented with the hypothetical scenario of risk of re-admission doubling from 15% to 30%, 74%
and 64% of intervention and standard care patients respectively would still opt for early discharge.
62

TABLE 34 Patient satisfaction and experience, by group
Statement Intervention (n = 54), n (%) Standard care (n = 60), n (%)
Satisfied with care received
Agree 52 (96.30) 59 (98.33)
Disagree 0 (0) 0 (0)
Uncertain 2 (3.70) 1 (1.67)
Satisfied with level of hospital support
Agree 53 (98.15) 58 (96.67)
Disagree 1 (1.85) 1 (1.67)
Uncertain 0 (0) 1 (1.67)
Believe treatment received was effective
Agree 52 (96.30) 57 (95.00)
Disagree 0 (0) 0 (0)
Uncertain 2 (3.70) 3 (5.00)
Happy with the place treatment received
Agree 53 (98.15) 58 (96.67)
Disagree 0 (0) 1 (1.67)
Uncertain 1 (1.85) 1 (1.67)
Concerned beforehand that treatment would not work
Agree 6 (11.11) 10 (16.67)
Disagree 38 (70.37) 41 (68.33)
Uncertain 10 (18.52) 9 (15.00)
Concerned beforehand how treatment would affect family/friends
Agree 8 (14.81) 8 (13.33)
Disagree 42 (77.78) 43 (71.67)
Uncertain 4 (7.41) 9 (15.00)
There was some evidence of completion errors regarding these hypothetical risk-based questions
observed in a small number of responses, showing some difficulty in understanding and interpreting
these scenarios.
In both groups, the bulk of respondents did not receive home care on a daily basis or have
dependents, as shown in Table 36. Of the 24 participants who stated they receive daily care at home,
there was a strong inclination to get home: 22 (92%) would accept the risk to be discharged early;
19/22 (86%) would accept the higher risk of re-admission in order to be discharged early. There
were seven patients who said they received daily care at home as well as having to care for children
or dependents.
TABLE 35 Patient preferences and risk-based decision-making, by group
Statement n Intervention, n (%) n Standard care, n (%)
Important to be discharged 1–2 days early 54 60
Agree 32 (59.26) 21 (35.00)
Disagree 9 (16.67) 25 (41.67)
Uncertain 13 (24.07) 14 (23.33)
Important to not be re-admitted to hospital for 54 60

further treatment
Agree 46 (85.19) 43 (71.67)
Disagree 7 (12.96) 16 (26.67)
Uncertain 1 (1.85) 1 (1.67)
Willing to accept small risk of re-admission if it meant 54 60

discharge 1–2 days early
Agree 39 (72.22) 39 (65.00)
Disagree 7 (12.96) 11 (18.33)
Uncertain 8 (14.81) 10 (16.67)
Preferred method of treatment for NS: 52 57
i.v. in hospital for at least 48 hours then switch to oral 15 (28.85) 31 (54.39)
i.v. in hospital for 12–24 hours then switch to oral 37 (71.15) 26 (45.61)
If the risk of re-admission increased from 15% to 30%, 53 56

would you choose to be discharged 1–2 days sooner?
Yes 39 (73.58) 36 (64.29)
No 14 (26.42) 20 (35.71)
TABLE 36 Home-based factors, by group
Do you receive care in your home on a daily basis?
Yes 13 (24.07) 11 (18.33)
No 41 (75.93) 49 (81.67)
Do you have children or dependents you care for?
Yes 16 (29.63) 15 (25.00)
No 38 (70.37) 45 (75.00)
Conclusion
The primary CUA showed that although the early switch to oral antibiotics led to small gains in HRQoL
and small cost savings the differences were not statistically significant. The probability of the intervention
being cost-effective was highest for all WTP thresholds in the PP sensitivity analysis. Although two
subsequent sensitivity analyses estimated the intervention as slightly more costly than standard care, the
ICERs were favourable (well under £20,000/QALY). There was a higher number of treatment failures in the
intervention group within the CEA, meaning the intervention was dominated by standard care. However,
64

subsequent analysis removing a high resource outlier showed a small and not statistically significant cost
saving for those receiving the intervention. This one patient, who had a prolonged ICU episode for an
uncommon condition that was not related to treatment allocation in this trial, appeared to bias the costs
allocated to the intervention arm. Given that this patient was not representative of patients with low-risk
NS, it was felt appropriate to consider the effect of removing this patient’s data.
The results of the CUA and CEA are not consistent, which may reflect the difference in individual
patient data used in the analyses as a result of missing data. While the CEA showed a greater number of
treatment failures in the intervention arm, there was a small but not statistically significant gain in QALYs
for this arm. This can be seen by the large number of bootstrapped ICERs in the NE and SE quadrants
of Figure 5, suggesting the intervention did indeed impact on patient HRQoL, albeit in a small way.
Interestingly the incremental QALYs went in the opposite direction to incremental treatment failures.
Although the trial was unable to conclude that the intervention is non-inferior to standard care, the CUA
showed both treatments had a similar impact on HRQoL. Therefore, although treatment failures as the
primary outcome are clinically important and relate to the intended purpose of treatment for NS, these
are not synonymous with HRQoL, as reflected in patient EQ-5D-5L responses, presenting a disparity
between what is valued by clinicians and patients.
The aim of the patient preference questionnaire was to elicit preferences for non-health outcomes,
and the responses showed the majority of patients were content with the treatment they received,
regardless of the group they were randomised to. This suggests both treatment options for NS are
acceptable to patients, and could support clinicians in helping patients make choices. Patients who were
worried about how their treatment would affect family and those receiving care at home were found to
be more prepared to accept higher levels of risk of re-admission in order to have an earlier discharge.
These data were particularly revealing since they indicate that patients have a much higher tolerance for
the possibility of treatment failure in order to enable early discharge for their primary admission.
A major strength of these analyses was the choice of perspective. By taking a hospital perspective, it
meant there was the ability to collect daily data and details of any re-admissions using hospital records.
The short follow-up duration also meant less of a burden for research staff and resulted in complete
cost data for all patients. There was complete QALY data for 87% of patients and over 90% of patients
provided responses to the patient preference questionnaire.
The health economics analysis had some limitations. Firstly, due to the challenges of collecting outcome
measures from patient questionnaires versus routine data retrieval from hospital records, there was a
higher number of patients with complete data for analysis in the CEA compared to the CUA (n = 124 and
n = 110, respectively). The impact on staff time reduction for administration of oral versus i.v. antibiotics
was not assessed, as given the time difference of only 24 hours, differences would be small. However, the
additional time spent in hospital and associated costs per hospital bed already includes staff costs. The
preferences questionnaire was administered mostly over the phone at day 14 (unless the patient had not
been discharged or had a visit), and given the complexity of some of the questions, processing them could
understandably lead to completion errors. To minimise error and increase acceptability, there is a need to
aid patients’ understanding of risk. This may have wider implications in relation to the consent process
in trials and practice, and considering whether or not risk has been satisfactorily explained to patients or
those consenting on their behalf. Furthermore, it would be preferable if patients were asked for treatment
preference before allocation as the results showed an allegiance to the assigned method and may have
been biased by patients’ experience of treatment.
Chapter 7 Discussion
Aim of the study
The NICE guidance in 2012 provided the first UK consensus guideline for treatment of NS while also
highlighting a number of outstanding questions regarding optimal management. NICE were unable to
recommend switching from empirical i.v. to oral antibiotics at < 48 hours even in patients at low risk
of infective complications because of uncertainty about whether this achieved comparable outcomes
to standard practice of longer-duration i.v. antibiotics. To bridge this evidence gap, the EASI-SWITCH
trial, commissioned by the UK NIHR, aimed to provide a definitive randomised trial evaluating the
effectiveness of early oral switch in low-risk NS patients.
Main findings and interpretation of results
The within-trial review of NS management enabled an evaluation of current management of NS in

the UK following publication of the NICE guidance, showing many local policies had been updated to
accurately reflect many of the recommendations. Clinicians also reported standard clinical practice
that appears to be compliant with many of the key aspects of the guidance but there appear to be no
standardised sepsis diagnostic criteria in widespread use and instead there is a range of approaches to
incorporating infectious/sepsis criteria into NS diagnostic and care pathways. There has been increased
use of routine risk assessment and consideration of early outpatient oral antibiotics for low-risk patients
but there appears to be a wide range of approaches to risk stratification, duration of treatment and
discharge from hospital. Consequently, despite challenges with recruitment, there was support for
continuation of EASI-SWITCH from clinicians across the UK due to its potential impact on current UK
practice. For clinicians and centres that already considered early oral antibiotics and discharge it was
felt the trial had the potential to validate their practice evolution and make a compelling argument for
further acute oncology service investment and modernisation.
Despite this support, recruitment remained challenging, resulting in early termination of the trial.
Multisite trial activity in the area of low-risk NS has been challenging to deliver in the UK. Prior to the
EASI-SWITCH trial, the ORANGE trial (ORal Antibiotics for Neutropenic sepsis Giving Early hospital
discharge), which opened in August 2007, aimed to evaluate immediate upfront oral antibiotic therapy
in low-risk NS patients,67 but closed in 2009 due to poor recruitment (27 patients registered and 12
randomised). The trial team reported that recruitment of investigator sites and patients was extremely
difficult, with sites unable to participate due to local admission and care pathways and conflicting clinical
management and local antibiotic protocols.68 While these barriers were overcome to some degree within
EASI-SWITCH, similar themes emerged from the surveys and interviews undertaken during the trial and
it is likely that a combination of these challenges and a shift in equipoise as the trial progressed towards
upfront or early oral therapy for patients with NS resulted in the plateau in accrual seen prior to closure.
The consequence of the smaller than anticipated sample size is that non-inferiority for early oral switch
cannot be proven. The conflicting results of the ITT and PP analyses for the primary outcome may
reflect this but also highlight the potential for analysis of different patient data sets to deliver conflicting
results. Because of this potential, we determined a priori that a firm conclusion on the non-inferiority
of the intervention would be reached only if both the ITT and PP analyses were in agreement. While
analysis of either population alone may lead to bias, there is particular potential for increased risk of
bias in ITT analyses due to non-adherence to treatment or deviations from the protocol resulting in a
higher likelihood of concluding non-inferiority incorrectly.69,70 Within our data set, of the 11 ITT patients
who were excluded from the PP population, 8 had been allocated to the intervention arm; of these,
4 had their antibiotic treatment stopped prematurely, 2 had substantial interruption to treatment (at
Discussion
least two consecutive missed doses), and 1 had less than the minimum of 12 hours initial i.v. treatment.
The three excluded patients in the standard care arm had received < 48 hours of i.v. antibiotics. As the
ITT population included these patients, who did not receive the complete protocolised intervention,
an ITT analysis risks underestimating the efficacy of the intervention; by comparison a PP analysis may
overcome this issue.
The trial was pragmatic in design; decisions such as non-blinding of patients and staff were guided by
the opportunity to assess the effect of early switch on timing of hospital discharge as well as advice
from our patient representatives that blinding was unlikely to be maintained in the course of patient
care. Open-label treatment has the potential to introduce performance bias; in this instance it may be
that physicians have a lower threshold for antibiotic escalation from oral therapy, resulting in treatment
failure and risk of bias towards concluding inferiority of the intervention. Similarly, non-blinding of
outcome assessment risks introduction of detection bias; however, the components of the composite
outcome measure were largely objective measurements of treatment failure rather than subjective
components or qualitative measures.
While non-inferiority of early switch could not be proven within this trial, it may be that an early switch
approach results in a shorter initial admission for treatment of NS although with the trade-off that the
risk of re-admission for treatment failure is more likely than with standard care therapy. Reassuringly,
and accepting the smaller than anticipated sample size, the risk of treatment failure and requirement
for antibiotic treatment escalation or re-admission with early switch was not associated with serious
consequences in terms of critical care admission or death. AEs were generally as anticipated in this
patient population and were reported at similar rates between the early oral switch and standard care
groups. Overall, therefore, it would seem that early switch could be a safe management option for
selected patients with low-risk NS.
Although the results did not permit a definitive conclusion on clinical efficacy of early oral switch in
relation to treatment failure, there were small, albeit not significant, gains in HRQoL and patients found
it an acceptable treatment approach. While the primary outcome measure of treatment failure is clearly
an important efficacy outcome for clinicians and patients, the observed increased rate of treatment
failure in the early switch arm was not reflected in the HRQoL results, highlighting the differences in
outcome measures valued by clinicians and patients.
The results suggest that early oral switch may be a cost-effective approach within existing NHS NS care
pathways. The primary CUA showed the early switch to oral antibiotics led to small, non-significant cost
savings and improvements in HRQoL compared to standard care. The probability of the intervention
being cost-effective was highest for all WTP thresholds in the PP sensitivity analysis. Although two
subsequent sensitivity analyses estimated the intervention as slightly more costly than standard care,
the ICERs were favourable (well under £20,000/QALY). There was a higher number of treatment
failures in the intervention group within the CEA, meaning the intervention was dominated by standard
care. However, subsequent analysis removing a high resource outlier showed a small, non-significant
cost saving for those receiving the intervention. A major strength of these analyses was the choice of
perspective. By taking a hospital perspective, it meant there was the ability to collect daily data and
details of any re-admissions using hospital records. The short follow-up duration also meant less of
a burden for research staff and resulted in complete cost data for all patients. However, due to the
challenges of collecting outcome measures from patient questionnaires versus routine data retrieval
from hospital records, there was a higher number of patients with complete data for analysis in the CEA
compared to the CUA (n = 124 and n = 110, respectively), with complete QALY data for 87% of patients.
In addition to global HRQoL, a patient preference questionnaire was used to better understand the
non-health outcome measures that are important to patients and their willingness to accept different
treatment approaches in NS management. Over 90% of patients provided responses to the patient
preference questionnaire, and the responses showed the majority of patients were content with the
68

treatment they received, regardless of the group they were randomised to. Patients who were worried
about how their treatment would affect family and those receiving care at home were found to be
more prepared to accept higher levels of risk of re-admission in order to have an earlier discharge. This
approach did have some limitations. The preferences questionnaire was administered mostly over the
phone at day 14 (unless the patient had not been discharged or had a visit), and given the complexity of
some of the questions, processing them could understandably lead to completion errors. To minimise
error and increase acceptability, there is a need to aid patients’ understanding of risk. This may have
wider implications in relation to the consent process in trials and practice, and considering whether or
not risk has been satisfactorily explained to patients or those consenting on their behalf. Furthermore, it
would preferable if patients were asked for treatment preference before allocation as the results showed
an allegiance to the assigned method and may have been biased by patients’ experience of treatment.
However, overall the data are revealing, indicating that patients have a much higher acceptance of the
possibility of treatment failure in order to enable early discharge for their primary admission than might
have been anticipated by clinicians.
Conclusion
A definitive conclusion about the clinical effectiveness of early switch to oral antibiotics in low-risk NS
was unable to be reached from the study findings due to the limited sample size.
While non-inferiority of early oral switch could not be definitively concluded, it may be that early switch
results in a shorter initial duration of hospitalisation for treatment of low-risk NS. However, it is uncertain
whether there is a consequent increased likelihood of re-admission to hospital compared to standard
care treatment.
Treatment failure or requirement for antibiotic escalation or re-admission was not associated with
serious outcomes such as critical care admission or death. There was no unexpected or increased risk of
AEs observed with early switch compared to standard care.
There were small, non-significant gains in HRQoL for early oral switch and patients found it acceptable.
Patients, particularly those with caregiver roles, were more prepared to accept the higher levels of risk of
re-admission in order to have an earlier discharge.
Given the findings, early oral switch may be an acceptable strategy for some patients who can adhere
to such a regimen and would prefer reduced duration of hospitalisation while accepting a potentially
increased risk of treatment failure, resulting in re-admission to hospital.
Implications for future research
EASI-SWITCH is the first UK multicentre RCT comparing early oral switch to the NICE recommendation
of 48 hours i.v. antibiotic therapy in low-risk NS. Delivery of the trial has highlighted the difficulties
with recruitment of patients to trials in the unscheduled care setting. Evidence supporting specific
interventions to improve recruitment in this setting is lacking71 and further work evaluating strategies
such as verbal provision of trial information and obtaining verbal consent is warranted across supportive
care trials in cancer patients, not just in the setting of NS.
A number of specialist cancer centres in the NHS have already established acute oncology services and/
or ambulatory care pathways to deliver early oral switch or upfront oral antibiotics.39–41 This results in
tension between delivering prospective trials evaluating management approaches for NS and accepting
that current ambulatory care pathways or antimicrobial strategies utilising upfront or early switch to
oral antibiotics are typically applied to highly selected patient populations. This shift in practice and our
Discussion
experience in delivering this trial, accompanied by the declining NS rates, suggest further randomised
trials in this patient population will remain challenging to recruit to. However, it is clear there remains
scope to optimise and unify management strategies for low-risk NS, in particular how best to identify
patients suitable for a de-escalation or ambulatory care approach from initial presentation. While the
MASCC score remains the most widely used within specialist cancer centres, others have reported that
stratification tools such as MASCC score or CISNE are too cumbersome to be applied in real-life ED
practice.46 Other scores that encompass ‘clinical judgement’ are similarly felt less applicable in ED or
acute medical settings than validated decision rules or algorithms. Further research should explore tools
for patient stratification for low-risk de-escalation or ambulatory pathways, including use of biomarkers
and/or point-of-care rapid viral, bacterial and fungal testing as an adjunct to clinical decision-making
tools. This could include application to shorter-duration antimicrobial therapy in line with antimicrobial
stewardship studies in other settings.
Evaluation of any future stratification tools, treatment strategies or ambulatory care pathways should
include a formal economic analysis in addition to assessment of clinical efficacy. This is particularly
important where novel algorithms or ambulatory care pathways are established but restricted to
specialist oncology services rather than general acute care or ED settings.
The EASI-SWITCH trial has highlighted the importance of patients’ perspectives in setting research
questions that encompass patients’ willingness to accept risk of treatment failure as a trade-off for
less intensive treatment and shorter duration of admission. The results of the patient preference
questionnaire could be used as a precursor for designing a future discrete-choice experiment to assess
patient preferences for treatment for NS. This method is used in eliciting strength of preferences in
health care by presenting hypothetical choices varying treatment options and levels of key attributes
(e.g. life expectancy, side effects), and in doing so respondents make trade-offs.72 They have been
effectively used in other cancer populations73 and it has been long thought by experts that NICE should
recommend their use in incorporating patient preferences,74 but while their US counterparts the FDA
have endorsed their use, NICE have yet to do so.
70

Acknowledgements
T he authors would like to thank all of the patients who took part in the EASI-SWITCH trial. They also wish
to thank all of the research and clinical team members at each of the trial sites for screening, recruitment,
management and follow-up of patients within the trial. Thanks are also extended to the staff of NICTU who
contributed to trial management and the Belfast HSC Trust Research Office for undertaking trial sponsorship.
Particular thanks are extended to Mrs Margaret Grayson, patient and public representative, who has been
an integral member of the study team from conception through to delivery and dissemination. Mrs Grayson’s
input was particularly invaluable in collating wider PPI opinion on the study design and continued importance
of the research question as the study progressed and the design revised. Additional thanks are extended to
Dr Caroline Forde, Clinical Research Fellow, who contributed significantly to study set-up and day-to-day trial
management and to Mrs Margaret McFarland for pharmacovigilance support.
The authors are also very grateful to the independent TSC and DMEC members for their continued
advice and guidance throughout the trial:
TSC:
Professor Kathy Bamford (chairperson, Imperial College Healthcare Trust, London, UK)
Capt. Robert Gray (independent PPI member),
Dr Ed Goodall (independent PPI member)
Dr Richard Jackson (independent statistician, University of Liverpool, Liverpool, UK)
Professor Christian Ottensmeier (University of Southampton, Southampton, UK)
DMEC:
Dr Mark Saunders (chairperson, The Christie NHS Foundation Trust, Manchester, UK)
Dr Ashley Jones (independent statistician, University of Liverpool, Liverpool, UK)
Professor Paul Dark (Salford Royal NHS Foundation Trust, Salford, UK)
The authors would also like to acknowledge the site investigators and their teams from 19 sites across
the UK who enrolled patients in the trial:
Belfast Health and Social Care Trust Professor Richard Wilson, Dr Audrey Fenton
University Hospitals of Leicester Professor Anne Thomas
The Newcastle Upon Tyne Hospitals NHS Foundation Trust Professor Ruth Plummer
Velindre NHS Trust Professor Richard Adams, Dr Hilary Williams
NHS Greater Glasgow and Clyde (Beatson) Dr Dawn Storey
Royal Marsden NHS Foundation Trust Dr Ian Chau
South Eastern Health and Social Care Trust Dr Lois Mulholland
Salisbury NHS Foundation Trust Dr Effie Grand
continued
Acknowledgements
Hampshire NHS Foundation Trust Dr Luke Nolan
Western Health and Social Care Trust Dr Sonali Dasgupta
The Mid Yorkshire Hospitals NHS Trust Dr Kostas Konstantinos
Heart of England NHS Foundation Trust Dr Joyce Thompson
Derby Teaching Hospitals NHS Foundation Trust Dr Mike Smith-Howell
Worcester Acute Hospitals NHS Trust Dr Bart Kurec
Poole Hospital NHS Foundation Trust Dr Amelie Harle
The Dudley Group NHS Foundation Trust Dr Jeffrey Neilson
North Middlesex University Hospital NHS Trust Dr Fharat Raja
Whittington Health NHS Trust Dr Pauline Leonard
Singleton Hospital Swansea Dr Ceri Powell
Contributions of authors
Vicky Coyle (https://orcid.org/0000-0001-9566-4130) (Senior Lecturer in Medical Oncology), trial

co-chief investigator, contributed to the concept and design of the trial, protocol development,
recruitment, trial management and interpretation of results.
Caroline Forde (https://orcid.org/0000-0001-5021-9973) (Clinical Fellow in Medical Oncology) was

the trial clinical fellow and contributed to trial design, protocol development and day-to-day trial
management and undertook the review of NS practice as the study progressed.
Richard Adams (https://orcid.org/0000-0003-3915-7243) (Professor of Clinical Oncology and

Cancer Clinical Trials) contributed to the trial design, protocol development, patient recruitment and
interpretation of results.
Ashley Agus (https://orcid.org/0000-0001-9839-6282) (Senior Health Economist), trial health

economist, contributed to trial design and development and led the concept and design of the health
economics evaluation including data analysis, interpretation of results and writing of Chapter 6.
Rosemary Barnes (https://orcid.org/0000-0002-0574-8670) (Professor of Medical Microbiology)

contributed to the trial design, protocol development and interpretation of results.
Ian Chau (https://orcid.org/0000-0003-0286-8703) (Consultant Medical Oncologist) contributed to the

trial design, protocol development, patient recruitment and interpretation of results.
Mike Clarke (https://orcid.org/0000-0002-2926-7257) (Professor of Research Methodology and

Director MRC Methodology Hub), trial methodologist, contributed to the trial design, protocol
development and interpretation of results.
Annmarie Doran (https://orcid.org/0000-0002-9802-008X) (Trial Coordinator) contributed to protocol

development and study set-up and was responsible for trial co-ordination and day-to-day management.
Margaret Grayson (https://orcid.org/0000-0002-1861-8541) (Chair Northern Ireland Cancer Research

Consumer Forum), trial PPI co-investigator, contributed to the trial design, trial development and
management, review of patient-facing materials, lay communication and co-ordinated PPI opinion on
revision of the trial design.
72

Danny McAuley (https://orcid.org/0000-0002-3283-1947) (Professor of Intensive Care Medicine)

contributed to the trial design, protocol development and interpretation of results.
Cliona McDowell (https://orcid.org/0000-0002-7644-7197) (Senior Statistician), trial statistician,

contributed to development of the protocol and statistical analysis plan and confidential data analysis
for the DMEC and led the analysis of primary and secondary outcome data.
Glenn Phair (https://orcid.org/0000-0001-8137-0959) (Health Economist), trial health economist,

contributed to the health economic data analysis, interpretation of results and writing of Chapter 6.
Ruth Plummer (https://orcid.org/0000-0003-0107-1444) (Professor of Experimental Cancer Medicine)

contributed to the trial design, protocol development, patient recruitment and interpretation of results.
Dawn Storey (https://orcid.org/0000-0002-6546-3183) (Consultant Medical Oncologist) contributed to

the trial design, protocol development, patient recruitment and interpretation of results.
Anne Thomas (https://orcid.org/0000-0003-1998-3134) (Professor of Cancer Therapeutics) contributed

to the trial design, protocol development, patient recruitment and interpretation of results.
Richard Wilson (https://orcid.org/0000-0001-8018-7730) (Professor of Gastrointestinal Oncology)

contributed to the trial design, protocol development, patient recruitment and interpretation of results.
Ronan McMullan (https://orcid.org/0000-0001-6760-6072) (Professor of Medical Microbiology),

co-chief investigator, contributed to the concept and design of the trial, protocol development, trial
management and interpretation of results.
Data-sharing statement
Requests for access to de-identified patient data can be made by researchers to the chief investigators,
and data will be shared subject to any constraints. Requests for access should be accompanied by a
proposal describing the aims and scope of the research, details of the data requested and data analysis
plan. Proposals will be considered by the Trial Management Group, co-investigators and sponsor who
will make a decision regarding data access. A data-sharing agreement will be signed between the
researchers, principal investigators and sponsor.
Patient data
This work uses data provided by patients and collected by the NHS as part of their care and support.
Using patient data is vital to improve health and care for everyone. There is huge potential to make
better use of information from people’s patient records, to understand more about disease, develop
new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure,
to protect everyone’s privacy, and it is important that there are safeguards to make sure that they
are stored and used responsibly. Everyone should be able to find out about how patient data are
used. #datasaveslives. You can find out more about the background to this citation here: https://
understandingpatientdata.org.uk/data-citation.
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80

Appendix 1 PPI survey on revision of

the EASI-SWITCH trial non-inferiority margin
Summary of trial and context provided to PPI representatives
Neutropenic sepsis (NS), or infection that develops in the setting of a low white blood cell count, is a
complication of chemotherapy treatment in patients with cancer. The ability to identify patients at low
risk of complication from infection offers the opportunity to avoid unnecessary treatment and hospital
stay which disadvantages both patients and the NHS.
We are carrying out a trial of patients at low risk of complications, to evaluate whether changing
from intravenous (i.v.) to oral antibiotics on the first day of treatment is clinically and cost-effective in
comparison with standard longer-duration i.v. antibiotics. The trial will study two patient groups: one
group will switch from i.v. to oral antibiotics 24 hours after i.v. treatment commences; in the other
group, patients will receive standard care i.v. antibiotic for at least 48 hours with subsequent antibiotic
continuation or switch to oral therapy at physician discretion based on their usual practice. We will then
compare the groups to see how effective the two different treatment strategies are.
The outcome that we will use to assess how well each treatment strategy works is ‘failure of treatment’ and
we will measure this on day 14 of follow-up. This is defined by the occurrence of one of several undesirable
outcomes that are all of importance to patients. These include: recurrence of fever; re-admission to hospital;
antibiotic side-effects; quality of life and death. However, the most common way that patients’ treatment
fails is that their fever comes back and they may need to be admitted to hospital again; by comparison,
death is uncommon in patients with NS who are at low risk of complications (the group we are studying).
Question for PPI consideration: how many patients to study?
We have designed this trial based on the findings of other small studies. These indicate that it is reasonable
to assume that early switch to oral treatment would have similar effectiveness to continuing on i.v. treatment
for longer. We are thinking about the number of patients we might need to include in a large trial to confirm
these findings. For example, with only one patient in each group, even if both had successful treatment, we
would not be confident that this would be reproduced if all patients received this treatment across the NHS.
By comparison, if we studied 10,000 patients in each group and found both treatments to be the same, we
would be highly certain that this would be reproduced in NHS practice – but the trial would be impossible to
do and cost tens of millions of pounds.
We are not trying to show that early oral switch is more effective than usual i.v. antibiotic treatment but
are focusing on whether it is not much less effective treatment. This type of trial design is a ‘non-inferiority’
design in which there are statistical rules and tests to show how certain we are that the new treatment
being tested is not much less effective than the usual treatment. Statisticians express how certain they are
about study results using a 95% confidence range either side of the result. This means that researchers
have very high certainty (95% certainty) that the true effectiveness of treatment lies within that range.
We are asking you to help us agree how wide this confidence range should be – or in other words what
level of trade-off between the benefits of shorter duration of treatment and the risk of treatment failure
is acceptable for patients. We also need to balance having enough patients to obtain meaningful results
and not having so many patients that the study is not achievable.
We propose setting the limit of the 95% confidence range for this at 15%. This means that, if we show that
both early oral antibiotic switch and longer courses of i.v. treatment effectively treat 85% of patients, we
Appendix 1
would have very high certainty (95% certainty) that the early oral switch approach had a ‘true’ effectiveness
of between 70% and 100%. In other words, the study might conclude that the two treatments are similar but
acknowledge that early oral switch is at least 70% effective while standard i.v. treatment is 85% effective.
In other words, for every 100 patients treated with an early oral switch strategy, all would benefit from
early discharge home. However, while 15 would be expected to need re-admission (whether they had
early switch or not), we would be acknowledging that early oral switch could lead to an extra 15 patients
needing re-admission (in comparison with those who receive prolonged i.v. treatment in the first
instance). Therefore, the trade-off we are asking you to consider is whether the possibility that an extra
15 patients may need re-admission is out-weighed by the advantage of the 100 patients receiving oral
switch and being discharged early.
The main question is whether this possible difference in effectiveness between the two treatment options is
acceptable. We had initially planned the study to assess whether the difference in effectiveness was no more
than 10%; however, we have found that recruiting the number of patients needed to do this makes the study
infeasible. Therefore, we are considering making a change to assess whether the difference in treatment
effectiveness is no more than 15%, since that requires fewer patients and makes the study achievable.
We need to decide whether it is better to continue the study using the 15% confidence range or
abandon the study altogether.
The main question is whether in your opinion it would still be useful to do the study if the confidence
range is increased from 10% to 15%. In other words, do you think patients would be similarly convinced
that switching to oral treatment earlier (to allow them to go home sooner) is a good idea if the additional
risk of needing re-admission may be up to 15%, rather than 10%?
Given that the advantage of early oral switch is likely to be early discharge from hospital and the main
consequence of the treatment being ineffective is re-admission we would like you to consider whether
this trade-off would be to patients’ advantage overall.
2. PPI responses to sample size/NI margin question
Input from a range of PPI representatives was sought on this proposed change via our PPI co-applicant,
Mrs Margaret Grayson, who distributed a summary of the study design and study progress including the
rationale for reviewing the sample size and specifically the NI margin. The information was distributed
to the Northern Ireland Cancer Consumer Forum and the Independent Cancer Patient Voice (a national
independent patient advocate group which has the support of the professional members of the NCRI
breast cancer Clinical Study Group).
Respondents were posed the question that if the NI margin was increased to 15% whether this level
of trade-off between the benefit of less intensive treatment and the risk of treatment failure would be
acceptable to patients; comments on the change were also welcomed.
There were 21 replies received and the majority of these supported this change (n = 19) with additional
comments received from seven of these respondents included below. One respondent did not support
this change and one was uncertain (comments from both included below).
PPI comments:
• We all know that there is a finite amount of funding and that the professionals are trying to do the
best for all within these limits. The fact that those who would require re-admission are being closely
monitored is very positive so having considered the points made in your paper I feel that 15%
re-admissions would be an acceptable level.
82

• Very interesting study and I think well worth doing. I believe that for most patients going home early
is key. Recovery at home is almost always preferably to being in hospital and I would definitely accept
the very small extra risk providing good home back-up is in place.
• I would recommend this study even if the risk of re-admission may be up to 15%. Having personally
seen this condition with my daughter when she had become neutropenic when she was being treated
for breast cancer. I believe she would have much preferred the oral method of treatment and getting
home sooner. As in her case she had to spend 2/3 days in hospital. She did not like this. But I must
add as only one person’s experience she may or may not have had to go back into hospital perhaps to
have i.v. treatment. Personally as her mother and carer I can see that it would be a very good study.
• This seems like a hard decision as it boils down to either doing the study or not doing the study. I
wonder why recruitment was such a problem for the original study. I suppose we just have to accept
that the study in its original form is not possible.
• It would certainly be advantageous for patients to be discharged early as no one wants to spend
any more time than necessary as an inpatient. My husband hated it and was always agitating to get
home! However, doubling the percentage of patients that then need re-admitted, seems, on the
face of it, rather a high number. Do these patients then need more protracted treatment, will their
sepsis be more difficult to treat, are they at risk of becoming more seriously ill? In essence, how much
additional danger are patients facing if such a change in treatment is implemented? Does it mean that
we would be content for 30% of patients to need re-admission? Sorry, I seem to be asking questions
rather than giving an opinion – but this is what is going around in my mind as I read the description.
Maybe it’s only after a study that such questions can be answered. For that reason alone, I would
tend to be supportive of the trial going ahead, though with reservations. I would expect that, should
the results begin to show a greater risk to patients, that the study would be stopped. Sorry if these
thoughts are not particularly helpful.
• I think it would be useful to proceed with the trial if the confidence range is increased from 10% to
15%. Switching to oral treatment earlier will allow the patient to go home earlier and this in itself
could aid recovery (psychological benefit) and reduce the risk of infection (less exposure to a wider
population at home than in hospital). I would assume patients on oral treatment will be closely
monitored at home with an identifiable easy/quick pathway for re-admission and i.v. antibiotics
if necessary, as opposed to being processed through A&E. The patient’s home situation would be
conducive to enabling close monitoring for indicators of infection occurring (maybe the presence of a
carer?) and that there are no concerns regarding the home situation itself or quality of care at home.
My feeling is that this study would be worthwhile.
• Margaret, I have read this and think that, on balance, it IS worth while making the change and trying
for the lower level but I honestly feel that there is really a decision for the researcher and the ethics
committee rather than a PPI decision.
• As you know I’m a fan of EASI-SWITCH, and believe that even with the increase in confidence range
it is worth continuing the Trial.
• Very difficult. Clearly good to reduce the amount of i.v. chemotherapy, but what would spook me is
the, albeit remote, possibility of death (certainly an ‘undesirable outcome’), for the sake of cutting the
stay in hospital by a day. But I can see that for someone with family responsibilities, the reduction in
the time in hospital might outweigh that risk. I don’t think that the switch to 85% confidence, rather
than 90%, would make any difference – but is it not possible to continue with the trial and as long
as the risks are clearly explained, give patients the choice? If the take-up is low, then the trial would
have to be abandoned.
• I am not convinced that the gains to be had here are worth the trial. I would also want to see a health
economic argument as re-admission to hospital may be more costly than reducing the initial stay by
a day. But then this may be one of the trial outcomes. People who have sepsis are often very poorly
for a long time and don’t always fully recover. I would want the treatment that’s going to give me the
best chance of recovery.
Appendix 2 UK clinician survey

O pinion was sought from clinicians nationally regarding the proposed extension of the non-inferiority
margin. The study co-investigators and site PIs were asked to disseminate the survey by e-mail
throughout their clinical network and beyond as widely as possible. A paper survey of attendees at the
Scottish Clinical Trials Showcase meeting was also undertaken. The supporting information provided
by both e-mail and hard copy is included at the end of this appendix. Finally, as the study is part of the
portfolio of the National Cancer Research Institute (NCRI) Colorectal Cancer Clinical Studies Group
(CSG), support was also sought from the relevant subgroup of the CSG.
Overall, almost all clinicians surveyed were supportive of extending the non-inferiority margin and
continuing the study. In total, responses were received from 38 consultants, 9 clinical fellows/specialty
trainees and 2 RNs. All but one of the respondents were supportive of the proposed revision. The
proposal was also discussed at the Adjuvant and Advanced Disease CSG Subgroup meeting on 16
January 2018. Membership of this group includes UK-wide representation from oncology and other
disciplines (including a statistician/CTU director). This group was also supportive of this revision to study
design and a letter of support from the Chair is also included.
An anonymised summary of the comments and respondents are included below:
• Very happy with this approach – sensible ethical and appropriate.

• An important question to try and answer, especially in current climate of bed shortage. No clinical
risk. Support continuing with 15% NI margin.
• I agree that the pragmatic solution is to expand the NI margin to 15%. A successful switch to oral
therapy for 70% of low-risk patients would still be a valuable outcome.
• This remains a critically important trial, the need for which was highlighted in the 2012 NICE
neutropaenic sepsis guidelines. A potential failure rate of 30% in low-risk neutropenic fever is
acceptable, given the safeguards built into the protocol.
• As you know from the outset I did have concerns about this study recruiting as years ago as an SpR in
Glasgow we failed to recruit well to the Liverpool-led ORANGE study (asking the same questions) – is
early switch and discharge safe in low-risk neutropenic patients using the MASCC score. That study
closed. I think the main two issues are: (1) we already make this switch in patients we perceive to be
low risk (prob not using MASCC score though) to reduce inpatient stay. (2) There are data from the
US studies showing this approach is safe. It is also part of ASCO guidelines 2013 and the infectious
diseases society of US guidance 2011 that MASCC score low-risk patients should be managed as
outpatients or discharged on orals after a brief inpatient stay. So I think its hard to randomise a
patient to more i.v.s when you want to do early switch and discharge based on guidance. However
what is a good thing about EASI-SWITCH is it will give us UK data and I think we should try to
complete the study and if switching to smaller non-inferiority margin makes no.s needed less then I
would support this and continue to look for patients.
• Most appropriate option especially given the suggestions within the survey findings, this remains
a relevant question and would still offer the potential to change practice dependent upon the
final results.
• As long as the trial is set up to show that (a) as long as sensible protocols are followed, death rates/
morbidity is no higher in comparable groups and (b) bed days are saved overall I would support this
change. The big picture shouldn’t be whether some end up needing a switch to i.v. antibiotics, but on
whether bed days are saved/health economics is favourable.
• I am worried about raising the bar of non-inferiority to 15% as the data interpretation shall become
less meaningful and may lose its clinical impact. The other issue is high anxiety levels of clinicians
in the past have led to failure of similar trials in low-risk neutropenic patients. If the consensus is
accepting the 15% as standard I am happy to with it.
Appendix 3 Trial sites and recruitment
TABLE 37 List of trial sites and numbers of patients recruited
Site Site/trust name Date opened Number recruited (%)
01 Belfast Health and Social Care Trust 17 February 2016 50 (38.8)
02 University Hospitals of Leicester 14 March 2016 4 (3.1)
03 The Newcastle Upon Tyne Hospitals NHS Foundation Trust 4 May 2016 15 (11.6)
04 Velindre NHS Trust 31 March 2016 13 (10.1)
05 NHS Greater Glasgow and Clyde (Beatson) 22 June 2017 2 (1.6)
06 Royal Marsden NHS Foundation Trust 17 July 2017 5 (3.9)
07 South Eastern Health and Social Care Trust 26 June 2017 5 (3.9)
08 Not allocated n/a n/a
09 Salisbury NHS Foundation Trust 18 September 2017 9 (7.0)
10 Hampshire NHS Foundation Trust 28 September 2017 1 (0.8)
11 Western Health and Social Care Trust 13 November 2017 7 (5.4)
12 The Mid Yorkshire Hospitals NHS Trust 18 January 2017 7 (5.4)
13 Heart of England NHS Foundation Trust 5 December 2017 3 (2.3)
14 Derby Teaching Hospitals NHS Foundation Trust 1 May 2018
15 Worcester Acute Hospitals NHS Trust 25 September 2018 1 (0.8)
16 Poole Hospital NHS Foundation Trust 1 November 2018 4 (3.1)
17 The Dudley Group NHS Foundation Trust 1 November 2018
18 North Middlesex University Hospital NHS Trust 18 July 2019 2 (1.6)
19 Whittington Health NHS Trust 1 July 2019 1 (0.8)
20 Singleton Hospital Swansea 15 July 2019
Appendix 4 Semistructured interview guide

for EASI-SWITCH investigators regarding
barriers to recruitment
Opening questions:
• How have you found recruitment to the EASI-SWITCH trial?

• Have you encountered any challenges in recruiting patients to the EASI-SWITCH trial?
Prompts:
• Have there been any difficulties at your site with:
– screening and identifying suitable patients

– consenting and randomising patients successfully
– any aspects of the protocol or trial-related materials
– data management or follow-up
– local resources or infrastructure
– research or clinical team members
– communication with CTU?
Appendix 5 Reasons for study screening

failure
E ight hundred and twenty-seven patients were screened for study entry in total, of whom 698 were
excluded. The most common reason for exclusion was failure to meet the eligibility criteria (n = 581)
and specific reasons for this are detailed below. Of the remaining patients, six were unable to provide
informed consent and the remainder failed screening for other reasons (n = 111).
Screen failures based on specific eligibility criteria (n = 581):
• patient 16 years or under (n = 1)

• patient not receiving SACT for diagnosis of cancer (n = 4)
• patient does not have a fever, that is, temperature > 38°C within 24 hours prior to randomisation
(n = 38)
• patient does not have either a temperature of at least 38°C or other sign or symptoms consistent
with clinically significant sepsis, for example, hypothermia (n = 70)
• patient does not have neutropenia, that is, absolute neutrophil count not ≤ 0.5 × 109/l within
24 hours prior to randomisation (during initial 6 month pilot; n = 15)
• patient does not have an absolute neutrophil count ≤ 1.0 × 109/l, and falling or expected to fall, with
a temperature of at least 38°C (following pause to recruitment; n = 301)
• expected duration of neutropenia ≥ 7 days (n = 3)
• patient has hypotension < 90 mmHg within 24 hours prior to randomisation (n = 11)
• patient has hypotension (systolic pressure < 90 mmHg or reduction of > 40 mmHg from known
baseline on > 1 measurement) within the 24 hours prior to randomisation (n = 5)
• patient has received i.v. piperacillin/tazobactam or meropenem for more than 24 hours (n = 16)
• patient was at risk of complications using MASCC score (i.e. MASCC score < 21; n = 28)
• patient is not able to maintain adequate oral intake and take oral medication (n = 7)
• patient does not have adequate hepatic (AST and/or ALT ≥ 5 × ULN) and renal function (serum
creatinine ≥ 3 × ULN) within 24 hours prior to randomisation (n = 7)
• patient’s physician in charge of care is not willing to follow either the intervention or standard care
protocol per randomisation, at enrolment, including not treating with CSF. Prophylactic use of CSF is
not an exclusion criterion if prescribed routinely as an integral component of a specific SACT regimen
(n = 25)
• patient has an underlying diagnosis of acute leukaemia (n = 38)
• patient has an underlying diagnosis of haematopoietic stem cell transplant (n = 3)
• patient has been enrolled in this trial with a prior episode of NS (n = 2)
• patient has prior allergy, serious AR or contraindication to any study drug (n = 22)
• patient is a pregnant woman (n = 1)
• patient has received treatment with fluoroquinolone or penicillin in preceding 14 days. *Question no
longer asked in non-randomisation (n = 7)
• patient has localising signs of severe infection (pneumonia, soft-tissue infection, central-venous
access device infection, presence of purulent collection; n = 15).72,73
Appendix 6 Unit costs of hospital services and

study drugs
U nit costs from the NHS Schedule of Reference Costs 2018–19,56 PSSRU Unit Costs of Health
and Social Care57 and British National Formulary (BNF)58 were combined with the individual-level
resource use to estimate a total hospital cost for each trial participant.
TABLE 38 Unit costs of hospital services and study drugs
Resource item Unit cost (£) Source Details
Ward bed-day 478.25 Department of Health Weighted average length of stay and cost of
NHS Costs 2018/19 non-elective long stays (WJ06A–WJ06J)
Critical care bed-day 933.19 Department of Health Adult Critical Care (XC06Z)
NHS Costs 2018/19
Outpatient 135 PSSRU Unit Costs

attendance 2019
Emergency 196 PSSRU Unit Costs See, treat and refer

department 2019
Piperacillin/tazobac- 7.65 BNF Drug Tariff Powder for solution for infusion vials
tam (2 g/250 mg) March 2020 (pack of one)
Meropenem (1 g) 17.78 BNF Drug Tariff Powder for solution for infusion vials. Cost per
March 2020 unit based on a pack of 10 (£177.80/10 = 17.78)
Ciprofloxacin 0.80 BNF Drug Tariff Cost per 750 mg tablet based on a pack of 10
(750 mg) March 2020 (£8.00/10 = £0.80)
(£8.00/10)
Co-amoxiclav 0.12 BNF Drug Tariff Cost per 500 mg/125 mg tablet based on a pack
(500 mg/125 mg) March 2020 of 21 (£2.50/21 = £0.12)
(£2.50/21)
Appendix 7 Patient preference questionnaire

P atient Follow-up Questionnaire
Interviewer
You were recently admitted to hospital with NS – an infection you developed during your anticancer
treatment. You kindly agreed to take part in the EASI-SWITCH trial. We would now like to ask you some
questions to find out what you think about the method of antibiotic treatment you received and also
find out your hypothetical preferences for future antibiotic treatment should you develop NS again. The
information you give us will be confidential and will only be used for the EASI-SWITCH trial. Your answers
will not influence the health care you are receiving now or any health care you might receive in the future.
I am now going to read out some statements to you about the most recent treatment for NS you
received. For each one, I would like you say whether you AGREE or DISAGREE with the statement, or if
you are UNCERTAIN about it. Please think about each one carefully.
Instruction for Interviewer
Please read out each statement and ask the respondent ‘Do you Agree or Disagree with this statement or are you UNCERTAIN?’
Agree Disagree Uncertain
1. I am satisfied with the medical care I received for NS ❑ ❑ ❑
2. I am satisfied with the level of support I received from ❑ ❑ ❑

the hospital
3. I believe that the antibiotic treatment I received was effective ❑ ❑ ❑
4. I am happy with the place I received my antibiotic treatment ❑ ❑ ❑
5. Before I was treated, I was concerned that the antibiotic ❑ ❑ ❑

treatment would not work
6. Before I was treated, I was concerned about how the ❑ ❑ ❑

antibiotic treatment I received would affect my family/friends
When you agreed to take part in the EASI-SWITCH trial you were told about the possible advantages
and disadvantages of each method of antibiotic treatment. Just to remind you of them – when patients
are switched early from i.v. to oral antibiotics, they may be discharged from hospital 1 to 2 days earlier
than those who continue on i.v. antibiotics. However, there is also a small risk that their infection
may not clear up as quickly as those who continue on i.v. antibiotics. As a result, they may need to be
re-admitted to hospital for further i.v. antibiotics.
Please keep this information in mind as I read out some statements about any future treatment for
NS you may need. Please remember, your responses will not influence the treatment you may actually
receive. Like before, I would like you to say whether you AGREE or DISAGREE with the statement, or if
you are UNCERTAIN about it. Please think about each one carefully.
Appendix 7
Instruction for Interviewer
Please read out each statement and ask the respondent ‘Do you Agree or Disagree with this statement or are you UNCERTAIN?’
Agree Disagree Uncertain
7. It would be important to me to be discharged ❑ ❑ ❑

1–2 days early
8. It would be important to me that I was not ❑ ❑ ❑

re-admitted to hospital for further treatment
9. I would accept the small risk of re-admission ❑ ❑ ❑

if it meant I was discharged 1–2 days early
10. If patients were to be offered a choice about which way they could be treated for NS in future,
which antibiotic treatment would you choose?
❑ Intravenously in hospital for at least 48 hours and then switching to oral antibiotics if necessary
❑ Intravenously in hospital for 12–24 hours and then switching to oral antibiotics
11. Can you tell us why you would choose this method?
There is a small risk of hospital re-admission for patients who have i.v. antibiotics (1–2 patients for
every 10 treated). The risk of hospital re-admission for patients who are switched early may be the same
as this or slightly higher but we will not know what this risk level really is until the EASI-SWITCH trial
is finished.
12. If the risk of re-admission was three in every 10 patients switched early (30%) instead of 1–2
patients (15%) would you choose to be discharged home on oral antibiotics 1–2 days sooner?
❑ Yes
❑ No
Finally, the last two questions will help us to understand the care situation in your home.
13. Do you receive care in your own home on a daily basis?
❑ Yes
❑ No
14. Do you have children or dependents that you care for?
❑ Yes
❑ No
Thank you very much for taking the time to answer these questions for us today.
96

For the interviewer
Please write down in the box below any feedback which will help us improve this questionnaire. E.g. did the respondent find
any question difficult to understand? Did they question why they were being asked the information?
Appendix 8 Health economics analyses using

all available data
TABLE 39 Health-related quality-of-life scores by group using all available data
Intervention Standard care
Variable n Mean (95% CI) n Mean (95% CI) Difference (95% CI)
EQ-5D-5L utilities
Baseline 59 0.77 (0.72 to 0.83) 62 0.74 (0.68 to 0.79) 0.04 (−0.04 to 0.11)
14 days 54 0.81 (0.76 to 0.86) 59 0.77 (0.72 to 0.83) 0.04 (−0.04 to 0.11)
EQ-VAS
Baseline 59 64.14 (58.59 to 69.68) 62 58.95 (53.82 to 64.08) 5.18 (−2.28 to 12.65)
14 days 56 74.70 (69.71 to 79.69) 59 70.32 (65.74 to 74.91) 4.37 (−2.32 to 11.07)
QALYs 52 0.03 (0.03 to 0.03) 58 0.03 (0.03 to 0.03) < 0.00 (−0.00 to 0.00)
100
Appendix 8
TABLE 40 Hospital resource use by group using all available data
Service n (%) Mean (95% CI) n (%) Mean (95% CI) Mean difference (95% CI)
Primary admission
Ward days 62 (100.00) 2.73 (2.14 to 3.31) 64 (100.00) 3.17 (2.73 to 3.61) −0.45 (−1.17 to 0.27)
Critical care days 1 (1.61) 0.15 (−0.15 to 0.44) 0 (0) n/a 0.15 (−0.14 to 0.43)
Emergency department 2 (3.23) 0.03 (−0.01 to 0.08) 2 (3.13) 0.03 (−0.01 to 0.08) 0.00 (−0.06 to 0.06)
Re-admission
Ward days 4 (6.45) 0.39 (−0.11 to 0.89) 2 (3.13) 0.17 (−0.07 to 0.41) 0.22 (−0.33 to 0.76)
Emergency department visits 4 (6.45) 0.06 (0.00 to 0.13) 2 (3.13) 0.03 (−0.01 to 0.08) 0.03 (−0.04 to 0.11)
DOI: 10.3310/RGTP7112
TABLE 41 Cost of hospital service use by group (all available data)
Primary admission
Ward days 1303.62 (1023.56 to 1583.67) 1516.95 (1307.80 to 1726.10) −213.33 (−557.91 to 131.24)
Critical care days 135.46 (−135.41 to 406.34) 0 −135.46 (−128.40 to 399.33)
Emergency department 6.32 (−2.54 to 15.19) 6.13 (−2.46 to 14.71) 0.20 (−12.02 to 12.41)
Re-admission
Ward days 185.13 (−53.11 to 423.37) 82.20 (−33.52 to 197.91) 102.93 (−156.72 to 362.58)

Emergency department visits 12.65 (0.32 to 24.97) 6.13 (−2.46 to 14.71) 6.52 (−8.27 to 21.31)
Medication
Concomitant medication 19.64 (3.41 to 35.87) 40.26 (7.84 to 72.68) −20.62 (−56.88 to 15.64)
Total 1718.26 (1254.92 to 2181.60) 1736.68 (1466.92 to 2006.44) −18.42 (−545.13 to 508.28)
101
EME
HSDR
HTA
PGfAR
PHR
Part of the NIHR Journals Library
www.journalslibrary.nihr.ac.uk
This report presents independent research funded by the National Institute for Health and Care Research (NIHR).
The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the
Department of Health and Social Care
Published by the NIHR Journals Library

Early Switch From Intravenous To Oral Antibiotic Therapy in Patients With Cancer Who Have Low-Risk Neutropenic Sepsis: The Easi-Switch RCT

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Health Technology Assessment

Early switch from intravenous to oral

Vicky Coyle ,1* Caroline Forde ,1 Richard Adams ,2

Published March 2024

This report should be referenced as follows:

Impact factor: 3.6

Editorial contact: journals.library@nihr.ac.uk

The full HTA archive is freely available to view online at www.journalslibrary.nihr.ac.uk/hta.

Criteria for inclusion in the Health Technology Assessment journal

Early switch from intravenous to oral antibiotic therapy in

Vicky Coyle ,1* Caroline Forde ,1 Richard Adams ,2 Ashley Agus ,3

Corresponding author v.coyle@qub.ac.uk

Background: Neutropenic sepsis is a common complication of systemic anticancer treatment. There is

NIHR Journals Library www.journalslibrary.nihr.ac.uk

List of abbreviations xvii

Plain language summary xix

Scientific summary xxi

Chapter 3 Pilot study results and review of study design 19

Chapter 4 Main trial progression 31

Chapter 5 Clinical effectiveness of early oral switch 39

NIHR Journals Library www.journalslibrary.nihr.ac.uk

Chapter 6 Health economic and patient preference analyses 51

Appendix 1 PPI survey on revision of the EASI-SWITCH trial non-inferiority margin 81

Appendix 2 UK clinician survey 85

Appendix 3 Trial sites and recruitment 87

Appendix 4 Semistructured interview guide for EASI-SWITCH investigators regarding

Appendix 5 Reasons for study screening failure 91

Appendix 6 Unit costs of hospital services and study drugs 93

Appendix 7 Patient preference questionnaire 95

Appendix 8 Health economics analyses using all available data 99

TABLE 2 Schedule of assessments 11

TABLE 3 Summary of progress of the embedded pilot study 19

TABLE 4 Summary of initial pilot phase 20

TABLE 5 Reasons for participant exclusion at sites 1 and 2 20

TABLE 7 Adjustments to eligibility criteria following the initial pilot phase 22

TABLE 10 Common reasons cited by survey respondents preventing early discharge

TABLE 11 Reasons for site non-participation in the EASI-SWITCH trial (n = 15 sites) 31

TABLE 12 Summary of recruitment activity 32

TABLE 13 Summary of barriers to recruitment encountered in the EASI-SWITCH trial,

TABLE 14 Most frequent barriers to recruitment as reported in the electronic survey

TABLE 15 Survey respondents’ impression of listed potential barriers to recruitment

TABLE 16 Recruitment by site 39

TABLE 17 Baseline characteristics 41

TABLE 18 Protocol deviations 43

TABLE 20 Constituents of the composite primary outcome measure leading to

TABLE 21 Constituents of the composite primary outcome measure leading to

TABLE 22 Secondary outcome measures 46

TABLE 23 Subgroup analyses 47

TABLE 24 Adverse events by treatment group 48

TABLE 27 Health-related quality-of-life scores by group (patients with complete

TABLE 28 Results of the cost–utility analyses at 14 days (1000 bootstrap samples) 54

TABLE 29 Incremental net benefit at various willingness-to-pay thresholds per

TABLE 32 Results of the cost-effectiveness analyses at 14 days (1000 bootstrap

TABLE 33 Incremental net benefit at various willingness-to-pay thresholds per

TABLE 34 Patient satisfaction and experience, by group 63

TABLE 35 Patient preferences and risk-based decision-making, by group 64

TABLE 36 Home-based factors, by group 64

TABLE 37 List of trial sites and numbers of patients recruited 87