Du Puy et al.

BMC Endocrine Disorders (2018) 18:67

https://doi.org/10.1186/s12902-018-0285-8

STUDY PROTOCOL Open Access

Study protocol: a randomised controlled

trial on the clinical effects of levothyroxine
treatment for subclinical hypothyroidism in
people aged 80 years and over
R. S. Du Puy1, I. Postmus2,3, D. J. Stott4, M. R. Blum5, R. K. E. Poortvliet1, W. P. J. Den Elzen6, R. P. Peeters7,
B. C. van Munster8, B. H. R. Wolffenbuttel9, R. G. J. Westendorp10,11, P. M. Kearney12, I. Ford13, S. Kean13,
C. M. Messow13, T. Watt14, J. W. Jukema15, O. M. Dekkers16, J. W. A. Smit17, N. Rodondi5,18, J. Gussekloo1,2
and S. P. Mooijaart2,3*

Abstract
Background: Subclinical hypothyroidism is common in older people and its contribution to health and disease
needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical
hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some
suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This
manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus
thyroid trial to generate the necessary evidence base.
Methods: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone
Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial
(TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for
the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in
the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over.
The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of
levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical
hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised
to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a
minimum follow-up of one and a maximum of three years.
Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life
patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive
cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and
mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial
fibrillation and heart failure.
(Continued on next page)

* Correspondence: S.P.Mooijaart@lumc.nl
2
Department of Gerontology and Geriatrics (C7-Q), Leiden University Medical
Center, PO Box 9600, 2300 RC Leiden, The Netherlands
3
Institute for Evidence-based Medicine in Old age, Leiden, the Netherlands
Full list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 2 of 14

(Continued from previous page)

Discussion: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged
over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of
levothyroxine treatment in 80-plus persons to date.
Trial registration: Nederlands (Dutch) Trial Register: NTR3851 (12–02-2013), EudraCT: 2012–004160-22 (17–02-2013),
ABR-41259.058.13 (12–02-2013).
Keywords: Subclinical hypothyroidism, 80-plus, Randomised controlled trial, Quality of life, Levothyroxine

Background Old Age (IEMO)80-plus thyroid trial. The TRUST trial

Subclinical hypothyroidism (SCH) is a common aberrant was not designed specifically to investigate the effects in
biochemical finding defined as an elevated serum 80-plus participants and was consequently inadequately
thyroid-stimulating hormone (TSH) and normal circulat- powered for a subgroup analysis in participants aged 80
ing thyroid hormone level [1]. SCH is associated with and over. The IEMO 80-plus thyroid trial was designed
multiple health problems in old age ranging from mild jointly with the TRUST trial as an ancillary trial using the
non-specific symptoms such as tiredness and emotional same trial infrastructure and protocol to allow a
susceptibility to coronary heart disease and decreased pre-planned, joint analysis of all participants aged 80 and
physical and cognitive functioning [2]. over. This combined endeavour will provide experimental
As 8–18% of those over 65 years are affected and infer- evidence on potential multimodal effects of levothyroxine
ence from both observational and experimental studies treatment from the largest sample of 80-plus persons with
maintain the clinical equipoise whether the merits of SCH to date.
levothyroxine treatment outweigh the risks [3], the Thy- Among the specific study objectives are:
roid hormone Replacement for Untreated older adults
with Subclinical hypothyroidism randomised placebo con- 1. Does levothyroxine treatment for SCH provide
trolled Trial (TRUST) [4] was designed to resolve this benefits for 80-plus persons with SCH?
clinical uncertainty. The outcomes of the TRUST trial 2. Are benefits seen across a wide range of outcomes,
provided robust information that for community-dwelling including health-related quality of life, muscle func-
persons of 65 years of age and older with SCH, levothyr- tion, cognition and prevention of cardiovascular
oxine treatment provides no apparent benefits [4]. disease?
There are ample data to suggest that thyroid function is 3. Are benefits seen in specific subgroups of people
mediated by age and that the effects of SCH may be pro- with SCH, including women, and those with mild
foundly different in octogenarians and older [3]. Older degrees of SCH (TSH 4.6–10 mU/L)?
persons generally require different dosages of levothyrox- 4. Are any benefits offset by adverse effects, such as
ine to achieve euthyroidism than younger counterparts atrial fibrillation or heart failure?
possibly due to changes in body weight, composition or
hormonal status [5] and are at higher risk of adverse ef- Methods and design
fects of overtreatment including cardiovascular events, ar- The IEMO 80-plus thyroid trial was designed as an ancil-
rhythmias and fractures [6]. In a large-scale, observational lary randomised double-blind placebo-controlled parallel
follow-up study among 599 community-dwelling partici- group trial of levothyroxine for persons over 80 years with
pants aged 85 years and over, increasing levels of TSH subclinical hypothyroidism. From the outset the study was
were associated with prolonged life span [7]. This associ- designed jointly and in parallel with the TRUST trial (de-
ation, however, could not be confirmed in a later Individ- tails provided elsewhere [10]) and both trials share a near
ual Patient Data meta-analysis investigating mortality identical design and infrastructure including study proto-
information in 4344 participants with SCH aged 80 years cols, standard operating procedures, independent data
and over [8]. In addition, members of families with excep- monitoring and endpoint committees, databases, statisti-
tional longevity are characterized by slightly higher TSH cians and study nurses.
and slightly lower circulating thyroid hormone levels Initially, the IEMO 80-plus thyroid trial aimed to in-
when compared with the general population [9]. clude 450 participants. Additionally, a pre-planned com-
To help resolve this clinical uncertainty of levothyroxine bined analysis with the data from all 80-plus participants
replacement treatment for SCH in older persons, we have from the TRUST trial, resulting in a total of 900 partici-
performed an randomized controlled trial including par- pants in the final pooled analyses, was conceived to
ticipants over 80 years old in the presence of comorbid maximise statistical power. During the inclusion phase,
conditions; the Institute for Evidence-Based Medicine in it became apparent that the proposed target of 450
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 3 of 14

80-plus participants was unfeasible within the allotted Intervention

study period (mirroring the experiences of the TRUST The investigational medicinal products are levothyroxine
trial [10]) and revised power calculations were proposed sodium (T4) as 25 or 50 microgram tablets for oral ad-
with the new projected target of 145 IEMO 80-plus trial ministration and a matching placebo. All tablets are
participants (see Sample size calculation). white and round in shape with the strength imprinted,
Originally the trial was executed in 4 regions of the identically packaged in blisters and packed in plain card-
Netherlands (Leiden University Medical Center, Erasmus board cartons to maintain study blinding. Participants
University Medical Center, University Medical Center are advised to take the suggested dose of study medica-
Groningen and the University of Amsterdam). During tion once daily half an hour before breakfast.
the inclusion period, in an attempt to maximise the in- The intervention group will start with levothyroxine
clusion rate, organisational changes were accepted allow- 50 micrograms daily (25 micrograms in participants with
ing for inclusion of participants from all locations within < 50 kg body weight or with a history of coronary heart
the Netherlands, coordinated by the Leiden University disease) and the control group with matching placebo
Medical Center. Additionally, because the trial infra- for six to 8 weeks.
structure was already in place for the TRUST trial, add- After 6–8 weeks a venous blood sample is taken for
itional participants were recruited from the University TSH assessment. Based on the TSH results, the data
Hospital Bern in Switzerland. centre advises the new dose of study medication or pla-
cebo to the clinical investigators.
Study population
One hundred forty five community-dwelling participants  If TSH < 0.4 mU/L: the treatment dose is reduced to
≥80 years with SCH are recruited. Similar to TRUST, 25 micrograms levothyroxine in those starting on 50
participants are identified from clinical and primary care micrograms; reduced to 0 in those starting on 25
laboratory databases from all patients having biochem- micrograms – effected by giving placebo matching the
ical features consistent with SCH. SCH is defined as per- 25 micrograms dose. These participants will have a
sistently elevated TSH levels (≥ 4.6 and ≤ 19.9 mU/L), further TSH check after 6–8 weeks. If TSH remains
measured on a minimum of two occasions at least < 0.4 mU/L participant will be withdrawn from
3 months and no more than 3 years apart prior to enrol- randomised treatment and referred to usual care.
ment and free thyroxine (fT4) within the laboratory ref-  If TSH ≥ 0.4 and < 4.6 mU/L: no change to the
erence range. All participants gave written individual treatment dose.
informed consent to participate.  If TSH remains elevated (≥ 4.6 mU/L): 25
Exclusion criteria micrograms of levothyroxine will be added. Giving a
total daily dose of 75 micrograms levothyroxine for
 Participants currently on levothyroxine, antithyroid those starting on 50 micrograms, or a total daily
medication (including carbimazole, methimazole, dose of 50 micrograms levothyroxine for those
propylthiouracil and potassium perchlorate), starting on 25 micrograms.
amiodarone or lithium.
 Recent thyroid surgery or radio-iodine therapy A maximum of two levothyroxine up-titrations at the
(within 12 months). start of the trial and one up-titration at 12 and 24 month
 Grade IV NYHA heart failure. (± 1 month) intervals with repeated TSH measurements
 Prior clinical diagnosis of dementia. after 6–8 weeks ensure adequate levothyroxine treatment
 Recent hospitalisation for major illness (within while avoiding potential over-replacement. The maximum
4 weeks). possible dose of levothyroxine is 150 micrograms.
 Recent acute coronary syndrome, including myocardial A mock titration adopting an adaptive schedule is per-
infarction or unstable angina (within 4 weeks). formed in the placebo group by the data centre. A simi-
 Acute myocarditis or acute pancarditis lar proportion of placebo patients will have up and
 Untreated adrenal insufficiency or adrenal disorder down titrations of study medication as the intervention
 Terminal illness. group to ensure the number of tablets and assessments
 Patients known to have rare hereditary problem of is similar in both groups.
galactose intolerance. Because all thyroid function measurements are avail-
 Participants who are participating in ongoing RCTs of able only to the data centre, the clinical investigators
therapeutic interventions (including clinical trials of remain fully blinded to the treatment allocation process
investigational medicinal products [CTIMPs]) during the trial.
 Plan to move out of the region in which the trial is Accountability logs recording the quantities of study
being conducted within the next 2 years. medication dispensed to and returned from study
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 4 of 14

participants, batch numbers and expiry dates are avail- and completing all the data to aid in any further treat-
able for all study drug movements. ment decisions with the GP.
Criteria for discontinuing or modifying allocated study All laboratory tests for TSH and fT4 are performed at
medication: the local GP and clinical laboratories. The results in the
treatment phase are uploaded to the independent data
 If overt biochemical hypothyroidism is identified centre which in turn advises the study site on dose titra-
(TSH > 20 mU/L and/or fT4 below the reference tion through the dedicated trial web portal. The study
range) a second TSH with fT4 within 2 weeks is team remains unaware of the results of the thyroid func-
requested. Upon confirmation of biochemical tion testing. Additionally, all cooperating GPs were
hypothyroidism the participant will be withdrawn asked to refrain from additional thyroid function mea-
from the study treatment and referred to the surements to ensure adequate blinding.
General Practitioner (GP) for usual care.
 If overt biochemical hyperthyroidism is identified Data collection
(TSH < 0.4 mU/L) in the placebo group, or Data collection will be performed by study research nurses
consecutively in the treatment group despite at baseline and predetermined follow-up visits at the par-
downtitrations, the participant will be withdrawn ticipant’s home or place of residence. All participants are
from the study treatment and referred to the GP for followed up for a minimum of 1 year with a likely average
usual care. of 2 years. Participants are reviewed face-to-face by the
 If for clinical reasons (e.g. major illness) a proposed study nurses at recruitment, study baseline, 6–8 weeks,
change in study medication or placebo is deemed 12 months, 24 months, 36 months and at the final visit.
inappropriate the algorithm is overridden by the This personal approach ensures data quality and promotes
local principal coordinator and no change in study participant retention and complete follow-up. In addition,
medication takes place. interim telephone contact or visits (depending on the de-
sire of the patient) are made by study nurses at 6, 18 and
Randomisation 30 months (depending on total duration of follow-up), in-
Participants are randomised to either the levothyroxine cluding recording of possible cardiovascular and serious
or placebo treatment arm (ratio 1:1) using the randomly adverse events (SAEs). For a timeline of assessments and
permuted block method, stratified by site, sex and start- visits see Table 1.
ing dose. The data centre (Robertson Centre for Biostat- All study nurses are trained simultaneously on the data
istics, University of Glasgow, Scotland) independently to be assessed. All measuring equipment is calibrated be-
provides the randomisation schedule. Mawdsley Brooks fore the start and annually thereafter to safeguard reliabil-
& Co. implements the schedule through identical pack- ity and validity. The Data centre will develop and manage
aging of levothyroxine and matching placebo tablets. a dedicated, anonymised trial web portal, including the
Patient allocation is conducted via the dedicated trial electronic case report forms in Dutch and Swiss Standard
web portal by the study nurses. When a participant is German. This portal is based on the dedicated trial web
eligible based on entering the eligibility criteria in an portal from the TRUST trial to maximize the homogeneity
electronic case report form (eCRF) supervised by a med- of data and to allow for pre-planned pooled analysis of the
ically certified Principle Investigator, a central computer results. Personal information used for trial logistics is col-
will trigger the decision. lected and stored in a separate electronic study database
in accordance with legal and ethical requirements.
Blinding Data validation checks give study personnel immediate
Participants are blinded to treatment allocation by using feedback on missing or out of range values. Logic checks
matching tablets and packaging for levothyroxine and reduce the possibilities of entering invalid data. Database
placebo. All study personnel remain blinded for the dur- validation checks are run routinely and are tracked and es-
ation of the trial through remote analysis of laboratory calated as appropriate. Data will be locked at the end of the
results of TSH in the data centre, ensuring the trial stays study according to preregistered lockdown procedures by
double blinded. GPs will remain blinded to treatment al- the data centre. The data centre will provide the independ-
location and TSH tests unless otherwise required in the ent data monitoring committee (IDMC) and the authorities
event of an emergency medical situation. An Interactive with (annual) safety reports on the Data.
Voice Response System at the data centre allows for in-
dividual emergency allocation information to be released Outcomes
to an unblinded study physician through 24-h telephone At 6–8 weeks we expect most patients allocated to
access. All participants will learn the treatment alloca- levothyroxine to be biochemically euthyroid, and at
tion within 15 working days of receiving the final visit this time point short-term improvements (such as in
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 5 of 14

Table 1 Detailed schedule of assessments

Months of follow up 0 6-8 wks 6m 12m 18m 24m 30m 36m Finala
visit visit
visit call/visit visit call/visit visit call/visit visit
Participant characteristics & medical history x
Weight, height, waist circumference and BMI x x x
Concomitant medication x x x x x x
Home support x x
Safety and monitoring
Morbidity, mortality, hospitalisation and GP contacts x x x x x x x x
Serious Adverse Events x x x x x x x x
Single-lead ECG (for AF) x x x x x
Drug adherence x x x x x x x x
Outcomes
Thyroid related quality of life (ThyPRO) x x x x
Generic quality of life (EQ-5D-3L) x x x x
Cognitive function
MMSE x
Letter Digit Coding Test x x
Functional ability
ADL (BI), IADL (OARS), falls questionnaire x x
Handgrip strength & 6-meter gait speed x x x
Blood pressure x x x
Fatal and non-fatal cardiovascular events x x x x x x x x
Arthritis complaints x
Treatment Satisfaction (TSQM vII) x
Laboratory analysis
Thyroid function x x x x x x
Haemoglobin x x
Blood samples for biobank x x
a
the final visit assessments may substitute for any assessment time between 12 and a maximum of 42 months

thyroid-related quality of life) will be assessed. By 1  Concomitant drugs used: prescribed medication,
year the medium-term effects of levothyroxine treat- over-the-counter non-steroidal anti-inflammatory
ment should emerge (such as muscle function). The drugs and aspirin
long term effects of treatment of SCH will be deter-  History of disease: Cardiovascular disease including
mined by assessment over the full course of the history of ischaemic heart disease (angina pectoris
study, with a mean of 2 years treatment duration. or previous myocardial infarction), cerebrovascular
In the screening phase, results from TSH and fT4 disease (ischaemic stroke, transient ischaemic attack)
tests, exclusion criteria, informed consent for the or peripheral vascular disease (intermittent
screening phase of the study, informed consent for claudication), or any revascularisation procedure for
the trial phase of the study are obtained by the study ischaemic vascular disease. History of atrial
nurses. fibrillation, epilepsy, hypertension, diabetes mellitus
During the baseline phase of the study the following data or osteoporosis.
are recorded:  Single lead ECG: to check for atrial fibrillation
 Cognitive function: Mini-mental state examination
 Participant characteristics: age, sex, ethnicity, (MMSE [11]) score as an indicator of general
information on alcohol and tobacco use, height. cognitive function. This will not be used as an
 Any clinical changes that would violate the inclusion outcome measure due to insensitivity to change
or exclusion criteria during the trial.
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 6 of 14

 Home support services: (e.g. home help, meals-on- atherosclerotic vascular disease (including for acute
wheels, district nursing) and home circumstances coronary syndrome and heart failure
(e.g. living alone, co-habiting, standard or sheltered hospitalisations).
housing, or entry to care home)
Additional measurements
Primary study endpoints
The main study primary endpoints are mean change  Treatment satisfaction with trial medication:
from baseline scores in thyroid-related quality of life and Treatment Satisfaction Questionnaire for
symptom burden assessed using the hypothyroid symp- Medication vII (TSQM [20]) and desire of post-trial
toms scale score and tiredness symptoms scale score on medication continuation recorded at final follow up.
the thyroid-related quality of life patient-reported out-  Arthritis: data regarding joints, skeletal functioning
come (ThyPRO) [12] at 12 months after recruitment. and arthritis are recorded through an arthritis
The primary analyses will be done in the 80 years and questionnaire at final follow up.
over group (IEMO and TRUST participants). The results  Haemoglobin: measured on a full blood count at
will be compared through subgroup analysis with those baseline and 12 months.
in the 79 years and under group (TRUST participants)
as a secondary analysis. The ThyPRO is an 85-item See Table 1 for detailed schedule of assessments.
patient-reported outcome measure, evaluating symp-
toms, well-being and function on 85 items summarised Safety
in 14 scales, ranging 0–100, with higher scores repre- Full details of all Serious Adverse Events (SAEs), Ad-
senting more symptoms or impact of disease. For this verse Events (AEs) of special interest (atrial fibrillation,
study three scales with 19 items are evaluated: Tired- heart failure, fractures, new diagnosis of osteoporosis),
ness, Hypothyroid physical symptoms and Hyperthyroid study treatment withdrawals and ThyPRO hyperthyroid
physical symptoms. symptoms are recorded at all visits and telephone con-
tacts. Participants and GPs have 24-h access to an emer-
Secondary study endpoints gency trial phone number operated by a certified
physician for the reporting of SAEs.
 Generic quality of life: EuroQOL EQ-5D-3 L [13] at
baseline, 6–8 weeks, 12 months and final follow up. Biobank
 Thyroid-related quality of life ThyPRO [12] at Blood samples for the IEMO biobank are collected at
baseline, 6–8 weeks and at final follow-up. baseline (40 ml venous blood) and at 12 months (10 ml
 Thyroid-related quality of life: ThyPRO-39 [14] re- venous blood). The following 19 aliquots (0.75 ml each)
corded at final follow-up (additional 28 questions). are stored per participant at baseline: 3 EDTA plasma, 1
 Executive cognitive function: Letter Digit Coding whole blood, 2 citrated plasma, 1 NaF plasma, 1 buffy
Test [LDCT] [15] at baseline and final follow-up. coat, 3 heparin plasma, and 8 serum aliquots. The
 Handgrip strength: Jamar hand dynamometer (best 12 months bloods are stored in four serum 0.75 ml ali-
of 3 measures in dominant hand) at baseline, quots per participant.
12 months and final follow up. Analyses in the IEMO biobank will be performed in
 Functional ability: Activities of Daily Living (Barthel combination with the TRUST biobank. Both biobanks
Index [BI] [16, 17]), Instrumental Activities of Daily are organised by the same biobank committee. The
Living (Older Americans Resources and Services IEMO biobank will be stored at the Department of Clin-
[OARS] [18]), 6- m gait speed [19], independent ical Chemistry of Leiden University Medical Center
living status and falls questionnaire at baseline and (LUMC), the Netherlands. The biobank consists of all
final follow up. plasma, serum, and DNA material of all randomised
 Blood pressure: systolic and diastolic measured at IEMO participants that provide consent for storing bio-
baseline, 12 months and final follow up bank material. The Department of Clinical Chemistry of
 Height, weight, waist circumference and body mass the LUMC is fully accredited (EN ISO 15189:2012) by
index: recorded at baseline, 12 months and final the Dutch Accreditation Council. The Biobank adheres
follow up to all necessary quality assurance standards and legal
 Mortality: all-cause and cardiovascular are requested guidelines.
through national mortality registries
 Fatal and non-fatal cardiovascular events: including Sample size calculation
acute myocardial infarction, stroke, amputations for The total number of participants in all published trials
peripheral vascular disease and revascularisations for on SCH before 2017 is 450 across 12 studies, including
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 7 of 14

only a small numbers of older people and very heteroge- 10% loss to follow-up in both trials a projected 145 add-
neous endpoints across studies. itional participants will be recruited in the IEMO trial.
We aim to study endpoints that are of particular rele- The follow up phase of the trial is expected to be
vance for the oldest old, including endpoints in those complete in May 2018 with one additional month of
with considerable comorbidity. SAE recording.
Originally, the IEMO 80-plus thyroid trial had set out
to analyse 450 participants with SCH aged 80 years and Data analysis
over. Additionally, a pre-planned pooled analysis of 900 The data centre (Robertson Centre for Biostatistics,
participants was agreed upon, of which 450 were re- Glasgow, ISO 9001/2008 certified) is responsible for
cruited directly through this study and a subset over the writing, implementing and revising a statistical analysis
age of 80 years from the TRUST trial would add another plan that is agreed upon before locking the study data-
450 participants, to further increase the statistical power base and will have full access to the final study database
to detect significant changes in this subgroup. The for the planned analyses. A copy of the statistical ana-
power calculations were based on two main study lysis plan is appended to this manuscript as Add-
endpoints: itional file 1. All analyses are based on a modified
intention-to-treat principle and the primary time-point
1. Fatal and non-fatal cardiovascular events. for analysis is after 12 months of treatment. The main
2. Change in thyroid-related quality of life (ThyPRO analyses will be based on the combined IEMO and
Tiredness and Hypothyroid physical symptoms). TRUST 80-plus participants (n = 291).
Analyses will be presented separately for:
Due to several limiting factors including delays in
starting the studies, caused by difficulties procuring – the IEMO 80-plus participant cohort (n = 145)
study medication and matching placebos, it proved im- – the TRUST 80-plus participant subset (n = 146)
possible to reach this number, similar to the experiences – the combined IEMO and TRUST 80-plus partici-
in the TRUST trial [10]. Therefore, in 2015, revised pants compared with the TRUST 80-minus partici-
power calculations were proposed (study protocol pants (n = 291 vs n = 591)
amendment 8, 04/06/2015) and accepted by the funding
agent, sponsor, medical ethical committee (15/07/15) Summary information for all participants and between
and competent authority (03/07/2015). These revisions the treatment groups will be made available. Similar to
detailed the change of primary study endpoint cardiovas- the TRUST trial [10], continuous variables measured at
cular events into a secondary study outcome, accepting baseline and follow-up will be analysed at each time
the possibility of being underpowered to answer this sec- point comparing treatment groups adjusting for stratifi-
ondary endpoint. This allowed the power calculations to cation variables and baseline levels of the same variable
be revised according to the remaining primary outcome using analysis of covariance. Additionally, repeated mea-
thyroid-related quality of life. sures regression analysis will be performed with regards
The resulting revised sample-size calculation is based to the primary time-point and final assessment for each
on the pre-planned pooled analysis of one of the participant. For calculating ThyPRO scores, raw total
co-primary endpoints of thyroid-related quality of life scores containing valid missing items will be scaled to
(ThyPRO Hypothyroid physical symptoms and Tired- maintain the maximum possible score. Clinical outcome
ness scale score). According to previous studies applying data will be analysed using time-to-first-event Cox pro-
the ThyPRO, a study should be adequately powered for portional hazards regression analysis in models that con-
at least a difference of 9 points to be clinically meaning- tain the randomised treatment allocation and
ful. Using an expected standard deviation of the differ- stratification variables as covariates. Treatment effect
ence of 26 [21] and a power of 80%, 132 participants are will be analysed using the Wald-test and corresponding
required per trial group adding to a total of 264 partici- point estimates and 95% confidence intervals for the
pants to be included in the combined 80-plus analyses. hazard ratio for treatment will be estimated. The as-
For all secondary continuous endpoints this sample size sumption of proportionality of hazards will be tested.
is deemed large enough to provide statistically robust re- Analysis of the primary outcomes will be performed in
sults. For the secondary endpoints on cardiovascular the modified intention to treat (ITT) population, based
events and mortality the possibility of being underpow- on participants with data available on the outcome of
ered is accepted. interest. The ITT population will be used for analyses
Over a recruitment period of almost 3 years the on efficacy and safety. In addition, analyses using mixed
TRUST trial recruited 737 participants to the trial of effects models and multiple imputations will be used for
which 146 participants were aged 80 and over. Assuming sensitivity analysis. The per protocol population will also
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 8 of 14

be used for all primary and secondary outcomes as ex- (PI), Dr. Rosalinde K.E. Poortvliet, Dr. Iris Postmus,
ploratory analyses. Robert S. Du Puy, MSc, Professor Robin. P. Peeters, Pro-
Owing to the intended similarities in study design be- fessor Bruce. H.R. Wolffenbuttel and Dr. Barbara. C. van
tween the IEMO 80-plus thyroid trial and the TRUST Munster. For Switzerland the organising committee was:
trial, the data allow for a pooled subgroup analysis of the Professor N. Rodondi (PI) and Dr. Manuel Blum,
TRUST and IEMO 80-plus participants compared with An Independent Data Monitoring Committee (IDMC)
the TRUST 80-minus participants. Outcome differences assesses safety data in order to protect the ethical and
between these groups will highlight the additional clin- safety interests of the participants recruited into the
ical merits or adverse effects of levothyroxine replace- study, while safeguarding, as far as possible, the scientific
ment therapy for older participants aged 80 and over. validity of the study. The IDMC reviews annual safety
Other pre-planned subgroup analyses include: baseline and efficacy data and may request additional data if con-
TSH in two groups (< 10/≥10 mIU/L) or in three groups sidered necessary. The IDMC meets at least once a year
(< 7/7–9.99/≥10 mIU/L), sex (male/female). However, we and is composed of medical experts and a biostatistician
accept that our study will be underpowered for some of without any involvement in the study as investigators or
the smaller subgroups, such as male participants, TSH as study participant care physicians. The committee is
above 10.0 and below 19.9 mIU/L. We should however empowered to make a recommendation on early stop-
have sufficient statistical power in the combined analysis ping when there is overwhelming evidence of benefit for
to detect beneficial effects in the larger or dominant sub- the primary outcome or when it considers there is ad-
groups, such as female and TSH in the range above 4.6 equate evidence of harm. The IDMC members are: Pro-
and below 10.0 mIU/L. fessor Gary Ford (Chair; Chief Executive Officer of the
Oxford Academic Health Science Network, Oxford),
Monitoring and committees Professor Thompson G Robinson (University Hospitals
To secure the highest quality of participant care and of Leicester NHS Trust, Department of Cardiovascular
safety, the careful titration algorithm avoids the possibility Sciences, Leicester Royal Infirmary, Leicester), Professor
of prolonged periods of levothyroxine over-replacement. Colin Dayan (Institute of Molecular and Experimental
Similarly, the system guards against participants develop- Medicine, Cardiff University School of Medicine, Heath
ing overt hypothyroidism that might require open-label Park, Cardiff ), Professor Kathleen Bennett (Department
levothyroxine use. of Pharmacology and Therapeutics, Trinity Centre for
All SAEs, AEs and AEs of special interest are recorded, Health Sciences, St James’s Hospital, Dublin).
notified, assessed, reported, analysed and managed in ac- A study Endpoint Committee, blinded to treatment al-
cordance with the Medicines for Human Use (Clinical location, provides independent and unbiased review of
Trials) Regulations 2004 and the study protocol. All clinical endpoint events which occur during the study,
events are followed up until resolution or stabilization ensures unified and unambiguous events evaluation
occurs, and are assessed for seriousness, expectedness practices across the study and compensates for regional
and causality by the chief investigator. Serious adverse diversity in medical practice at the site of endpoint
events are reported to the sponsor by thorough record- evaluation and classification. All causes of death, stroke,
ing in the eCRF and to the local accredited Medical Eth- myocardial infarction and heart failure hospitalisations
ics Committee and competent authority. Annually and are potential endpoints to be reviewed on the data sup-
at the end of the trial 100% study monitoring visits are plied through the eCRF and if necessary acquired source
conducted by independent clinical research associates, in documentation. The Endpoint Committee members are:
accordance with the Netherlands Federation of Univer- Professor Peter Langhorne (Chair; Professor of Stroke
sity Medical Centres’ report ‘Kwaliteitsborging van Care, Institute of Cardiovascular and Medical Sciences,
Mensgebonden onderzoek’. All important decisions University of Glasgow), Professor J Wouter Jukema
made leading to protocol modifications are communi- (Vice-chair; Professor of Cardiology, Leiden University
cated to all relevant parties, including the trial registry, Medical Center, The Netherlands), Dr. Tin Hai Collet
ethical committees and competent authorities. (Department of Ambulatory Care and Community
All main decisions for the study were made by the Medicine, University of Lausanne, Switzerland), Profes-
steering group. Its members are: Dr. Simon P. Mooijaart, sor Olaf M Dekkers Leiden University Medical Center,
Dr. Jacobijn Gussekloo, Dr. Olaf M. Dekkers, Dr. Jan The Netherlands) and Dr. Anne Marie O’Flynn (Depart-
Smit, Dr. J.Wouter Jukema, Dr. Anton. J.M. de Craen ment of Epidemiology and Public Health, UCC, Ireland).
(Leiden, the Netherlands, Deceased). A TRUST/IEMO Biobank committee supervises the
Each national site was supervised by a local organising storage and analysis of the biobank samples. Members
committee and Principle Investigator. For the Netherlands are: Professor Patricia M. Kearney, Dr. H. Anette van
the organising committee was: Dr. Simon P. Mooijaart Dorland (Bern, Switzerland), Dr. Wendy P.J. den Elzen.
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 9 of 14

Each national study site is supervised by a local spon- largest experimental evidence base on the multimodal
sor, responsible for the oversight of the clinical trial and effects of levothyroxine treatment in 80-plus persons to
supplying proper insurance to cover any liabilities during date. Trial results are expected to be publicly dissemi-
and after the trial arising from trial conduct and partici- nated in the fall of 2018.
pation. The sponsors is not involved in the preparation,
or approval of any scientific outputs. Appendix 1: Patient Information leaflet for
screening
Dissemination Thyroid hormone replacement for older persons with
This study is well suited to promote effective dissemin- mild thyroid dysfunction.
ation of the results and implications. Arrangements re- In the past 3 years blood was drawn at your general
garding sharing of data and joint publication are laid practice office or in the hospital. The results showed that
down in a Memorandum of Understanding between the you may be eligible for participating in the IEMO 80+
TRUST trial and IEMO 80-plus thyroid trial project Thyroid Trial. For this reason your general practitioner
group. Due to its role as a knowledge centre with an or hospital specialist sends you this letter and the infor-
education and research program in the field of ageing, mation leaflet regarding this research study.
vitality and geriatric medicine, the Leiden Academy on 1. What is the purpose of the research study?
Vitality and Ageing is well placed to play a coordinating Thyroid hormone has many important functions in
role in the dissemination activities. Schildklier Organisa- the human body, for example supporting the correct
tie Nederland, the patient advocacy group, will closely function of the muscles, circulation, the brain and me-
collaborate with the study team to help align the study tabolism. When a shortage of thyroid hormone is
outputs with the patients and public need. present, bodily functions may not work optimally.
The Institute for Evidence-based Medicine in Old Age The results of one of your blood tests from the past
(the Netherlands) is ideally placed to ensure that the re- suggest that you may have mild thyroid dysfunction
sults of the study are considered by relevant profes- (subclinical hypothyroidism). This is when thyroid hor-
sionals, and will be included in the leading clinical mone levels are within the normal laboratory limits, but
guidelines. In cooperation with the Cochrane collabor- signs are present that the body is urging the thyroid
ation the results of the trial will be offered for the update gland to work harder. This is usually a chance finding.
of the Cochrane systematic review of treatment of sub- This particular blood test result is common in older per-
clinical hypothyroidism, allowing for independent scien- sons: of all persons aged 65 years and over 1 in 6 may
tific interpretation, placing results in context and have subclinical hypothyroidism. It is currently unknown
maximising understanding of the implication of the trial. whether it is beneficial to treat subclinical
To comply with the general social responsibility asso- hypothyroidism with artificial thyroid hormone. The
ciated with clinical research, the trial results will be pro- IEMO 80+ Thyroid Trial was set out to investigate this
actively disseminated to the general public and key problem. The purpose of the IEMO 80+ Thyroid Trial is
public health stakeholders through established media to find out what effects (good and bad) thyroxine re-
networks. placement has in older people with subclinical
hypothyroidism. In total 150 Dutch participants will par-
Discussion ticipate in the IEMO 80+ Thyroid Trial.
In the latest Cochrane review of levothyroxine replace- 2. What drug will be investigated?
ment therapy for SCH (12 studies, only 491 participants We investigate the effect of synthetic thyroid hormone
in total) most studies excluded those who suffered from (Levothyroxine) in older persons with subclinical
multimorbidity, none of the studies reported on oldest hypothyroidism. This thyroid hormone is given by tablet
old separately and two trials excluded those over the age orally (by mouth). We will compare the effects of the
of 80 years [22]. Robust evidence for the potential clin- thyroid hormone tablets with effects of a placebo tablet.
ical merits or adverse effects in 80-plus persons with The placebo tablets contain no active drug, but are iden-
SCH is greatly needed to help guide clinical practice. tical in look, taste and smell.
The IEMO 80-plus thyroid trial is a representative ran- 3. How will the research study be conducted?
domised controlled trial on levothyroxine treatment for You have been asked to take part in this study because
SCH, with representative 80-plus persons and a wide your recent screening blood test has suggested that you
range of characteristics and morbidities, studying may have subclinical hypothyroidism. In some persons
end-points that are relevant to the older population and subclinical hypothyroidism corrects over time, whilst in
clinical practice. The combined analysis of participants other persons a clear shortage of thyroid hormone is
in the IEMO 80-plus thyroid trial with those aged over identified. For this reason the first phase (the selection
80 who participated in the TRUST trial will provide the phase) will determine whether you have a persistent
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 10 of 14

subclinical hypothyroidism. Only when this is the case, hypothyroidism the research study may yield important
are you eligible for the second phase of the study (the information. The blood measurements taken will most
treatment phase). likely not result in harmful effects.
If you agree to participate in the selection phase of the 5. What happens if you decide not to participate in
study we ask you to complete and sign the consent form the research study?
and send this in the enclosed envelope to the study cen- Your participation is entirely voluntary and you are
ter in the Leiden University Medical Centre. The study not in any way obliged to take part. You decide whether
center will return a laboratory form and will ask you to you want to participate. If you decide not to participate,
visit your general practice laboratory or hospital research no further action is required, and you are not required
facility for a screening visit within 2 weeks. In this to provide a reason for not participating. If you do de-
screening visit a blood test will be performed to assess cide to participate, you reserve the right to withdraw
the levels of thyroid hormone. The results of this test from the research study at any given time without pro-
will be send to the research center in the Leiden Univer- viding a reason to do so. Whether you decide to partici-
sity Medical Centre. If you are unable to visit the labora- pate or not will in no way affect the standard of care you
tory, please contact the study center. They will arrange receive or the relationship you have with your general
for a laboratory nurse to visit you at home. practitioner or hospital specialist.
If the results from the screening test indicate that you 6. Will the research study result in additional ex-
are not eligible for the treatment phase, the study center penses/provide compensation?
will inform you in writing with the screening results and No. You will not be charged for expenses related to
an explanation. The screening result will be shared with the study medication or blood tests. Participating in this
your general practitioner or hospital specialist. research study will not affect your policy excess for med-
If the results from the screening tests are satisfactory ical insurance. No compensation is provided for partici-
you will be invited to take part in the treatment phase of pating in the research study.
the study. A research nurse will contact you with the 7. Further information?
screening results and to plan an appointment for a home Should you have any additional questions regarding
visit. During this home visit the research nurse will ex- the research study you are welcome to contact the
plain the treatment phase of the research study and you IEMO secretary, telephone 071–526 84 93, or the cen-
may decide to participate in the treatment phase. tral study coordinator: The Institute for Evidence-Based
If you decide to take part, you will be asked to Medicine in Old Age | IEMO.
complete and sign a second consent form. After signing Email: iemo_schildklierstudie@lumc.nl. More informa-
the form some medical questions will be asked (includ- tion can be found on the study website:
ing general questions regarding health, medication use www.iemoschildklierstudie.nl
and quality of life) as well as some additional measure- For questions or problems you may also contact the
ments taken (including blood pressure, heart rhythm independent general practitioner, Dr. Niels H. Cha-
and grip strength). vannes, telephone 071–526 84 44, n.h.chavanne-
After the home visit a computer will randomly allocate s@lumc.nl. He is up-to-date with all proceedings of the
you to either the levothyroxine or placebo treatment trial, but is not involved with the conduct.
group. The chance of allocation to either group is equal 8. Appendices
(50%). The study drug will be taken daily, at least 1. Informed consent form.
30 min before breakfast, during a maximum of 2 years. 2. envelope.
A research nurse will perform home visits at the start
of the research study, after 6–8 weeks, after 12 months Appendix 2: Patient Information leaflet for
and after 24 months. We will ask you to visit the general randomisation
practice laboratory before every home visit to assess thy- Thyroid hormone replacement for older persons with
roid hormone levels. mild thyroid dysfunction
4. What are the possible risks and benefits in Several weeks ago your general practitioner or hospital
participating? specialist has invited you for a blood screening test. Ac-
It is not certain whether you will gain personal benefit cording to the test results you still have mild thyroid dys-
from participating in the research study. After all, the function (subclinical hypothyroidism). You are being
purpose of this research study is to assess whether treat- invited to take part in a research study:
ment with levothyroxine provides important benefits. A The IEMO 80+ Thyroid Trial
potential benefit is that your thyroid function will be as- In this leaflet you’ll find detailed information regarding
sesses regularly, both in the screening and treatment the research study. Please take your time to review the
phase. For future older persons with subclinical contents carefully and discuss these with your partner,
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 11 of 14

friends or family. Should you have additional questions mouth). We will compare the effects of the thyroid hor-
you are welcome to discuss these with your general prac- mone tablets with effects of a placebo tablet. The pla-
titioner, a researcher or the research nurse. Additionally cebo tablets contain no active drug, but are identical in
you may contact the independent general practitioner, look, taste and smell. You will not be informed which of
who knows a lot about the study, but is not involved with the two treatments you will receive. The study nurses
the conduct. Contact information can be found on the are also unaware of your allocation.
final page. You will start with 1 tablet, that will contain either 50
1. What is the purpose of the research study? micrograms of levothyroxine (or 25 micrograms if your
Thyroid hormone has many important functions in weight is below 50 kg or have a history of coronary stric-
the human body, for example supporting the correct tures) or placebo. After 6–8 weeks all participants will
function of the muscles, circulation, the brain and me- have their blood hormone levels analysed. Based on
tabolism. When a shortage of thyroid hormone is these results a decision is made to change the treatment
present, bodily functions may not work optimally. dose. If the laboratory results indicate a change in treat-
The results of one of your blood tests from the past ment dose is warranted a research nurse will explain this
suggest that you may have mild thyroid dysfunction to you. From this point annual blood tests will monitor
(subclinical hypothyroidism). This is when thyroid hor- the response to the treatment (after 12 and 24 months).
mone levels are within the normal laboratory limits, but 3. How will the research study be conducted?
signs are present that the body is urging the thyroid You have been asked to take part in this study because
gland to work harder. This is usually a chance finding. your recent screening blood test has suggested that you
This particular blood test result is common in older per- may have subclinical hypothyroidism.
sons: of all persons aged 65 years and over 1 in 6 may If you agree to participate in the selection phase of the
have subclinical hypothyroidism. It is currently unknown study we ask you to complete and sign the consent form
whether it is beneficial to treat subclinical and send this in the enclosed envelope to the study cen-
hypothyroidism with artificial thyroid hormone. ter in the Leiden University Medical Centre. We ask
Having subclinical hypothyroidism is associated with your permission to store additional blood samples for fu-
slightly higher odds of developing cardiovascular dis- ture research on blood and hereditary materials (DNA)
eases. Earlier small scale research demonstrated that that may influence the effects of thyroid hormone on
treatment with synthetic thyroid hormone may provide bodily functions (such as the circulation, muscle
beneficial effects on the circulation in older persons with strength, memory problems or frailty). The DNA will be
subclinical hypothyroidism. Alternatively, synthetic thy- isolated from the blood and stored for future research.
roid hormone treatment may also result in unwanted This blood sample (equivalent to 8 teaspoons) will be
side effects. Both the good and bad effects of thyroid taken during the first home visit. Other research not re-
hormone treatment have not been proven to this date. lated to this research study will not have access to the
The purpose of the IEMO 80+ Thyroid Trial is to find stored blood and DNA samples and any information in
out what effects (good and bad) thyroxine replacement the samples cannot be retraced to individual persons. If
has in older people with subclinical hypothyroidism. you object to the storage of blood and DNA you may
The research study has a specific aim to prevent car- choose not to participate in this particular portion of the
diovascular diseases, and to improve the quality of life trial.
(for example by alleviating tiredness complaints), muscle After signing the consent form some medical ques-
strength and brain function. In total 150 persons in the tions will be asked (including general questions regard-
Netherlands will take part in the IEMO 80+ Thyroid ing health, medication use and quality of life) as well as
Trial. ‘IEMO 80+’ means that the research study is per- some additional measurements taken (including blood
formed in persons aged 80 years and older. IEMO is an pressure, heart rhythm and grip strength). This home
abbreviation for the Institute for Evidence-Based Medi- visit will take approximately1 to 1.5 h.
cine in Old Age, the institute responsible for coordinat- After the home visit a computer will randomly allocate
ing the research study. you to either the levothyroxine or placebo treatment
2. What drug will be investigated? group. The chance of allocation to either group is equal
We investigate the effect of synthetic thyroid hormone (50%). The study drug will be taken daily, at least
(Levothyroxine) in older persons with subclinical 30 min before breakfast, during a maximum of 2 years.
hypothyroidism. This synthetic thyroid hormone is iden- A research nurse will perform home visits at the start
tical to the thyroid hormone produced by the human of the research study, after 6–8 weeks, after 12 months
body and is the standard treatment when a definite and after 24 months. We will ask you to visit the general
shortage of thyroid hormone is identified in the blood. practice laboratory before every home visit to assess thy-
This thyroid hormone is given by tablet orally (by roid hormone levels.
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 12 of 14

4. What is expected of you? 8. What happens if you decide not to participate in

If you decide to participate in the research study, you the research study?
will be asked: Your participation is entirely voluntary and you are
not in any way obliged to take part. You decide whether
 To take between 1 and 3 tablets, once every day, in you want to participate. If you decide not to participate,
the morning no further action is required, and you are not required
 To attend home visits with a research nurse for to provide a reason for not participating. If you do de-
measurements cide to participate, you reserve the right to withdraw
 To visit the general practice laboratory for thyroid from the research study at any given time without pro-
hormone tests (after 6–8 weeks, after 12 months viding a reason to do so. Whether you decide to partici-
and after 24 months). pate or not will in no way affect the standard of care you
receive or the relationship you have with your general
There are no lifestyle or dietary restrictions in this re- practitioner or hospital specialist.
search study. Data from your medical records at the gen- 9. What happens after the research study is
eral practice office or hospital specialist will be collected. finished?
Your general practitioner or hospital specialist will be in- When the treatment phase of the study completes, the
formed of your participation in the study. results will be analysed by the coordinating researchers.
5. Are there other treatment options? This process will last several months after the last par-
There are no other treatment options for mild thyroid ticipant has finished the duration of the study. You and
dysfunction (subclinical hypothyroidism). your general practitioner will be informed in writing of
6. What are the possible side effects? your results during the study, and whether you were al-
Side effects from levothyroxine treatment are only located to the levothyroxine or placebo group. Based on
rarely seen, particularly if blood tests are done regularly this information you and your general practitioner may
and adjustments to levothyroxine dosages are made to discuss whether further treatment with levothyroxine is
keep thyroid hormone levels in the normal range. If in your best interest.
levothyroxine is prescribed in too high dosages there is a 10. Are you insured during the research study?
risk of side effects such as heart palpitations, tremors, All participants of the research study are covered by
sweating, feeling agitated, tiredness and shortness of insurance for potential damages resulting from the
breath and chest pains. Overmedication may cause leg study, both during the study period and within 4 years
swelling and there may be an increased risk of thinning of ending the study. At the end of this letter you will
of the bones (osteoporosis) and fractures. find the insured amounts, exceptions and contact infor-
If you suffer from epilepsy overmedication with thy- mation of the insurance agency.
roid hormone may result in an increased risk of seizures. 11. What if new information becomes available?
If you are on an anticoagulant it is possible that the The data from all study participants are reviewed at
dose may need to be adjusted to prevent your blood be- fixed time points by a specially installed independent
coming too thin. commission. If the safety or quality of life of the partici-
If you are allocated to the inactive tablets (placebo) there pants is in jeopardy, this commission is entitled to stop
is a risk that the thyroid gland may slow down further, the research study. The study team will contact you dir-
and they may develop symptoms of an underactive thy- ectly should this occur.
roid, including tiredness and lethargy. Should this develop 12. What happens to the data collected?
during the research study the blood tests will identify an In this research study data from interviews, question-
underactive thyroid and your general practitioner or hos- naires and measurements will be collected. As well as
pital specialist will be consulted for starting treatment. blood sample analysis. All data and materials collected will
7. What are the possible risks and benefits in be handled and stored confidentially. Only the lead inves-
participating? tigator will have access to personal information.
It is not certain whether you will gain personal benefit Unauthorized personnel will have no access to your data.
from participating in the research study. After all, the pur- The results from this research study will be published in
pose of this research study is to assess whether treatment scientific journals; the data will not be traceable to individ-
with levothyroxine provides important benefits. A potential ual persons. Anonymised research data will be made avail-
benefit is that your thyroid function will be assesses regu- able to the IEMO 80+ Thyroid Trial investigators.
larly, both in the screening and treatment phase. For future 13. Will your general practitioner/hospital special-
older persons with subclinical hypothyroidism the research ist be informed of study participation?
study may yield important information. The blood measure- We think it is important that your general practitioner
ments taken will most likely not result in harmful effects. or hospital specialist is informed when study medication
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 13 of 14

is given. For this reason we will inform your general Funding

practitioner or hospital specialist in writing of your par- The IEMO 80-plus thyroid trial has been peer reviewed and approved for
funding under the ZonMw programme Evidence-based Medicine in Old
ticipation. A specific section of the consent form ex- Age, ZonMW programme number: 627001001. The Swiss part of the trial was
plains this in more detail. It is not possible to participate supported by grants from the Swiss National Science Foundation to Dr.
in the research study without this consent. Rodondi (SNF 320030–150025 and 320030–172676).
The TRUST study was supported by a research grant from the European
14. Will the research study result in additional ex- Union FP7-HEALTH-2011 programme - Investigator-driven clinical trials for
penses/provide compensation? therapeutic interventions in elderly populations. Grant agreement number
No. You will not be charged for expenses related to 278148. Study medication was supplied free of charge by Merck KGaA.

the study medication or blood tests. Participating in this Availability of data and materials
research study will not affect your policy excess for med- The authors welcome proposals for joint use of the study data after the
ical insurance. No compensation is provided for partici- planned publications of the study data have been completed. Proposals
should be sent to the corresponding author.
pating in the research study.
15. Who has reviewed the study? Authors’ contributions
The Medical Ethics Committee from the Leiden Uni- All authors have fulfilled the following: 1. made substantial contributions to
conception and design, or acquisition of data, or analysis and interpretation
versity Medical Centre has reviewed and approved the of data; 2. been involved in drafting the manuscript or revising it critically for
research study. important intellectual content; 3. given final approval of the version to be
16. Further information? published. Each author should have participated sufficiently in the work to
take public responsibility for appropriate portions of the content; and 4.
Should you have any additional questions regarding agreed to be accountable for all aspects of the work in ensuring that
the research study you are welcome to contact the questions related to the accuracy or integrity of any part of the work are
IEMO secretary, telephone 071–526 84 93, or the cen- appropriately investigated and resolved. Contributions to the TRUST trial
have been specified elsewhere [10]; most importantly DJS (head PI), NR, PMK,
tral study coordinator: The Institute for Evidence-Based RGJW, JG (national PI’s), IF (lead statistician). Notable additional contributions
Medicine in Old Age | IEMO. for the IEMO 80 + trial and the over-80 combined analyses: Study conception
Email: iemo_schildklierstudie@lumc.nl. More infor- and design: SPM (lead), JG, RGJW, DJS; lead on interpretation of data for the
work AND Lead in finalising the manuscript: SPM; acquired funding for IEMO
mation can be found on the study website: 80+ study: SPM (lead), RPP, BCvM, BHRW, JG, RGJW. Primary Investigator
www.iemoschildklierstudie.nl Netherlands: SPM (lead); Primary Investigator Switzerland: NR; IF Director of
For questions or problems you may also contact the Clinical. Trials Unit, University of Glasgow; Drafting of initial manuscript: RDP,
IP, JG.
independent general practitioner, Dr. Niels H. Cha-
vannes, telephone 071–526 84 44, n.h.chavanne- Ethics approval and consent to participate
s@lumc.nl. He is up-to-date with all proceedings of the For the Netherlands site the study was approved by the Medical Ethical
Committee on Research Involving Human Subjects (CCMO). For the
trial, but is not involved with the conduct. Switzerland site the study was approved by the Bern ethical board and by
the Swiss competent authority for drugs (Swissmedic). All participants
provided written informed consent for both the screening and the
Additional files participation phase (Additional files 2 and 3).

Additional file 1: Statistical analysis plan. (PDF 114 kb) Consent for publication
Not applicable.
Additional file 2: Participant consent form for screening. (PDF 68 kb)
Additional file 3: Participant consent form randomisation. (PDF 83 kb) Competing interests
ZonMw and the Swiss National Science Foundation, as the funder, had no
role in the design and conduct of the study nor in the preparation, review
Abbreviations or approval of the manuscript. Merck KGaA provided the study medication
AE: Adverse event; eCRF: Electronic case report form; fT4: Free thyroxine; and matching placebos without recompense. Merck KGaA was not involved
GP: General practitioner; IDMC: Independent Data Management Committee; in the design, funding or execution of the study or manuscript. The authors
IEMO: Institute for evidence-based medicine in old age; RCT: Randomised declare that they have no competing interest.
controlled trial; SAE: Serious adverse event; SCH: Subclinical hypothyroidism;
ThyPRO: Thyroid-related quality of life patient-reported outcome;
TRUST: Thyroid hormone replacement for untreated older adults with
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
subclinical hypothyroidism - a randomised placebo controlled trial;
published maps and institutional affiliations.
TSH: Thyroid stimulating hormone
Author details
1
Acknowledgements Department of Public Health and Primary Care, Leiden University Medical
The authors would like to thank K. Broekhuizen and C. van Beuzekom for Center, Leiden, the Netherlands. 2Department of Gerontology and Geriatrics
their significant investments in an earlier phase of this research. Merck KGaA (C7-Q), Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The
provided the study medication and matching placebos without recompense. Netherlands. 3Institute for Evidence-based Medicine in Old age, Leiden, the
The logistics of handling and distributing the study medication was done by Netherlands. 4Geriatric Medicine, Institute of Cardiovascular and Medical
Mawdsley Brooks & Co. Randomisation and providing an electronic data Sciences, University of Glasgow, Glasgow, UK. 5Department of General
capture and safeguarding system was performed by the Robertson Centre Internal Medicine, Bern University Hospital, University of Bern, Bern,
for Biostatistics. We also thank all members of the Independent Data Switzerland. 6Department of Clinical Chemistry and Laboratory Medicine,
Monitoring Committee. Leiden University Medical Center, Leiden, the Netherlands. 7Department of
Sponsor contact information: Trial Sponsor: Leiden University Medical Center, Internal Medicine, Erasmus University Medical Centre, Rotterdam, the
Address Albinusdreef 2, 2333 ZA, Leiden, Telephone: + 3171 5269111. Netherlands. 8Department of Internal Medicine, Academic Medical Center,
Du Puy et al. BMC Endocrine Disorders (2018) 18:67 Page 14 of 14

Amsterdam, the Netherlands. 9Department of Endocrinology, University 17. Quinn TJ, Langhorne P, Stott DJ. Barthel index for stroke trials: development,
Medical Center Groningen, University of Groningen, Groningen, the properties, and application. Stroke. 2011;42(4):1146–51.
Netherlands. 10Department of Public Health, University of Copenhagen, 18. George LK, Fillenbaum GG. OARS methodology. A decade of experience in
Copenhagen, Denmark. 11Center for Healthy Aging, University of geriatric assessment. J Am Geriatr Soc. 1985;33(9):607–15.
Copenhagen, Copenhagen, Denmark. 12Department of Epidemiology and 19. Bohannon RW. Measurement of gait speed of older adults is feasible and
Public Health, University College Cork, Cork, Ireland. 13Robertson Centre for informative in a home-care setting. J Geriatr Phys Ther (2001). 2009;32(1):22–3.
Biostatistics, University of Glasgow, Glasgow, UK. 14Department of Internal 20. Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of
Medicine, Copenhagen University Hospital Herlev, Gentofte, Denmark. the treatment satisfaction questionnaire for medication (TSQM version II)
15
Department of Cardiology, Leiden University Medical Center, Leiden, the among outpatient pharmacy consumers. Value Health. 2005;8(Suppl 1):S9–s24.
Netherlands. 16Department of Endocrinology and metabolic disorders, 21. Winther KH, Cramon P, Watt T, Bjorner JB, Ekholm O, Feldt-Rasmussen U,
Leiden University Medical Center, Leiden, the Netherlands. 17Radboud Groenvold M, Rasmussen AK, Hegedus L, Bonnema SJ. Disease-specific as
University Medical Center, Nijmegen, the Netherlands. 18Institute of Primary well as generic quality of life is widely impacted in autoimmune
Health Care (BIHAM), University of Bern, Bern, Switzerland. hypothyroidism and improves during the first six months of levothyroxine
therapy. PLoS One. 2016;11(6):e0156925.
Received: 3 May 2018 Accepted: 3 August 2018 22. Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement
for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;3:
CD003419.

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