Narrative review

Clinical trials for the prevention and treatment of

COVID-­19: current state of play
Joshua S Davis1,2 , David Ferreira2 , Justin T Denholm3,4, Steven YC Tong5

S
ince coronavirus disease 2019 (COVID-­19) emerged from Summary
Wuhan, China in December 2019, the pace of scientific
progress has been breathtaking. The COVID-­19 pandemic • Since coronavirus disease 2019 (COVID-19) emerged in Wuhan,
China in December 2019 and spread around the world, over 1100
is unprecedented in our lifetimes in many ways: the speed and
clinical studies have been registered globally on clinical trials reg-
scale of the global spread of disease, the impact on national and istries, including over 500 randomised controlled trials.
global economies, and in parallel the spread of information, mis-
• Such rapid development and launch of clinical trials is impressive
information (inadvertently incorrect) and disinformation (mali- but presents challenges, including the potential for duplication
ciously incorrect). and competition.
In this context, we have seen a fundamental change in the way • There is currently no known effective treatment for COVID-19.

that clinical trials are designed, implemented and reported.

• In order to focus on those studies most likely to influence clinical
practice, we summarise the 31 currently registered randomised
Rather than the usual timeline of at least 12–24 months from trials with a target sample size of at least 1000 participants.
clinical trial concept to first patient enrolled, since COVID-­19 • We have grouped these trials into four categories: prophylaxis;
disease was widely recognised, over 1100 clinical studies have treatment of outpatients with mild COVID-19; treatment of hos-
been registered, of which more than 500 are randomised tri- pitalised patients with moderate COVID-19; and treatment of hos-
als. Let us pause for a moment to reflect on how remarkable pitalised patients with moderate or severe disease.
this is: in December 2019, no one had heard of severe acute • The most common therapeutic agent being trialled currently is
respiratory syndrome coronavirus 2 (SARS-­CoV-­2) or the dis- hydroxychloroquine (24 trials with potential sample size of over
25 000 participants), followed by lopinavir–ritonavir (seven trials)
ease it causes, COVID-­19. Within weeks of the first cases pre-
and remdesevir (five trials)
senting in Wuhan, the causative pathogen had been identified
and sequenced and diagnostic tests were developed. Within
• There are many candidate drugs in pre-clinical and early phase de-
velopment, and these form a pipeline for future large clinical trials
1–2 months, multiple clinical trials had been launched, in- if current candidate therapies prove ineffective or unsafe.
cluding securing funding and investigational product sup-
ply, writing of protocols, ethics and site approvals, database
design, data capture and randomisation schedules, statistical To help clarify which studies are most likely to influence clinical
analysis plans, and safety monitoring. All of this was achieved practice, this narrative review summarises currently registered
in the midst of an evolving pandemic that was overwhelm- large clinical trials of therapeutic agents for COVID-­19.
ing hospitals and health services, and during government-­
sanctioned social distancing, when face-­to-­face meetings were
not possible. Scope of this article
In part, this extraordinary speed was assisted by what we have We have only included:
learned from similar recent pandemics: severe acute respiratory
syndrome (SARS) in 2003,1 Middle East respiratory syndrome
(MERS) in 2012,2 and H1N1 influenza in 2009.3 SARS and MERS
• trials registered in one or more national or international clini-
cal trials registries;
are caused by coronaviruses which are closely related to SARS-­
CoV-­2, and several candidate drugs for their treatment were • trials including at least two arms, with interventions allocated
identified by in vitro assays followed by animal studies and lim- by randomisation;
ited clinical trials.4,5 These drugs were the first to be repurposed • trials assessing therapeutic or prophylactic agents, including an-
for clinical trials in COVID-­19. Most of the drugs being tested in tiviral, immunomodulatory and miscellaneous drugs or blood
larger trials have either been shown to have an in vitro antivi- products. We have excluded trials assessing devices (eg, oxygen
ral effect against SARS, MERS or SARS-­CoV-­2,6,7 or to have an delivery devices), therapeutic strategies (eg, higher versus lower
immunomodulatory effect which would be expected to reduce positive end expiratory pressure, liberal versus restrictive fluid
the uncontrolled lung inflammation in late COVID-­19 disease8 strategies), and other non-pharmacological interventions; and
(Box 1). • trials with a target total sample size of at least 1000 partici-
Following the 2009 H1N1 influenza pandemic, international ob- pants. We chose this arbitrary threshold because such trials
servational studies and research platforms were designed and are the most likely to result in findings which influence clin-
MJA 213 (2) ▪ 20 July 2020

sat ready to activate for the next pandemic. These include the ical practice, and it filters out phase 1 and 2 trials of agents
International Severe Acute Respiratory and Emerging Infection which may never enter clinical practice.
Consortium (ISARIC), whose data collection tools have been
used for many of the current COVID-­19 trials.9 Finally, the World We excluded trials assessing traditional Chinese medicines,
Health Organization (WHO) rapidly developed and made pub- because their results will be unlikely to be implementable in-
licly available a master protocol in early March, in an attempt to ternationally, as well as trials which have been suspended or
guide and harmonise COVID-­19 clinical trials. abandoned.

1
Menzies School of Health Research, Darwin, NT. 2 John Hunter Hospital, Newcastle, NSW. 3 Royal Melbourne Hospital, Melbourne, VIC. 4 University of Melbourne, Melbourne, VIC. 5 Peter
86 Doherty Institute for Infection and Immunity, Melbourne, VIC. joshua.davis@menzies.edu.au ▪ doi: 10.5694/mja2.50673
The unedited version of this article was published as a preprint on mja.com.au on 27 April 2020.
 Narrative review
We searched the following clinical trials registries: the United
States National Institutes of Health-­ hosted ClinicalTrials. 1 Characteristics of included trials (N = 31)
gov (www.clini​caltr​ials.gov), the Australian New Zealand No. of trials Comments
Clinical Trials Registry (www.anzctr.org.au), and the WHO
Patient setting
International Clinical Trials Registry Platform (www.who.
int/ictrp), which includes trials from all major national reg- Prophylaxis 12 6 pre exposure, 6 post
istries worldwide. We used a sensitive but non-­specific search exposure
strategy, using the search terms “COVID”, “SARS-­CoV-­2” and Mild disease 7
“Coronavirus”. We then reviewed each hit against the inclu- (outpatients)
sion criteria. The search was carried out on 7 April 2020 and
Moderate disease 4
repeated on 21 April 2020. In addition, we used two recently
created COVID-­ 19 metaregistries: a European collaborative Moderate to severe 9
disease
project (www.covid-nma.com) and a US-­led global collabo-
ration created by a commercial research organisation (www. Therapeutic agent
covid​19-trials.com). We encourage readers to consult these
Chloroquine or 24 Directly antiviral,
sources as the field is changing so rapidly. hydroxychloroquine immunomodulatory
Very variable dosing regimens
We found 31 currently registered trials which met our inclu-
sion criteria. Their key characteristics are summarised in Box 1. Antiretrovirals 8 Directly antiviral
We have grouped these trials into four categories: prophylaxis; 7 lopinavir–ritonavir
1 emtricitabine–tenofovir
treatment of outpatients with mild COVID-­19; treatment of hos-
pitalised patients with moderate COVID-­19; and treatment of Remdesivir 5 Directly antiviral
hospitalised patients with moderate through to severe disease Only available intravenously
caused by COVID-­19. Interferon 5 Upregulates host antiviral
immune responses
Prophylaxis trials Angiotensin 2 receptor 3 Attenuates angiotensin
blockers 2-­induced lung injury
We found 12 trials assessing prophylactic agents for COVID-­19
Cytokine blocking 3 Attenuates cytokine storm —
(Box 2). Analyses of COVID-­19 transmission in Shenzhen, China monoclonal induced lung damage
demonstrated household and close contact secondary infection antibodies Anakinra (IL-­1), tocilizumab
rates of 15% and 10%, respectively.10 Trials assessing prophylac- (IL-­6), sarilumab (IL-­6)
tic agents can be divided into pre-­exposure prophylaxis (PrEP; Small molecule kinase 2 Inhibits viral endocytosis
where the agent is taken continuously during a period of risk) inhibitors Imatininb, baricitinib
and post-­exposure prophylaxis (PEP; where the agent is taken
Vitamin C 2 Immunomodulatory
for a limited time, starting as soon as possible after exposure
to a known case). PEP has the theoretical advantage of preserv- Azithromycin 2 Immunomodulatory
ing precious drug supplies; PrEP strategies rely on entire at-­risk Other 5 Aspirin, statin, colchicine,
populations taking prophylactic drugs, only a small proportion faviparavir, dexamethasone,
of whom will actually be exposed. BCG vaccine

We found six registered trials assessing PrEP (Box 2), all of Sponsor-­t ype
which target health care workers and first responders, with a Investigator initiated 27
combined target sample size of over 110 000 participants. Four
Commercial 4
of these examine the benefit of the antimalarial and immuno-
modulatory drug hydroxychloroquine/chloroquine (COPCOV, Publicly available
WHIP COVID-­19 and CROWN CORONA) and one used the HIV protocol
drug emtricitabine–tenofovir (EPICOS). All have clinical end Yes 3
points of infection incidence and severity. One open label trial,
No 28
based in Australia, will randomise 4000 health care workers to
BCG vaccine, used for its purported off-­target immunomodula-
tory effects of reducing the risk of common infections other than
tuberculosis,11 or no intervention.
without hospital admission, and many clinical trials use outpa-
We also found six large PEP trials (Box 2). Hydroxychloroquine tient management as a surrogate for mild disease. About 80% of
is the interventional agent in five of these trials, while patients who contract COVID-­19 have mild or trivial symptoms;
MJA 213 (2) ▪ 20 July 2020

CORIPREV-­LR is using the HIV protease inhibitor lopinavir– this cohort is therefore large and important to include in clini-
ritonavir. Of note, secondary end points in CORIPREV-­LR will cal trials.12 Therapeutic agents which prevent disease progres-
include the short and long term psychological impact of corona- sion and thus the need for hospital admission would clearly be
virus exposure. of great benefit both to individual patients and to the health care
system as a whole. There are several randomised controlled tri-
als currently investigating the management of these patients
Outpatients with mild COVID-­19 (Box 3). Broadly, these trials can be classified based on target
population: the general infected population and those at high
Mild disease is variably defined, but is usually taken to mean
risk of worsening disease.
cough, fever, malaise and upper respiratory tract symptoms
without dyspnoea or the need for supplemental oxygen ther- Trials investigating treatment of the general infected popula- 87
apy.12 This overlaps substantially with the ability to manage tion include ACT COVID19, COVID-­19 PEP and a United States
 Narrative review

2 Randomised trials of prophylactic therapies for COVID-­19

Target Publicly
Trial acronym/ Country/ sample available
number Trial name region Sponsor type size Trial domains/arms Primary outcome protocol

Pre-­e xposure prophylaxis

COPCOV Chloroquine/ Europe, Asia Investigator 40 000 1. Chloroquine or Symptomatic infection No

(NCT04303507) Hydroxychloroquine initiated hydroxychloroquine and respiratory
Prevention of Coronavirus 2. Placebo severity score at 100
Disease (COVID-­19) in the days
Healthcare Setting

EPICOS Randomized Clinical Trial Spain Investigator 4000 1. Emtricitabine–tenofovir Confirmed No

(NCT04334928) for the Prevention of SARS-­ initiated disoproxil and symptomatic infection
CoV-­2 Infection (COVID-­19) hydroxychloroquine at 12 weeks
in Healthcare Personnel 2. Emtricitabine–tenofovir
disoproxil and placebo
3. Hydroxychloroquine and
placebo
4. Placebo and placebo

WHIP COVID-­19 Will Hydroxychloroquine United States Investigator 3000 1. Daily hydroxychloroquine Number of infections No
(NCT04341441) Impede or Prevent initiated 2. Weekly in health care workers
COVID-­19 hydroxychloroquine at 8 weeks
3. Placebo

CROWN CORONA CROWN CORONATION: Australia, Investigator 55 000 1. Low dose chloroquine or Symptomatic infection No
(NCT04333732) Chloroquine RepurpOsing Canada, initiated hydroxychloroquine and WHO 7-­point
to healthWorkers for Novel Ireland, South 2. Mid dose chloroquine or ordinal scale at 3
CORONAvirus mitigaTION Africa, United hydroxychloroquine months
Kingdom, US, 3. High dose chloroquine or
Zambia hydroxychloroquine
4. Placebo

BRACE BCG Vaccination to Protect Australia Investigator 4170 1. BCG vaccine Incidence of infection No
(NCT04327206) Healthcare Workers Against initiated 2. No intervention and severe infection at
COVID-­19 6 months

NCT04320238 Experimental Trial of rhIFNα China Investigator 2944 1. Low risk: recombinant New infection up to 6 No
Nasal Drops to Prevent initiated human interferon-α1b weeks
2019-­nCOV in Medical Staff 2. High risk: recombinant
human interferon-α 1b
and thymosin-α 1

Post-­e xposure prophylaxis

COVID-­19 PEP* Post-­e xposure Prophylaxis Canada, US Investigator 3000 1. Hydroxychloroquine Incidence of infection No
(NCT04308668) / Preemptive Therapy for initiated 2. Placebo and 3-­point ordinal
SARS-­Coronavirus-­2 scale at 14 days post
enrolment

NCT04318444 Hydroxychloroquine Post US (New York Investigator 1600 1. Hydroxychloroquine Symptomatic No

Exposure Prophylaxis for City) initiated 2. Placebo laboratory confirmed
Household Contacts of infection at 14 days
COVID-­19 Patients post enrolment

NCT04328961 Efficacy of US Investigator 2000 1. Hydroxychloroquine Laboratory confirmed No

Hydroxychloroquine for initiated 2. Vitamin C infection from day 1 to
Post-­e xposure Prophylaxis 14 and at day 28
to Prevent Severe Acute
Respiratory Syndrome
Coronavirus 2 Infection
Among Adults Exposed to
Coronavirus Disease

SHARP COVID-­19 Safety and Efficacy of Singapore Investigator 3000 1. Hydroxychloroquine Laboratory confirmed No
(NCT04342156) Hydroxychloroquine as initiated 2. Standard preventive infection until day 28
COVID-­19 Prophylaxis for At measures
Risk Population: A Cluster
Randomized Controlled Trial

HCQ4COV19 Treatment of Spain Investigator 3040 1. Hydroxychloroquine and Incidence of secondary No

(NCT04304053) COVID-­19 Cases and initiated public health measures infection among
Chemoprophylaxis of 2. Public health measures contacts at 14 days
MJA 213 (2) ▪ 20 July 2020

Contacts as Prevention

CORIPREV-­L R COVID-­19 Ring-­based Canada Investigator 1220 1. Lopinavir–ritonavir RNA confirmed No

(NCT04321174) Prevention Trial with initiated 2. Control infection at 14 days
Lopinavir/Ritonavir

* This trial is also listed in Box 3. ◆

trial comparing hydroxychloroquine to vitamin C (Box 3). All with the macrolide antibiotic azithromycin. Follow-­up is from
three investigate the efficacy of hydroxychloroquine or chlo- 2 to 6 weeks with clinical primary end points of infection se-
88 roquine; however, ACT COVID19 combines the antimalarial verity, hospitalisation, mechanical ventilation and death. With
 Narrative review

3 Randomised trials of therapies for mild, outpatient COVID-­19

Target Publicly
Trial acronym/ Country/ Sponsor sample Primary available
number Trial name region type size Trial domains/arms outcome protocol

ACT COVID19* Anti-­Coronavirus Canada Investigator 1500 1. Chloroquine plus Hospitalisation No

(NCT04324463) Therapies to Prevent initiated azithromycin or death at 6
Progression of 2. Standard of care weeks post
COVID-­19 Trial enrolment

COVID-­19 PEP † Post-­e xposure Canada, Investigator 3000 1. Hydroxychloroquine Incidence of No

(NCT04308668) Prophylaxis / United initiated 2. Placebo infection and
Preemptive Therapy for States 3-­point ordinal
SARS-­Coronavirus-­2 scale at 14 days
post enrolment

NCT04334967 Hydroxychloroquine in US Investigator 1250 1. Hydroxychloroquine Hospitalisation No

Patients with Newly initiated 2. Vitamin C or mechanical
Diagnosed COVID-­19 ventilation at
Compared to Standard 14 days post
of Care enrolment

COVERAGE Home treatment of France Investigator 1057 1. Hydroxychloroquine Hospitalisation No

(2020-­001435-­27) elderly patients with initiated 2. Imatinib or death at
symptomatic SARS-­ 3. Favipiravir 14 days post
CoV-­2 infection 4. Telmisartan enrolment

COLCORONA Colchicine Coronavirus Canada Investigator 6000 1. Colchicine Hospitalisation No

(NCT04322682) SARS-­CoV2 Trial initiated 2. Placebo or death at
30 days post
enrolment

A27736297878 Randomized, pragmatic, Brazil Commercial 1300 1. Hydroxychloroquine Hospitalisation No

open study evaluating 2. Standard of care or uncontrolled
Hydroxychloroquine asthma within
for prevention of 30 days
Hospitalization
and Respiratory
Complications in
outpatients with
confirmed or
presumptive diagnosis
of Infection by
COVID-­19

PRINCIPLE Platform Randomised United Investigator 3000 1. Hydroxychloroquine Hospitalisation No

(ISRC trial of interventions Kingdom initiated 2. Standard of care or death
TN86534580) against COVID-­19 in
older peoPLE

* This trial is also listed in Box 4. † This trial is also listed in Box 2. ◆

a combined sample size of more than 3000, the studies should and amenable to study, as there is expected to be a reasonably
provide helpful guidance on the management of those with frequent rate of clinically important events (eg, 20% of hospital-
mild disease. ised patients may progress to requiring advanced respiratory
support) compared with mild disease, where the low event rate
Trials examining patients at high risk of disease progression in-
makes powering of studies more difficult. The lower event rate
clude COLCORONA, COVERAGE and a study based in Brazil
may also mean that concerns of drug toxicities and expense are
comparing hydroxychloroquine to standard of care (Box 3).
harder to justify if the benefit is likely to be marginal. On the
These trials have sparked interest globally. There is a diversity
other hand, in comparison to severe disease trials, commencing
of therapies in these studies: COLCORONA is assessing the effi-
antiviral treatment before a patient requires advanced respira-
cacy of the antimetabolite colchicine, while COVERAGE is using
tory support may have the benefit of reducing viral replication at
a multi-­arm multi-­stage design to compare hydroxychloroquine,
an earlier stage. Immunomodulation may also be more effective
MJA 213 (2) ▪ 20 July 2020

imantinib, telmisartan and favipiravir. These trials are enrolling

if commenced when immune dysregulation is just beginning
patients aged > 65 years, patients with diabetes, and those with
rather than well established.
respiratory and cardiovascular disease, and all have primary
end points ranging from 14 to 30 days. We identified only four trials that were restricted to this mod-
erate patient group (Box 4), noting that some trials include
Hospitalised patients with moderate COVID-­19 both moderate and severe patients and are discussed below.
The primary end point for these studies is either death or need
Moderate disease is defined as patients requiring hospitalisa- for advanced respiratory support; or the WHO 7-­point ordinal
tion but not requiring advanced respiratory support (invasive or scale (ranging from 1 for outpatients with no limitations on ac-
non-­invasive ventilation) or intensive care unit admission at the tivity through to 7 for death). The investigational agents were 89
time of enrolment. The moderate COVID-­19 group is important hydroxychloroquine, lopinavir–ritonavir, and remdesivir. Only
 Narrative review

4 Randomised trials of therapies for moderate COVID-­19

Target Publicly
Country/ Sponsor sample Primary available
Trial acronym/number Trial name region type size Trial domains/arms outcome protocol

ASCOT Australasian Australia Investigator 2400 1. Lopinavir–ritonavir Advanced Yes

(ACTRN126200 COVID-­19 Trial and New initiated 2. Hydroxychloroquine respiratory
00445976) Zealand 3. Lopinavir–ritonavir plus support or
hydroxychloroquine death at 15
4. Standard of care days post
enrolment

NCT04292730 Study to Evaluate United Commercial 1600 1. Remdesivir 5 days WHO 7-­point No
the Safety and States, 2. Remdesivir 10 days ordinal
Antiviral Activity Europe 3. Standard of care scale at 11
of Remdesivir days post
(GS-­5 734™) in enrolment
Participants With
Moderate COVID-­19
Compared to
Standard of Care
Treatment

ACT COVID19* Anti-­Coronavirus Canada Investigator 1500 1. Hydroxychloroquine plus Mechanical No

(NCT04324463) Therapies to Prevent initiated azithromycin ventilation
Progression of 2. Standard of care or death at 6
COVID-­19 Trial weeks post
enrolment

HYCOVID Hydroxychloroquine France Investigator 1300 1. 1.Hydroxychloroquine Mechanical No

(NCT04325893) Versus Placebo in initiated 2. Placebo ventilation
COVID-­19 Patients or death at
at Risk for Severe 14 days post
Disease enrolment

* This trial is also listed in Box 4. ◆

one trial is placebo-­controlled with blinding of participants and end points, particularly quality-­of-­life assessment, typically 3
investigators. months after enrolment.
Trials are exclusively enrolling adult participants, and pregnancy
Hospitalised patients with moderate to severe COVID-­19 and severe renal disease are generally exclusion criteria. While
global experience to date continues to indicate that children are
We identified eight trials of patients with moderate to severe
unlikely to develop severe COVID-­19, the systematic exclusion
COVID-­19 with plans to enrol over 15 000 participants (Box
of pregnant women and those with chronic renal failure is likely
5). Severe disease is defined as patients requiring advanced
to mean that safety and efficacy of potential therapies will be
respiratory support (non-­i nvasive or invasive mechanical ven-
largely unaddressed in these risk groups with severe disease.
tilation) or intensive care unit admission. All trials will allo-
cate participants hospitalised with confirmed COVID-­ 19 to A way of coping with the rapidly changing landscape of
receive an agent with potential antiviral activity, with several COVID-­19 epidemiology and emergent treatment data is to use
also enrolling participants for an immunomodulatory therapy. adaptive trial designs. Adaptive platform trials can study mul-
Antiviral therapies studied in this population are most com- tiple interventions, across several domains (eg, antiviral and
monly hydroxychloroquine or chloroquine (seven trials) and/ immunomodulatory) for one disease, using a single master pro-
or lovinavir–ritanavir (five trials), with remdesivir evaluated tocol.13 Moreover, key elements of the trial can change over time,
in three trials. The dose of hydroxychloroquine used for trials according to strict pre-­specified rules. These include changing
varies notably, with doses ranging from a total of 4 g to 6 g the sample size, adding or dropping interventions (or arms), and
over 7–14 days of treatment. All studies included an arm for altering the ratio of randomisation following frequent interim
participants receiving standard of care, underscoring the lack analyses so that a patient enrolled in the platform is statistically
of treatments with established efficacy in even these high risk more likely to receive a more effective drug. REMAP-­CAP (Box
cohorts. In addition to antiviral arms, four trials included im- 5) is an example of such a trial design, and was an existing plat-
MJA 213 (2) ▪ 20 July 2020

munomodulatory arms, with studies considering the impact of form trial examining multiple domains in patients with severe
corticosteroids, interferon-­β 1a, and interleukin blockers such community-­acquired pneumonia admitted to intensive care.14 It
as anakinra and tocilizumab. has added two new pandemic domains for COVID-­19 patients:
one antiviral and one immunomodulatory.
The primary outcome measure in most of these trials is a clin-
ically assessed ordinal scale, ranging from fully recovered
to death. While assessment generally uses the WHO 7-­point Discussion
scale at 15 days after enrolment, several groups have modified
the scale or are using alternative time points. There are, how- The 31 large randomised trials described in this article share
90 ever, no patient-­reported outcomes among primary end points. several common themes. First, nearly all of them are investiga-
Several trials include patient-­reported outcomes as secondary tor initiated. While pharmaceutical companies and commercial
 Narrative review

5 Randomised trials of therapies for moderate and severe COVID-­19

Target Publicly
Trial acronym/ Country/ Sponsor sample Primary available
number Trial name region type size Trial domains/arms outcome protocol

REMAP CAP Randomized, Embedded Australia and Investigator 7100 Antiviral domain 1. All-­c ause Yes
(NCT02735707) Multifactorial Adaptive New Zealand, initiated (a subset mortality (90
Platform Trial for United States, will have 1. Lopinavir–ritonavir days)2. Days
Community-­Acquired Europe COVID-­19) 2. Hydroxychloroquine alive and out of
Pneumonia 3. Lopinavir– intensive care
ritonavir plus unit (21 days)
hydroxychloroquine
4. Standard of care
Immunomodulatory
domain

1. Interferon-β 1a
2. Anakinra
3. Tocilizumab
4. Sarilumab
5. Standard of care

SOLIDARITY Public health emergency Europe, Asia, Investigator Not given 1. Remdesivir All-­c ause No
(ISRCTN83971151) SOLIDARITY trial of Canada, South initiated 2. Lopinavir/ ritonavir mortality
treatments for COVID-­19 America, South 3. Lopinavir/ ritonavir
infection in hospitalized Africa plus interferon-β
patients 4. Hydroxychloroquine or
chloroquine
5. Standard of care

RECOVERY A randomised trial of United Investigator 5000 1. Lopinavir–ritonavir All-­c ause Yes
(ISRCTN50189673) treatments to prevent Kingdom initiated 2. Hydroxychloroquine mortality (28
death in patients 3. Interferon-β 1b days)
hospitalised with (inhaled)
COVID-­19 4. Dexamethasone (6 mg
daily)
5. Standard of care

DISCOVERY Trial of Treatments for Europe Investigator 3100 1. Remdesivir WHO 7-­point No
(NCT04315948) COVID-­19 in Hospitalised initiated 2. Lopinavir–ritonavir ordinal scale
Adults 3. Lopinavir–ritonavir at 15 days post
plus interferon-β 1a enrolment
4. Hydroxychloroquine
5. Standard of care

NOR Solidarity The NOR Solidarity Europe Investigator 1218 1. 1.Remdesivir All-­c ause No
(NCT04321616) Multicenter Trial on the initiated 2. Hydroxychloroquine in-­hospital
Efficacy of Different mortality (21
Anti-­v iral Drugs in SARS-­ days)
CoV-­2 Infected Patients

CRASH-­19 Coronavirus Response Nigeria, Investigator 10 000 1. Aspirin (75 mg daily) All-­c ause No
(NCT04343001) – Active Support for Pakistan initiated 2. Losartan mortality (28
Hospitalised COVID-­19 3. Simvastatin days)
Patients 4. Low dose aspirin and
losartan
5. Aspirin and
simvastatin
6. Aspirin, losartan and
simvastatin
6. Standard of care

NCT04292899 A Phase 3 Randomized US, Europe, Commercial 6000 1. Remdesivir 5 days WHO 7-­point No
Study to Evaluate the Asia 2. Remdesivir 10 days ordinal scale
Safety and Antiviral at 14 days post
Activity of Remdesivir enrolment
(GS-­5 734™) in
Participants With Severe
COVID-­19
MJA 213 (2) ▪ 20 July 2020

COVIDMED Comparison Of US Commercial 3111 1. Lopinavir–ritonavir 8-­point ordinal No

(NCT04328012) Therapeutics for 2. Hydroxychloroquine scale at 60 days
Hospitalized Patients 3. Losartan post enrolment
Infected With 3. Placebo
SARS-­CoV-­2

NCT04321993 Treatment of Moderate Canada Investigator 1000 1. Lopinavir–ritonavir No

to Severe Coronavirus initiated 2. Hydroxychloroquine
Disease (COVID-­19) in 3. Baricitinib
Hospitalized Patients 4. Sarilumab
5. Standard of care

91
 Narrative review
research organisations are also running trials, most of their can- is not possible, harmonisation of trial design (eg, by using the
didate drugs are not sufficiently advanced to run large phase same end points and data collection) is easy to achieve and will
3 or 4 trials. There are over 300 registered randomised trials of allow planned prospective individual patient meta-­analyses to
smaller sample size or earlier phase. Many of the drugs tested increase the overall power of all of these trials. Coordination at
in these smaller trials never proceed to larger studies owing to national and international levels is needed to avoid deleterious
toxicity, lack of efficacy, or commercial reasons, and they are be- trial competition, as well as to prevent unnecessary duplicate tri-
yond the scope of this article. However, it is important to note als from proceeding. The United Kingdom has taken an effective
that this drug development pipeline is crucial in our response to approach to this problem by only endorsing three key trials and
COVID-­19. There is a reasonable chance that none of the thera- encouraging all sites and investigators to focus their efforts on
pies currently being tested will prove beneficial, or that a few these: one in the pre-­hospital space (PRINCIPLE; Box 3), one in
will but with a small effect size. We urgently need candidate non-­severe hospital patients (RECOVERY; Box 5) and one in in-
drugs joining the queue to be tested in large trials. Second, most tensive care unit patients (REMAP-­CAP; Box 5). Partly as a result
of the trials are testing hydroxychloroquine or chloroquine, and of this policy (as well as the unfortunate explosion of COVID-­19
all of the antiviral drugs are being repurposed from an existing case numbers in the UK), the RECOVERY trial randomised over
approved indication. Remdesevir is an exception — it is a broad-­ 5000 patients within weeks of opening.
acting antiviral with activity against viral RNA-­dependent RNA
While some trials have already published their results,18 gener-
polymerase. It has been tested against other coronaviruses (SARS
ating intense media interest, none have been sufficiently pow-
and MERS) and Ebola virus, but without sufficient data to allow
ered to change practice, and all enrolled well under 1000 patients
registration.15–17 While it is possible (or even likely) that there are
and have therefore not been described in this article. Ongoing
current large trials that we have inadvertently omitted from this
key trials described here to which Australians have access in-
review, this is not likely to change the overall pattern of find-
clude BRACE (Box 2), ASCOT (Box 4) and REMAP-­CAP (Box 5).
ings described above. We are also aware of several planned large
trials which are not yet registered, including newer treatments The near instant dissemination of information and opinion that is
such as convalescent plasma, angiotensin 2 receptor blockers prevalent in today’s world makes properly designed clinical trials
and non-­steroidal anti-­inflammatory drugs. more important than ever. US President Donald Trump’s promo-
tion of hydroxychloroquine (based on information from a pre-
The rapid creation and roll out of clinical trials for COVID-­19
print of a small and poorly designed study19) led to a huge surge
means we are likely to find accurate answers relatively quickly
in the use of the drug, with a consequent depletion of supply in
about candidate therapeutic agents, but it also presents chal-
many countries, well in advance of any definitive data from clin-
lenges. Foremost among these is the potential for competition
ical trials. The fact that many scientists and clinical trialists have
between trials for participants, sites and funding. To avoid this,
dropped everything to work on vaccines, therapeutics and clinical
it is crucial that before planning a clinical trial, investigators de-
trials for COVID-­19 augurs well that we will have access to safe
termine if one that could serve their patients already exists. It is
and effective prevention and treatment strategies for COVID-­19
hoped that this article will help in this regard, along with the
within months, rather than the usual time scale of decades.
WHO metaregistry and COVID-­19 trial summary websites men-
tioned above. Trialists should openly communicate with each Competing interests: No relevant disclosures.
other and the public about their trial protocols, their data collec-
tion plan, and their drug supply. Unfortunately, only a few of the Provenance: Commissioned; externally peer reviewed. ■
31 large trials described in this article have made their trial pro-
tocol publicly available (Box 1). Even if joining an existing trial © 2020 AMPCo Pty Ltd

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