Chloroquine/ Hydroxychloroquine Prevention of Coronavirus Disease (COVID-19) in the Healthcare Setting; a Randomised, Placebo-controlled Prophylaxis Study (COPCOV)
Phase: NA
Conditions: COVID19, Coronavirus, Acute Respiratory Illnesses
Sponsor: University of Oxford

Protocol version 6.0 dated 13 January 2021
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Study Title: Chloroquine/ hydroxychloroquine prevention of coronavirus disease
(COVID-19) in the healthcare setting; a randomised, placebo-controlled prophylaxis
study (COPCOV)
Internal Reference Number / Short title: COPCOV
OxTREC Ref: 25-20
Protocol number: VIR20001
Date and Version No: Version 6.0 dated 13 January 2021
Co-Principal Investigators:
Professor Sir Nicholas White (nickw@tropmedres.ac)
Chairman Wellcome Trust Southeast Asian Tropical Medicine
Programmes & Consultant Physician
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Dr William Schilling (william@tropmedres.ac)
Research Physician & Infectious Diseases/ Microbiology Registrar
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Investigators:
Professor Nicholas Day
Director & Consultant Physician
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Dr Walter Taylor
Senior Clinical Researcher and Infectious Diseases Physician
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Dr Elizabeth Ashley
Director & Consultant Clinical Microbiologist/ Infectious Diseases
Physician
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Lao PDR

Protocol version 6.0 dated 13 January 2021
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Associate Professor Phaik Yeong Cheah
Head of Bioethics & Engagement
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Professor Arjen Dondorp
Deputy Director and Head of Malaria & Critical Illness
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Professor Amanda Adler
Consultant Physician and Director of the Diabetes Trials Unit
The University of Oxford
Associate Professor Mayfong Mayxay
Head of Malaria and Field Research, Vice President of the Lao National
University of Health Sciences
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Lao PDR
Assistant Professor Weerapong Phumratanaprapin
Dean of the Faculty of Tropical Medicine
Mahidol University, Thailand
Professor Yoong Poovorawan
Professor of Paediatrics,
Chulalongkorn University, Bangkok, Thailand.
Dr James Callery
Research Physician
Mahidol Oxford Tropical Medicine Research Unit, Thailand

Protocol version 6.0 dated 13 January 2021
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Dr Arjun Chandna
Research Physician & Infectious Diseases/ Microbiology Registrar
Cambodia-Oxford Medical Research Unit, Cambodia
Professor Paul Turner
Director & Consultant Clinical Microbiologist
Cambodia-Oxford Medical Research Unit, Cambodia
Dr Cintia Cruz
Paediatrician and Clinical Pharmacologist
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Associate Professor Lorenz von Seidlein
Senior Clinical Researcher and Infectious Diseases Physician
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Dr Dora Buonafrate
Infectious Disease Physician
Centre for Tropical Diseases, Sacro Cuore Don Calabria Hospital, Italy
Professor Piero Olliaro
Infectious Diseases Physician
Nuffield Department of Medicine, Oxford University, UK
Professor Martin Llewelyn
Consultant in Infectious Diseases
Brighton and Sussex Medical School, UK
Dr Sophie Yacoub
Consultant in Infectious Diseases and General Medicine

Protocol version 6.0 dated 13 January 2021
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Oxford University Clinical Research Unit/ Wellcome Programme,
Vietnam
Professor Guy Thwaites
Director & Consultant Clinical Microbiologist/ Infectious Diseases
Physician
Oxford University Clinical Research Unit/ Wellcome Programme,
Vietnam
Dr Mehul Dhorda
Senior Scientist
Mahidol Oxford Tropical Medicine Research Unit, Thailand
Sponsor:
The University of Oxford
Funder:
ACT-Accelerator Therapeutics Partnership
Signatures:
Professor Sir Nicholas White
_______________________
______________________
(Co-Principal Investigator)
(Signature)
(Date)
Dr William Schilling
_______________________
______________________
(Co-Principal Investigator)
(Signature)
(Date)
Confidentiality Statement
This document contains confidential information that must not be disclosed to anyone other than the
authorised individuals from the University of Oxford, the Investigator Team and members of the Oxford
Tropical Research Ethics Committee (OxTREC) and local Ethics Committee, unless authorised to do so.
TABLE OF CONTENTS

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SYNOPSIS ............................................................................................................................................... 7
ABBREVIATIONS..................................................................................................................................... 9
BACKGROUND AND RATIONALE.......................................................................................................... 10
OBJECTIVES AND OUTCOME MEASURES............................................................................................. 15
STUDY DESIGN..................................................................................................................................... 16
PARTICIPANT IDENTIFICATION AND RECRUITMENT ........................................................................... 18
6.1.
Study Participants........................................................................................................................ 18
6.2.
Inclusion Criteria.......................................................................................................................... 18
6.3.
Exclusion Criteria......................................................................................................................... 19
STUDY PROCEDURES ........................................................................................................................... 19
7.1.
Recruitment................................................................................................................................. 19
7.2.
Screening and Eligibility Assessment........................................................................................... 20
7.3.
Informed Consent........................................................................................................................ 20
7.4.
Clinical examination .................................................................................................................... 20
7.5.
Randomisation and blinding........................................................................................................ 20
7.6.
Baseline Assessments.................................................................................................................. 21
7.7.
Subsequent Visits ........................................................................................................................ 21
7.8.
Sample Handling.......................................................................................................................... 22
7.9.
Discontinuation/Withdrawal of Participants from Study............................................................ 23
7.10.
Definition of End of Study ....................................................................................................... 24
STUDY MEDICATION (CHLOROQUINE or HYDROXYCHLOROQUINE/PLACEBO) .................................. 24
8.1.
Study Medication Description..................................................................................................... 24
8.2.
Storage of Study Medication....................................................................................................... 24
8.3.
Compliance with Study Medication ............................................................................................ 24
8.4.
Accountability of the Study Medication...................................................................................... 24
8.5.
Concomitant Medication............................................................................................................. 25
8.6.
COVID-19 Vaccination ................................................................................................................. 25
8.7.
Post-trial Treatment .................................................................................................................... 25
SAFETY REPORTING ............................................................................................................................. 25
9.1.
Definition of Serious Adverse Events .......................................................................................... 25
9.2.
Definitions ................................................................................................................................... 26
9.3.
Causality ...................................................................................................................................... 27
9.4.
Procedures for Recording Adverse Events .................................................................................. 27
9.5.
Reporting Procedures for Serious Adverse Events...................................................................... 28

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9.6.
Reporting Procedures for Pregnancy .......................................................................................... 28
9.7.
Data Safety and Monitoring Board.............................................................................................. 28
STATISTICS AND ANALYSIS................................................................................................................... 29
10.1.
Description of Statistical Methods .......................................................................................... 29
10.2.
The Number of Participants .................................................................................................... 29
10.3.
Analysis of Outcome Measures............................................................................................... 29
DATA MANAGEMENT.......................................................................................................................... 30
11.1.
Access to Data ......................................................................................................................... 30
11.2.
Data Handling and Record Keeping......................................................................................... 30
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES............................................................ 30
ETHICAL AND REGULATORY CONSIDERATIONS................................................................................... 31
13.1.
Declaration of Helsinki............................................................................................................. 31
13.2.
Guidelines for Good Clinical Practice ...................................................................................... 31
13.3.
Approvals................................................................................................................................. 31
13.4.
Participant Confidentiality....................................................................................................... 31
13.5.
Expenses and Benefits............................................................................................................. 31
13.6.
Reporting................................................................................................................................. 31
13.7.
Other Ethical Considerations................................................................................................... 31
13.8.
Community and public engagement ....................................................................................... 32
FINANCE AND INSURANCE .................................................................................................................. 32
14.1.
Funding.................................................................................................................................... 32
14.2.
Insurance ................................................................................................................................. 32
PUBLICATION POLICY........................................................................................................................... 32
REFERENCES ........................................................................................................................................ 33
APPENDIX A: EXAMPLE OF SEVERITY OUTCOME MEASURES............................................................. 35
APPENDIX B: SCHEDULE OF STUDY PROCEDURES.............................................................................. 36
APPENDIX C: EXAMPLE OF COMMUNITY AND PARTICIPANT ENGAGEMENT..................................... 38
APPENDIX D: POTENTIAL SITES............................................................................................................ 39
APPENDIX E: AMENDMENT HISTORY ................................................................................................. 41

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SYNOPSIS
Study Title
Chloroquine/ hydroxychloroquine prevention of coronavirus disease (COVID-
19) in the healthcare setting; a randomised, placebo-controlled prophylaxis
study (COPCOV)
Protocol number
VIR20001
Study Design
Randomised double-blind, placebo-controlled trial
Study Participants
Healthcare workers and other persons at risk of contracting COVID-19.
Adults (exact age is dependent on local country requirements).
Planned Sample Size
40,000 total participants
Planned Study Period
12 months; individual trial duration maximum 5 months
Objectives
Outcome Measures
Primary
To determine if chloroquine or
hydroxychloroquine prophylaxis
prevents symptomatic COVID-19
infection in healthcare workers and
other persons at risk of contracting
COVID-19.
The number of symptomatic
COVID-19 infections will be
compared between participants
randomised to chloroquine or
hydroxychloroquine, and placebo
groups.
Secondary
To determine if chloroquine or
hydroxychloroquine prophylaxis
attenuates COVID-19 infections.
The symptoms severity and
duration of COVID-19 illness, in
those who become infected during
the study will be compared
between the two groups using a
respiratory severity score.
To determine if chloroquine or
hydroxychloroquine prophylaxis
prevents asymptomatic COVID-19
infection.
The number of asymptomatic
cases of COVID-19 will be
determined by comparing serology
in all participants at time of
enrolment and at the end of follow
up.
To determine if chloroquine or
hydroxychloroquine prophylaxis
prevents all-cause symptomatic acute
respiratory illnesses.
The number and severity of
symptomatic acute respiratory
illnesses will be compared in
participants randomised to
chloroquine or
hydroxychloroquine, and placebo
groups.
Tertiary
To characterise genetic and baseline
biochemical markers associated with
symptomatic COVID-19, respiratory
illness and disease severity.
Genetic loci and levels of
biochemical components will be
correlated with occurrence of and
disease severity of COVID-19 or
other Acute Respiratory Infections
(ARIs).
To assess the impact of chloroquine or
hydroxychloroquine prophylaxis on
work and behaviour during the
pandemic.
The days lost to work, and the
relationship between the
subjective assessment of well-
being and the decision to self-

Protocol version 6.0 dated 13 January 2021
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isolate when unwell (i.e. not go to
work) will be examined in relation
to the infection and treatment
arm.
To perform health economic analyses
to assess the impact of chloroquine or
hydroxychloroquine prophylaxis on
costs and quality of life measures.
The trial will collect data on use of
health care resources and health
related quality of life (EQ-5D-3L) to
determine the effects between
treatment groups.

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ABBREVIATIONS
ARI
Acute Respiratory Infection
COVID-19
Coronavirus Disease 2019. The disease caused by the virus SARS-CoV-2
CPAP/ BiPAP
Continuous Positive Airway Pressure and Bilevel Positive Airway Pressure
CRF
Case Report Form
DBS
Dried Blood Spot
DSMB
Data Safety and Monitoring Board
ECMO
Extracorporeal Membrane Oxygenation
ePRO
Electronic Patient Reported Outcomes
EQ-5D-3L
EuroQol 5 Dimension 3 levels
GCP
Good Clinical Practice
ICF
Informed Consent Form
LTFU
Lost to follow-up
MORU
Mahidol Oxford Tropical Medicine Research Unit
OxTREC
Oxford Tropical Research Ethics Committee
PI
Principal Investigator
PIS
Participant Information Sheet
PPE
Personal Protective Equipment
RCT
Randomised controlled trial
RR
Respiratory Rate. Number of breaths per minute
SARS-CoV
Severe acute respiratory syndrome coronavirus
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2. The virus responsible for COVID-
19
SLE
Systemic Lupus Erythematosus
SmPC
Summary of product characteristics
SOP
Standard Operating Procedure
THN
Tropical Health Network
URTI
Upper Respiratory Tract Infection (coryza, sore throat)

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BACKGROUND AND RATIONALE
As of writing, the novel betacoronavirus SARS-CoV-2 has infected more than 80,000,000 individuals, killed
more than 1,800,000 people and has spread globally1. The main mode of transmission of COVID-19 is
respiratory droplet spread but spread by direct contact also occurs; with the finding of SARS-CoV-2 in
faeces, an oral faecal route of transmission is also possible (1). There is no proven effective prophylaxis
and no widely available proven effective antiviral treatment. Corticosteroids are life-saving in hospitalised
patients requiring supplemental oxygen (2), and although vaccines have been licensed, they are not yet
widely available in some countries, and it will take time to fully vaccinate the world’s population.
Chloroquine and hydroxychloroquine have antiviral activity against coronaviruses and are widely available
now. Drugs with a modest benefit in preventing COVID-19 could still save many lives in this, and future
pandemics. The crude mortality of symptomatic infections is currently greater than 2%. This is some ten
times higher than seasonal influenza virus which infects up to 1 billion people a year and kills between
290,000 to 650,000 (3) 2. The estimated COVID-19 basic reproductive ratio (R0) of 1.25 to 3.0 is similar to,
or slightly higher than, that of seasonal (1.3) or pandemic influenza (1.4 to 1.8) (4, 5). Recently, highly
transmissible variants have been selected and spread in some countries.
We have been in a race against time to find effective treatments and preventive measures as the pandemic
continues to grow. There is unequivocal evidence that hydroxychloroquine does not benefit patients
already hospitalised with COVID-19. At this stage of illness inflammatory processes predominate (and
dexamethasone is life-saving). Antiviral drugs are much more likely to be beneficial in prevention or early
treatment. The potential role of chloroquine and hydroxychloroquine in the prevention of COVID-19 has
been discussed extensively and numerous small, mainly observational, studies have been reported. Meta-
analysis of the post-exposure randomised controlled trials (RCTs) are generally in favour of
hydroxychloroquine but these are inconclusive. There have been no large RCTs examining the efficacy of
4-aminoquinolines in the prevention of disease, and capable of detecting small, yet clinically significant
benefits. The question whether these drugs could be beneficial in preventing COVID-19 remains
unanswered. In the absence of a currently widely available vaccine the answer to this question remains
important. There remains a major concern that COVID-19 could devastate countries with limited capacity
for testing and case isolation, and overwhelm their fragile healthcare systems. The risks to the healthcare
system, as seen with SARS-CoV previously, and then in Wuhan and elsewhere with COVID-19, could be a
major threat to healthcare operations overall (6).
Chloroquine, an antimalarial drug discovered in 1934 and introduced generally in 1947, is probably the
drug to which humans have been most exposed. With an adult treatment dose of 1.5g for malaria, an
annual global consumption of hundreds of metric tonnes for over 50 years, and an elimination half-life of
approximately one month, the average person in many tropical countries once had detectable chloroquine
in their blood. Chloroquine has a very large apparent volume of distribution because of extensive tissue
binding and slow elimination (7-9). Plasma concentration profiles with daily dosing are determined mainly
by distribution rather than elimination. The main metabolite desethyl chloroquine also has significant
biological activity. Chloroquine is inexpensive and simple to administer. It remains a first-line treatment
for non-falciparum malaria and is on the World Health Organization’s List of Essential Medicines3.
Chloroquine has been used extensively as continuous chemoprophylaxis against malaria for individual
periods often exceeding five years and has been the prophylactic drug of choice in pregnancy (10). It is
safe in all age groups. In addition to its antimalarial use both chloroquine, and the closely related and
slightly more hydrophilic hydroxychloroquine, are used in continuous daily dosing for rheumatoid arthritis,
systemic and discoid lupus erythematosus and psoriatic arthritis. Chloroquine and hydroxychloroquine at
doses of 2.4mg base/kg (155 mg)/day for years is used for rheumatoid arthritis and other conditions. Daily
1 World Health Organization’s COVID-19 situation report
2 World Health Organization’s Factsheet on Seasonal Influenza
3 World Health Organization’s list of Essential Medications

Protocol version 6.0 dated 13 January 2021
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doses up to 620mg base have been given for months or years. Chloroquine given at the correct dose has
an excellent safety profile. It has even been added to salt to prevent malaria by mass exposure (11).
Chloroquine has significant antiviral activity against SARS-CoV-2 in cell culture, as it does for the related
SARS-CoV (12-15). A half-maximal effective concentration (EC50 or the concentration associated with a
decrease in the cytopathic effect of the virus by 50%) of 1.13 µM on Vero E6 cells has been reported with
a corresponding EC90 of 6.9 µM. Several other laboratory studies confirm activities in the low micromolar
range for chloroquine and hydroxychloroquine (16). This effect occurred when the drug was given either
before or after viral inoculation. These are relatively high concentrations by comparison with therapeutic
exposures in the treatment of malaria but could be achieved with daily oral dosing. Chloroquine has
complex pharmacokinetic properties, having a very large total apparent volume of distribution and a
relatively small central compartment with extensive tissue binding, including in the lung. The relationship
between plasma concentrations and concentrations in respiratory epithelium is not known precisely,
though in rats the concentration in lung is between 124 and 748-fold that in plasma (17). Chloroquine
concentrations in the human lung would be expected to exceed those required for the EC90 after an initial
dose.
Hydroxychloroquine was synthesised first in 1946 and has largely replaced chloroquine for the
management of autoimmune diseases as it has a slightly better adverse effect profile (higher thresholds
for toxicity in experimental animals, less abdominal discomfort, higher threshold for retinal toxicity). It has
very similar pharmacokinetic properties except for a smaller apparent volume of distribition, probably
because of its greater hydrophilicity. In vitro it has approximately twice the activity of chloroquine against
the SARS-CoV-2 virus in some studies (16). Hydroxychloroquine may cause less itching than chloroquine in
dark-skinned patients. The pharmacology appendix contains more information on the pharmacology of
these two 4-aminoquinoline drugs.
We hypothesise that chloroquine and hydroxychloroquine might both slow viral replication in exposed
participants, attenuating or preventing the infection even if they are shown not to work in treatment or in
post-exposure prophylaxis. It is a basic principle of infectious diseases that preventing an infection
developing (i.e., preventing pathogen multiplication) requires less drug activity (I.e. lower doses or a less
active drug) than treatment. In COVID-19 illness the total viral burden is highest at the time of initial
illness.. Viral burdens are often reducing by the time of hospitalisation in COVID-19 so the window of
opportunity for antiviral medicines is at the earliest stages of infection. In addition, in vitro studies show
the greatest activity of chloroquine and hydroxychloroquine at the initial time of cellular infection and
decreasing in vitro antiviral effects if the drug is exposed at later time points. We believe these drugs may
have their greatest utility in preventing COVID-19 in pre-exposure prophylaxis (9, 18-20). Given the
enormous experience of use in chemoprophylaxis, excellent safety and tolerability profile and its very low
cost, if it proved effective then it would be a readily deployable and affordable preventative measure.
Main research questions:
The primary objectives are is to determine if prophylactic chloroquine or hydroxychloroquine prevents
symptomatic COVID-19 illness.
The secondary objectives include:

Attenuation of the clinical severity of COVID-19 infections.

The prevention of asymptomatic COVID-19.

The prevention of symptomatic all-cause acute respiratory infections (ARI).

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Overview of primary endpoint ascertainment:
During the
study
RT-PCR for SARS-CoV-
2
Initial
serology
End serology
Diagnosis
Illness
Positive
Negative
Negative or
Positive
COVID-19
Illness
Positive
Positive
Negative or
Positive
COVID-19
Illness
Negative
Negative
Positive
COVID-192
Illness
Negative
Positive1
Negative or
Positive
Indeterminate
Illness
Negative
Negative
Negative
ARI not COVID-19
No Illness
-
Negative
Positive
Asymptomatic
case
No Illness
-
Positive1
Positive
Indeterminate
No Illness
-
Negative
Negative
Not infected
1Participants will be enrolled only if they have not had a previous confirmed diagnosis of COVID-19. It is
anticipated some participants may have had asymptomatic infections and so are found during subsequent
analysis to have antibody present at study enrolment.
2Unless the PCR from a nose/ throat swab taken during the febrile illness by the hospital is positive for
influenza virus. Other viruses isolated will not change the primary end-point determination. Although later
studies will look for other viruses in the study swab – for the primary endpoint this will only be a SARS-
CoV-2 PCR.
Brief description of the intervention:
The study is a double-blind, randomised, placebo-controlled trial that will be conducted in facilities
involved in COVID-19 case management. After obtaining fully informed consent, we will recruit healthcare
workers and other persons at risk of contracting COVID-19, who can be followed up reliably for up to 5
months.
A loading dose of 10 mg base/kg (four 155mg tablets for a 60kg participant), followed by 155 mg daily
(250mg chloroquine phosphate salt or 200mg of or hydroxychloroquine sulphate) will be taken by all
participants for 3 months. Subsequent episodes of symptomatic respiratory illness, including symptomatic
COVID-19, clinical outcomes, and asymptomatic infection with the virus causing COVID-19, will be
recorded during the follow-up period. If participants are diagnosed with COVID-19 during the period of
prophylaxis, they will continue their prophylaxis unless advised to discontinue by their healthcare
professional or they become hospitalised as a result of COVID-19 (not for quarantine reasons), in which
case they will be asked to stop. If they are hospitalised prior to the diagnosis of COVID-19, they will
continue prophylaxis until the diagnosis of COVID-19 is confirmed unless advised to discontinue by their
healthcare professional.
If participants become unwell during the study period due to COVID-19 or other ARI, they will continue to
be followed up until 28 days from the beginning of illness. If complete recovery does not occur within 28

Protocol version 6.0 dated 13 January 2021
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days, follow-up will be extended for up to a maximum of 60 days from the beginning of illness. For
participants who become unwell on Day 90, follow-up may therefore continue until Day 150.
Investigation of a suspected case:
The procedures for identifying a case and the subsequent isolation and management will follow local and
national guidelines; this study will not interfere in the usual local investigation and management of COVID-
19 cases. Study diagnoses will be made at the end of the study, where possible participants will be
informed if they had or did not have COVID-19 infections as defined above. Chloroquine and
hydroxychloroquine have very few drug-drug interactions and should not interfere with the management
of pneumonia.
Summary of findings of previous studies:
No large randomised controlled studies have published results on chloroquine or hydroxychloroquine for
the pre-exposure prophylaxis of COVID-19 in humans and there remains clinical equipoise as to whether
the drug will have a clinically significant benefit in this indication. Studies of these drugs in late treatment
suggest they are not life-saving, but no antiviral has proven so, and the benefit of an anti-inflammatory
drug, dexamethasone, at this late stage suggests that at this point it is too late for an antiviral, when
inflammation predominates (21, 22). The drugs are more likely to be beneficial if given earlier, when the
virus is replicating and the available, pooled RCT data are suggestive of a modest benefit at this earlier
stage (23).
However, chloroquine has been used widely and a wealth of experience and data testify to its safety both
for mass drug administration (MDA) for malaria, as routinely prescribed antimalarial prophylaxis, and for
rheumatological conditions for which people may be take the drug daily at doses comparable to those in
this study for decades with few ill-effects. Hydroxychloroquine has been used widely for over 50 years in
the treatment of rheumatoid arthritis, SLE and other similar conditions.
The risks of chloroquine or hydroxychloroquine chemoprophylaxis are minimal compared with the risks of
COVID-19 and there are currently no other proven chemoprophylactic agents, widely available effective
treatments, other than steroids in those requiring supplemental oxygen, or a widely-available vaccine in
all countries. Assumptions of the study include that the in vitro effects of chloroquine or
hydroxychloroquine against SARS-CoV-2 will translate to an in vivo effect and a benefit in human
participants. As described, chloroquine or hydroxychloroquine should reach levels in human tissues,
including the lungs, which were shown to have a viral suppressive effect in vitro. However, the exact
distribution of chloroquine or hydroxychloroquine within the respiratory tract, and whether these in vitro
findings will translate into clinical benefit, is unknown.
Summary of known and potential risks and benefits of the study:
Risks
Risks related to chloroquine phosphate/ sulphate/ hydrochloride and hydroxychloroquine sulphate are
verylow, unless the drug is taken in overdose. These are verysafe and generally well-tolerated medications
but adverse reactions relating to the cardiovascular system, the central nervous system, the skin,
hypoglycaemia, hypersensitivity, gastrointestinal, and retinal toxicity have all been described though
usually after high doses or protracted exposures. Headache and gastrointestinal side-effects (e.g. nausea,
diarrhoea) are the most common adverse effects (24). Another adverse effect is itching, in particular with
chloroquine, in dark-skinned individuals; Africans are much more commonly affected compared to Asians.
These risks will be mitigated by excluding participation if people have had a previous serious adverse
reaction to chloroquine, or hydroxychloroquine, 4-aminoquinoline compounds, any components of the
tablet or retinal or visual field changes of any aetiology.

Protocol version 6.0 dated 13 January 2021
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Despite an excellent track record of safety with over 70 years of use of these drugs, during COVID-19 there
has been much written about the potential cardiotoxicity of these drugs. Many of these reports did not
consider dose (COPCOV uses the lowest range of the daily dose used safely for long periods of time without
need for ECG monitoring or concerns), the cardiotoxicity seen with chronic use (as opposed to the short
period of the COPCOV study), do not distinguish use of the drugs alone (safe) from the potentially
cardiotoxic combination with azithromycin, and ignore the wealth of clinical and epidemiological data
suggesting the excellent safety of these drugs. The mild QT prolonging effect of hydroxychloroquine and
chloroquine has been well-known and has not been associated with a significant risk of ventricular
tachyarrhythmias such as torsade de pointes. The WHO pharmacovigilance database (VigiBase) contains
reports of 83 episodes of TdP or other forms of ventricular tachycardia which were associated with
hydroxychloroquine over a 52 year period, of which 7 were fatal. This experience does not distinguish
acute from chronic use and most pertains to diseases with an increased risk of cardiac disease. This should
be viewed in the context of approximately one million people using hydroxychloroquine continuously
worldwide (based on manufacturing outputs).
Despite the opinion pieces, case reports and uncontrolled observational studies about safety concerns of
these drugs, the high-quality randomised controlled trial evidence from COVID-19 is reassuring. The
RECOVERY and SOLIDARITY studies, despite using much higher doses in a sick population (approximately
4 times higher than the COPCOV study) showed no excess of cardiac arrhythmias (21, 22). In addition, data
from outpatient RCTs using lower doses also support the safety of these drugs. In contrast to reported
observational data these RCTs do control adequately for confounders of the disease and its treatment. Of
2795 participants recruited into 3 RCTs using HCQ in the outpatient setting, 1633 received HCQ and the
study concluded that “gastrointestinal side effects were common but mild with the use of
hydroxychloroquine,
while
serious
side
effects
were
rare.
No
deaths
occurred
related
to
hydroxychloroquine” (24). Together these data suggest that the safety and tolerability profile of
chloroquine and hydroxychloroquine in COVID-19 is similar to that in rheumatological conditions. Finally,
high-quality, controlled observational data of participants taking hydroxychloroquine for rheumatological
conditions confirm the safety and suggest the drugs may be antiarrhythmic in the short-term. In a recent
retrospective observational review of 956,374 rheumatoid arthritis patients starting treatment with
hydroxychloroquine, there was a lower risk of arrhythmia in the first 30 days of treatment (calibrated
hazard ratio (CalHR) 0.89 (95% confidence interval 0.77 to 1.04) compared with sulphasalazine recipients
(n = 310; 350) (25). The levels of drug in the blood have been modelled based on available data, and data
from deliberate overdose, and are well below the threshold for toxicity (26, 27).
In conclusion, the evidence from clinical trials in COVID-19 support the well-established safety record of
the 4-aminoquinolines (chloroquine and hydroxychloroquine) at the correct dosage.
A full description for each product is provided in the relevant summary of product characteristics (SmPC).
A physician’s guidance document is also available for reference.
Benefits

Access to a drug which may potentially prevent or ameliorate COVID-19 infection. No other proven
preventive medication or widely-available vaccine around the globe currently exists. The main
potential benefit is to the participant in the chloroquine or hydroxychloroquine arm (direct
protection) but individuals in the placebo arm may benefit from indirect protection through
decreased ability of the infection to spread.

Awareness that their participation may lead to an intervention which may save many lives around
the world or, alternatively, may show chloroquine or hydroxychloroquine prophylaxis is ineffective
so trials can move on to evaluate other possible interventions with a minimum of delay, and the
prophylactic use of these drugs around the world can stop.

Protocol version 6.0 dated 13 January 2021
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Description of the population to be studied and the population to whom the results of the study may be
generalisable:
The population to be studied comprises adult healthcare workers and other persons at risk of contracting
COVID-19.
These
could
include
nurses,
healthcare
assistants
(HCAs),
doctors,
pharmacists,
physiotherapists, porters and anyone who is at risk of exposure to COVID-19.
If shown to be beneficial, this study would be generalisable to all people around the world at risk of COVID-
19.
OBJECTIVES AND OUTCOME MEASURES
Objectives
Outcome measures
Timepoint(s) of
evaluation of this
outcome measure
(if applicable)
Primary Objective
To determine if chloroquine or
hydroxychloroquine prophylaxis
prevents symptomatic COVID-19
infection in healthcare workers and
other persons at risk of contracting
COVID-19.
Primary Outcome
The number of symptomatic COVID-19
infections will be compared between
participants randomised to chloroquine or
hydroxychloroquine, and placebo groups.
During the trial
period
Secondary Objectives
To determine if chloroquine or
hydroxychloroquine prophylaxis
attenuates COVID-19 infections.
Secondary Outcomes
The symptoms, severity and duration of
COVID-19, in those who become infected
during the study will be compared
between the two groups using a
respiratory severity score.
During the trial
period
To determine if chloroquine or
hydroxychloroquine prophylaxis
prevents asymptomatic COVID-19
infection.
The number of asymptomatic cases of
COVID-19 will be determined by
comparing serology in all participants at
time of enrolment and at the end of
follow up.
During the trial
period
To determine if chloroquine or
hydroxychloroquine prophylaxis
prevents all-cause symptomatic
acute respiratory illnesses.
The number and severity of symptomatic
acute respiratory illnesses will be
compared between the chloroquine or
hydroxychloroquine, and placebo groups.
During the trial
period
Tertiary Objectives
To characterise genetic and
baseline biochemical markers
associated with symptomatic
COVID-19, respiratory illness and
disease severity.
Tertiary Outcomes
Genetic loci and levels of biochemical
components will be correlated with
occurrence of and disease severity of
COVID-19 or other ARIs.
During and after
the trial period
To assess the impact of chloroquine
or hydroxychloroquine prophylaxis
The days lost to work, and the
relationship between the subjective
assessment of well-being and the decision
to self-isolate when unwell (i.e. not go to
During and after
the trial period (to

Protocol version 6.0 dated 13 January 2021
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on work and behaviour during the
pandemic.
work) will be examined in relation to
infection and treatment arm.
the limit of follow
up)
To perform health economic
analyses to assess the impact of
chloroquine or hydroxychloroquine
prophylaxis on costs and quality of
life measures.
The trial will collect data on use of health
care resources and health related quality
of life (EQ-5D-3L) to determine the effects
between treatment groups.
During and after
the trial period
Additional exploratory objectives will be defined prior to study analysis, e.g., pharmacokinetic (PK) analysis
of study medication levels, or potential attenuation of antibody levels by study drug in vaccinated
participants
STUDY DESIGN
The study is a double-blind, randomised, placebo-controlled trial that will be conducted primarily in
healthcare settings and other facilities directly involved in COVID-19 case management. We will recruit
healthcare workers and other persons at risk of contracting COVID-19, who can be followed reliably for 5
months. 40,000 participants will be recruited and we predict an average of 400-800 participants per site
in 50-100 sites.
Before the trial enrolment starts there will be engagement with the potential participants to inform them
about the trial and possibly obtain baseline demographic information from potential participants. Eligible
participants will give written informed consent. As part of the informed consent process the risks and
benefits of the study will be explained to them in their language, including potential side-effects of
chloroquine and hydroxychloroquine. They will also be informed that biological samples will be stored and
may be processed for genetic material, biochemical tests, and other pathogens. They will also consent to
having clinical information shared with the study team, although these data will remain pseudonymised
and stored and processed in accordance with national and international standards and in accordance with
regulating bodies. The participant will be instructed how to contact the study team and how to use the
simple reporting application (app) on their mobile phone. While well, the participant will continue their
normal duties and activities (e.g. in the healthcare facility). The study procedure of reporting side-effects
and adverse reactions will be explained (reporting to the site local PI and if necessary, stopping the
medication). The participant will also be informed what to do if they develop symptoms of an acute
respiratory infection (ARI), which will be to alert the study team and follow institutional and governmental
guidelines to get tested for COVID-19 (dependent on site).
The participant will be randomised to receive either chloroquine or placebo (1:1 randomisation), or to
hydroxychloroquine or placebo (1:1 randomisation). A loading dose of 10mg base/kg (four 155mg tablets
for a 60kg subject), followed by 155 mg daily (250mg chloroquine phosphate salt/ 200mg
hydroxychloroquine sulphate) will be taken for 3 months.
If the participant is diagnosed with COVID-19, they will take continue to take the study medication until:

90 days after enrolment (i.e., completion of kit)

hospitalised due to COVID-19 disease (i.e., not for quarantine purposes) in which case they will
stop, or

advised to stop by their healthcare professional for other reasons
If participants are hospitalised with symptoms consistent with COVID-19, they will continue the study
medication until they are formally diagnosed with COVID-19 or unless advised to stop by their healthcare
professional. If the participant misses a dose, they can take this dose later, up until the time they would

Protocol version 6.0 dated 13 January 2021
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take their next daily dose. If they do not take their dose within this period of time, they will not take it and
this dose will be classified as missed. They should continue to take their medication regularly. The missed
dose will be reported to the study team via the mobile app and at the subsequent follow up visit at the
study site.
Episodes of symptomatic respiratory illness, including symptomatic COVID-19, and clinical outcomes will
be recorded in the CRF during the follow-up period.
At the initial visit participants will provide demographic and basic clinical data and have their weight and
height measured. 10mls of blood will be taken, centrifuged and the serum, plasma and cell fraction stored
at -80°C for future analysis. This sample will be used for baseline antibody testing, chloroquine/
hydroxychloroquine levels, biochemical tests and host genetics related to susceptibility to respiratory
illness and COVID-19 infection and chloroquine/ hydroxychloroquine levels.
Participants will be given a participant ID number (a card in most settings), randomised and given 30 days
of study medication and asked to see the local PI or study nurse 28-30 days later. The drug will be taken
once daily in the morning (or evening for night shifts). The card will have contact numbers for the study
team members whom they are to inform should they develop adverse reactions/ side-effects or
symptoms. The initial weight-based loading dose will be observed by the study nurse. Participants will also
be given a thermometer, and requested to record their temperature twice a day, as well as any significant
exposures or symptoms.
Participants will be prompted to record twice daily temperature readings and symptoms via a mobile-
based application or web interface. The data will be transferred securely to the team and merged with
other study data for analysis. Participants who do not record symptoms and temperature readings at
minimum daily will be contacted within 24-48 hours by the study team. Participants who report being
unwell will be further assessed by the study team. Should participants be unable to access the mobile
application or website, the study team will phone them and record the data on their behalf.
If symptoms consistent with COVID-19 occur, the participant will alert the study team and will arrange for
nose and throat swab samples (even if a sample has been taken previously for clinical purposes) following
strict adherence to personal protection. In some instances, a sputum sample may also be taken. The
participant should continue his/ her chloroquine/ hydroxychloroquine or placebo, unless otherwise
advised by a medical professional or the study team, or they are diagnosed with COVID-19 and hospitalised
with infection (not for quarantine purposes). Prescribing medical professionals should be mindful that
participants may or may not be taking chloroquine/ hydroxychloroquine and in some cases, determined
per site specific guidance, this may necessitate unblinding.
If there is a subsequent significant clinical change in the participant or the participant has further episodes
of ARI within the trial period, this process will be repeated. Samples will be stored at -80°C and tested for
respiratoryviruses at the end of the trial. The participant will self-isolate, as per local or national guidelines.
If a clinical sample has been taken for local analysis and is negative for COVID-19, then self-isolation can
stop according to local or national guidance.
If a diagnosis of COVID-19 from a clinical sample is confirmed then the isolation practices and contact
tracing will follow the local practices and guidelines, and chloroquine/ placebo or hydroxychloroquine/
placebo will continue unless the participant is advised to stop by their healthcare professional or they
become hospitalised with infection (not for quarantine purposes). The participant will continue to give an
update of their clinical condition on the app, or will be called by mobile phone until recovered and followed
up once more at 28 days by phone. If the participant develops an ARI within the final 60 days of the study
which is not diagnosed as COVID-19, they should continue chloroquine or hydroxychloroquine/ placebo as
normal (unless advised by a medical professional or the study team) but will be followed up for 28 days
after the onset of infection. For all participants with an ARI, including those confirmed to have COVID-19,
if the participant has not recovered by 28 days this period can be extended up to 60 days.

Protocol version 6.0 dated 13 January 2021
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As well as twice daily electronic reporting, participants will be reviewed by the study team at least monthly
to assess drug tolerability, well-being, respiratory and other symptoms and fever, and whether the local
authorities have taken a swab for COVID-19 (in case they had not contacted the study team). This will be
done in person (if the participant is not symptomatic; if symptomatic separate provisions will be arranged)
and will be combined with:

Collection of a study adverse events questionnaire;

A dried blood spot (DBS) sample on filter paper for hydroxychloroquine/ chloroquine levels +/-
COVID-19 diagnostic tests;

Dispensation of further study drugs.
Participants will be requested to give a further 5ml clotted blood sample at the end of the trial. They will
be asked not to take their trial medication on the morning of review the medication will be taken after
the interview.
Participants who are offered a COVID-19 vaccine prior to D90 should inform the study team at the earliest
possible opportunity. Prior to vaccination, or up to 3 days after first dose of COVID-19 vaccine, the study
team will collect 5ml of clotted blood and DBS. The study team will advise the participant to stop taking
the study medication but will confirm the participant will continue in the study for remote follow up
through D90. Vaccinated participants will then be asked to give a further venous blood sample of 5mls at
28 days (+/- 3 days) after first dose of vaccine, in order to determine whether antibody responses differ
between those who are on active drug or placebo.
For those who develop symptomatic COVID-19 illness or ARI, a continuous severity score will be used to
assess severity, and these will be captured longitudinally over time. In order to discriminate between
severity at the lower end of the spectrum we will use a logarithmic scale and a Wilcoxon test can then be
used to compare ranks between the two groups.
Participants will remain enrolled until one of the following events occur:

The trial ends

They choose to withdraw consent or no-longer wish to participate in the trial

An adverse event warrants removal from the study

Discontinued by the investigator
Participants who discontinue study medication early will be encouraged to complete all other study
assessments through Day 90.
PARTICIPANT IDENTIFICATION AND RECRUITMENT
6.1. Study Participants
The study population is adult healthcare workers and other persons defined by the site investigator at
risk of contracting COVID-19.
6.2. Inclusion Criteria
1.
Participant is willing and able to give informed consent for participation in the study and
agrees with the study and its conduct
2.
Agrees not to self-medicate with chloroquine, hydroxychloroquine or other potential
antivirals
3.
Adults (exact age is dependent on countries) less than 70 years old at the time of consent

Protocol version 6.0 dated 13 January 2021
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4.
Not previously diagnosed with COVID-19
5.
Not currently symptomatic with an ARI
6.
Participant is a healthcare worker or is a person at risk of contracting COVID-19.
7.
Possesses an internet-enabled smartphone (Android or iOS)
6.3. Exclusion Criteria
The participant may not enter the study if ANY of the following apply:
1.
Hypersensitivity reaction to chloroquine, hydroxychloroquine or 4-aminoquinolines
2.
Contraindication to taking chloroquine as prophylaxis e.g. known epileptic, known creatinine
clearance < 10 ml/min
3.
Already taking chloroquine, hydroxychloroquine or 4-aminoquinolines, or history of these
medications within the previous 7 days
4.
Taking a concomitant medication described in Section 8.5
5.
Known retinal disease
6.
Inability to be followed up for the trial period
7.
Known prolonged QT syndrome (however ECG is not required at baseline)
8.
Known pregnancy or women who are actively trying to become pregnant
9.
Prior diagnosis of porphyria
10. Previously received any dose of COVID-19 vaccine
The investigator may consult the physician’s guidance documents for any further questions regarding
eligibility of potential participants.
STUDY PROCEDURES
7.1. Recruitment
Study sites will be initially pre-selected on the following criteria if ALL of the following are met:

There is local agreement that the study can be conducted in the facility

Local or national ethical/ IRB approval can be put in place rapidly

It is a facility where there are cases of either proven or suspected COVID-19 and/or the site
investigator defines other potential participants at risk of COVID-19 infection

There are adequately trained personnel able to conduct the study procedures described in the
protocol and appropriate equipment

Each site would be able to recruit a projected 400 participants during the trial period (200
participants per site may be possible on discussion)
Study sites may then be selected if ANY of the following criteria are met:
•
Confirmed nosocomial spread of COVID-19 in the healthcare facility, or neighbouring facilities
•
Confirmed cases of COVID-19 in the healthcare facility, or neighbouring facilities
•
Confirmed person-to-person transmission of COVID-19 in the local area
Recruitment of individuals into the study once sites are confirmed and local or national ethical/ IRB
approval is in place:
Facilities will contact their staff or other persons locally defined at risk of contracting COVID-19 to inform
them of the study through usual means. In addition, with the local ethics committee approval and

Protocol version 6.0 dated 13 January 2021
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institution’s consent, the site study PI may advertise the study with posters, social networking and through
word of mouth. Recruitment into the study will occur in person either in, or nearby, the facility.
7.2. Screening and Eligibility Assessment
Eligibility assessment will occur at the point of screening. If, based on the inclusion and exclusion criteria,
the participant is eligible, they will be randomised to receive chloroquine / hydroxychloroquine or placebo.
7.3. Informed Consent
The participant must personally sign and date the latest approved version of the Informed Consent form
before any study specific procedures are performed.
Written and verbal versions of the Participant Information and Informed Consent will be presented to the
participants detailing no less than: the exact nature of the study; what it will involve for the participant;
the implications and constraints of the protocol; the known side effects and any risks involved in taking
part; their samples being stored and being processed for host genetic material and other pathogens; and
for any clinical and other personal data during the trial, being shared with the study team.
It will be clearly stated that the participant is free to withdraw from the study at any time for any reason
without prejudice to future care, and with no obligation to give the reason for withdrawal.
The participant will be allowed as much time as wished to consider the information, and the opportunity
to question the Investigator or other independent parties to decide whether they will participate in the
study. Written Informed Consent will then be obtained by means of participant dated signature and dated
signature of the person who presented and obtained the Informed Consent. The person who obtained the
consent must be suitably qualified and experienced, and have been authorised to do so by one of the
Investigators. A copy of the signed Informed Consent will be given to the participant. The original signed
form will be retained at the study site.
7.4. Clinical examination
There will be no physical clinical examination. Basic demographic information, and details of past medical
history, concomitant medications, allergies, smoking and other drug intake will be noted. The height,
weight, and temperature will be recorded.
7.5. Randomisation and blinding
Chloroquine phosphate tablets containing 155mg base equivalent and identical placebo pills will be packed
in opaque blister packs containing 10 tablets. Hydroxychloroquine sulphate tablets containing 155mg base
equivalent and identical placebo pills will also be packed in opaque blister packs containing 10 tablets.
Each participant will receive a study box containing up to 100 tablets. The initial dose to be taken from the
starter blister pack is 10mg/kg, which will be between three and five tablets depending on the weight of
the participant.
A randomisation list will be prepared by a statistician using block randomisation in a 1:1 ratio for the
chloroquine/ hydroxychloroquine arm versus the placebo and stratified by site. The randomisation will be
computer-generated and programmed in Stata 15. An appropriate computer seed will be used to allow
reproducibility of the randomisation list. The list will be provided directly to the pharmaceutical company
by the trial statistician to allocate a drug kit containing 10 blister packs with 10 tablets in each blister to
participants based on the computer pre-generated randomisation list. The packaging of study drug kits will
be performed by independent staff at the pharmaceutical company and will follow the computer-
generated randomisation list provided by the statistician. Should the company not have capacity to pack

Protocol version 6.0 dated 13 January 2021
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treatment, the packaging of study drug kits will be performed by independent staff at MORU. At enrolment
the participant’s kit number/ ID will be written on the study drug kit and on each blister pack (only if
possible), and the starter blister pack and first 30 tablets dispensed to the participant. The kit number/ ID
will be linked to the treatment that has been allocated to each participant. All study team members will
be blinded to the actual treatment and only the trial statistician and the backup statistician will have access
to the randomisation code. The unblinded randomisation list and the randomisation programs will be
securely kept by the statistician and backed-up. The study drug kits will be kept securely by the study team.
Subsequent 30 tablets (3 blister packs) will be dispensed at each monthly check with the study team.
Individual unblinding will be done only on consultation with the study PI. Only the study statistician will
have the drug allocation list.
A separate procedure will be provided to study teams to describe details of randomisation and study
medication management.
7.6. Baseline Assessments
At Day 0 (D0), participants will be given a card with a participant ID number, have an app installed on their
mobile phone, be randomised and given 30 days of study medication, and asked to see the local PI 28-30
days later. The study medication will be taken in the morning (or evening for night shifts). The card will
have contact numbers for the study team members whom they are to inform should they develop adverse
reactions, side-effects or symptoms.
Participants will also be given a thermometer, will be requested to record their temperature twice a day,
as well as any significant exposures or symptoms on an app (phone-based) reporting software application.
The mobile app will be set up on the participant’s phone and they will be instructed in its use in the
presence of the study team at D0, as well as instructing them on how to report symptoms and use the
thermometer. Those reporting to be unwell or those who do not respond on the app will be contacted by
the study team.
At the initial visit participants will provide demographic and basic clinical data, including co-morbidities
and concomitant medications, information on well-being, and have their weight and height measured.
10mls of blood will be taken and two blood spots will be collected on filter paper for baseline chloroquine/
hydroxychloroquine levels. The serum, plasma and cell fraction will be stored at minus 80°C for future
analysis.
The participant will be observed taking the first (weight-based dose) dose of study drug by the study team.
7.7. Subsequent Visits
At Day 30, if the participant is asymptomatic they will present in person to collect a further 30 days of
study medication. This process will occur every 30 days for a total 3 months. If the participant does not
present, they will be contacted and the appointment will be arranged, and provision made for the
participant to collect the study product.
The expected schedule for follow up visits is every 28-30 days based from Day 0, a visit window of 27-31
days is allowed to accommodate participant scheduling during study conduct. The final follow up visit
(D90) has a visit window from D87-D97 to ensure data for important study endpoints are collected.
At each visit (D30, D60 and D90):

Participant identification will be confirmed. Use of the mobile telephone number given at the
initial assessment will suffice as long as the study team has no reason to suspect the participant is
not the same person.

Protocol version 6.0 dated 13 January 2021
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
Adherence will be reviewed via question and pill count. The used blister pack will be returned,
checked and stored. The time of the last dose will be noted.

Well-being, adverse reactions or side-effects will be assessed.

Symptoms compatible with COVID-19, testing for and results of testing for the infection.

A finger prick for 2 blood spots will be performed on a filter paper.

At the final visit (D90), 5ml of venous blood will be taken in a clotted bottle and 2 blood spots will
be collected on a filter paper.
Additionally, during this period the study participant will be asked to record entries twice daily via a mobile
phone app. They will be reminded to take their tablet. These data will be transferred securely to the team
and analysed. Those reporting to be unwell or those who do not respond on the mobile app will be
contacted by the study team.
If via the app or by phone, the participant reports to feel unwell with an ARI (potential COVID-19
symptoms) or potential drug side-effects, they will be contacted by the study team. The study team will
ask the participant further questions and if required, within 48 hours a nose and throat swab will be
organised according to study SOP. Further follow-up of initial unwellness by the study team would be a
the discretion of the assessing physician, however participants should continue to report data via the app.
If a significant clinical deterioration should occur, or further ARIs occur in the study period, the nose and
throat swab will be repeated. If the participant is producing sputum, a sample will be collected in a pot, or
a sputum pot will be left with the participant, for later collection.
The participant will be advised to inform their healthcare professional that they are in the study along with
the study medications they may be taking. If they are hospitalised with confirmed COVID-19 as a result of
the infection (not for quarantine purposes), the study medication should be stopped. If the participant’s
healthcare professional starts a treatment which is known to prolong the QT interval, while the participant
is enrolled in the study, then an ECG should be performed by this professional and checked for QT
prolongation.
If the participant is offered a COVID-19 vaccine prior to D90, the study team will:

Advise immediate discontinuation and return of study medication.

If possible to obtain prior to vaccination or up to 3 days after first vaccine dose, collect 5ml of
venous blood in a clotted bottle and 2 blood spots via a filter paper.

Collect a further 5ml of clotted blood 28 days (+/-3 days) after first vaccination.

Confirm the participant will agree to continue other data entry and monitoring through D90 or 28
days after first vaccination, whichever comes later.

The team will continue to follow up reports of potential ARIs or other illnesses, including collection
of a swab where indicated.
7.8. Sample Handling
On D0, 10mls of venous blood will be taken [EDTA (4mL) and clotted bottle (6mL)]. Both samples will be
centrifuged at 1500g for 10 minutes. Three aliquots of serum from the clotted bottle and three aliquots of
plasma from the EDTA tube will then be stored at minus 80°C until further notice. Additionally, a single
aliquot of the cell fraction from the EDTA tube will also be aliquoted and stored at minus 80°C. Two spots
(50 µL each) of blood will be collected on a filter paper and stored in an individual small plastic bag with a
desiccant sachet.
At D30 and D60 of the trial, when participants attend for review, finger prick will be performed to collect
2 blood spots on the filter paper.

Protocol version 6.0 dated 13 January 2021
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On the last day of the trial 5mL of venous blood will be collected in a clotted bottle, which will subsequently
be centrifuged and aliquoted to 3 cryovials as described above. Two blood spots will also be collected on
a filter paper.
Nose and throat swabs will be taken in accordance with the provided study SOP and frozen immediately
at minus 80°C in their collection tube, or handled per local procedure if agreed with MORU team. Sputum
will either be frozen in the container in which it is collected (if amenable to freezing) at minus 80°C or the
sample will be transferred to a viral swab and stored at minus 80°C.
Samples will be transferred to MORU Tropical Health Network laboratories or designated testing facilities
in other regions, where they will undergo testing in accordance with best practice laboratory measures
and safety procedures.
Validated antibody tests for SARS-CoV-2 are currently being developed rapidly. The plasma and serum
aliquot samples will be stored until a time that validated assays for these have been developed or we have
completed our own in-house serological tests and validations. The criteria for a positive test are thus yet
to be determined, but as with other serological tests, a four-fold increase in titre of SARS-CoV-2 antibodies
between the initial and final sample will likely be used to determine exposure to the virus. Additionally,
we will be able to determine if exposure to SARS-CoV-2 has occurred prior to enrolment in the trial if the
initial antibody titre is above a predetermined and validated level. Serological tests for other circulating
coronaviruses may also be performed to determine the interaction of these with COVID-19, as well as
other pathogens which may be of clinical significance.
Testing of the serum samples for other biological parameters which may impact susceptibility to infection,
such as ACE2, zinc and vitamin D levels, may also be considered at a later date.
Nose and throat swabs will be processed using validated multiplex RT-PCR to detect SARS-CoV-2 as well as
other respiratory viruses including some or all of the following: influenza A, influenza B, respiratory
syncytial virus, rhinovirus, other coronaviruses (OC43, NL63, 229E and HKU1), metapneumovirus,
parainfluenza 1-4, adenovirus and bocavirus. The cycle threshold (CT) value of positive results will be
recorded.
The cell fraction aliquot will be processed to assess for host genetic markers of respiratory disease
susceptibility. These tests may be done in Thailand or elsewhere in Asia, the UK or Europe, once material
transfer agreements are in place.
DBS samples will be used for measurement for chloroquine/ hydroxychloroquine levels and may be used
for diagnostic tests for COVID-19 (antibody, antigen or PCR).
The samples will be retained per Oxford and local site regulations. Consenting participants may rescind
their consent at a later date and refuse the use of their samples (which will be destroyed) or data at any
time up until the completion of the study.
7.9. Discontinuation/Withdrawal of Participants from Study
Each participant has the right to withdraw from the study at any time. In addition, the Investigator may
discontinue a participant from the study at any time if the Investigator considers it necessary for any
reason including:

Ineligibility (either arising during the study or retrospectively having been overlooked at screening)

Significant protocol deviation

Significant non-compliance with treatment regimen or study requirements

Withdrawal of Consent

Loss to follow up (LTFU)

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Participants who discontinue study medication early, e.g. due to COVID-19 vaccination or pregnancy, will
be asked to remain in the study to complete all other defined study procedures.
The reason for withdrawal will be recorded in the Case Report Form.
Participants who withdraw or are removed from the study will not be replaced.
7.10. Definition of End of Study
The end of the study will be the date of the last visit of the last participant, the last dose of the study drug
or up to 60 days after the diagnosis of COVID-19/ ARI of the last participant enrolled in the study, whichever
comes last.
STUDY MEDICATION (CHLOROQUINE or HYDROXYCHLOROQUINE/PLACEBO)
8.1. Study Medication Description
The trial intervention is the administration of the study product. This will either be chloroquine or placebo,
or hydroxychloroquine or placebo. It is expected that chloroquine will be used in Asian sites and
hydroxychloroquine in Europe, specific drug allocation will be determined by country prior to activation
based upon factors such as inventory availability and importation requirements.
Characteristics of each product are described in the SmPC.
Chloroquine and hydroxychloroquine will be in the dose of 155mg chloroquine base (250mg of chloroquine
phosphate or 200mg of hydroxychloroquine sulphate). On D0 the participant will be supervised taking
10mg base/kg by the study team (usually 3-5 tablets depending on weight; where the dose is split then
only the initial part of this dose will be observed) and they will be given a further 30 tablets of 155mg base
to be taken once daily. The placebo will comprise identical tablets and the regimen will be the same with
1 tablet/ 15kg at D0 and a further 30 tablets to be taken once daily. Neither the participant, nor those
conducting the study will know if the participant is receiving chloroquine/ hydroxychloroquine or placebo.
8.2. Storage of Study Medication
The medication will be stored securely per manufacturer instructions in the institution’s pharmacy or other
secure location. The medication will only be accessible to the designated study team members.
8.3. Compliance with Study Medication
Adherence will be assessed by direct questioning of the participant. Participants will receive reminders to
take
the
medication
from
the
app.
The
monthly
pre-dose
capillary
blood
chloroquine
or
hydroxychloroquine measurement will be an independent measure of exposure. Given that the study will
be conducted on healthcare workers or other participants potentially at higher risk of infection, and the
current concern relating to COVID-19 is so great, we do not anticipate poor adherence. In the event of lost
medication or more than 3 consecutive missed doses the participant should contact the study team, if they
have not already been contacted by the study team.
8.4. Accountability of the Study Medication
The medication and placebo supplies will be supervised at all times by study teams. Medication counts will
occur to ensure that no tablets are missing. Dispensation and return of study drugs will be recorded in the
Study Drug Accountability Log.

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8.5. Concomitant Medication
Chloroquine or hydroxychloroquine must be avoided if the participant is taking the following medications:
Antiarrhythmic medications: digoxin, amiodarone, sotalol, flecainide
Antiparasitic/malarial agents: mefloquine, halofantrine, praziquantel
Antibiotics: levofloxacin, moxifloxacin, ciprofloxacin, azithromycin, clarithromycin, erythromycin
Antifungal drugs: fluconazole, ketoconazole, itraconazole, terfenadine
Psychoactive drugs: lithium, quetiapine, chlorpromazine, thioridazine, ziprasidone, haloperidol,
droperidol, methadone
Migraine treatment: sumatriptan
Antihistamines: astemizole
Antiemetics: prochlorperazine, metoclopramide
Cancer treatments: abiraterone, dabrafenib, dacomitinib, enzalutamide, idelalisib, mitotane
Other specific drugs: ciclosporin, conivaptan, agalsidase alfa or beta, mifepristone, stiripentol
PIs will also be directed to crediblemeds.org to check other agents that may prolong QT interval
8.6. COVID-19 Vaccination
The study team have carefully considered how the development and planned global roll out of COVID-19
vaccines may impact upon the primary study outcomes. Consequently, anyone who receives a COVID-19
vaccination will not be eligible for enrolment in the COPCOV study and those participants who are
vaccinated during the study period will stop the study medication but will remain in the study and be
followed through D90, or 28 days after the 1st dose of vaccine, whichever comes later. The study will not
interfere with participants being vaccinated. The participant will be asked to provide a venous blood and
DBS sample (as would normally be obtained at D90), for ascertainment of the study’s endpoints. In
addition, participants vaccinated during the study will have a further venous blood test drawn at 28 days
(+/-3 days) after the first vaccine dose to determine if the study medication has any effect on the antibody
response. We foresee that we may collect additional AEs and SAEs not related to the study medication,
but caused by the vaccine; however we consider it is important to determine if there are any interactions
between the study drugs and the COVID-19 vaccines.
It is hoped that all participants in the COPCOV study will eventually receive one of the COVID-19 vaccines.
It is important therefore to ensure that there are no untoward effects in hydroxychloroquine or
chloroquine recipients should they receive vaccine during the study. Drug administration will stop and the
efficacy endpoint censored at the time of vaccination, but adverse effects will continue to be monitored
through final assessment. . Blood samples will be drawn at the time of and 28 days post-vaccination, to
evaluate that the drugs do not attenuate antibody responses.
8.7. Post-trial Treatment
We are currently not planning to provide the chloroquine or hydroxychloroquine post-trial. They are
readily available and affordable.
SAFETY REPORTING
9.1. Definition of Serious Adverse Events
A serious adverse event is any untoward medical occurrence that:

Protocol version 6.0 dated 13 January 2021
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
results in death

is life-threatening4

requires inpatient hospitalisation5 or prolongation of existing hospitalisation

results in persistent or significant disability/ incapacity

consists of a congenital anomaly or birth defect
Other ‘important medical events’ may also be considered serious if they jeopardise the participant or
require an intervention to prevent one of the above consequences.
9.2. Definitions
Adverse Event (AE)
Any untoward medical occurrence in a participant to whom a medicinal
product has been administered, including occurrences which are not
necessarily caused by or related to that product.
Adverse Reaction (AR)
An untoward and unintended response in a participant to an
investigational medicinal product which is related to any dose
administered to that participant.
The phrase "response to an investigational medicinal product" means
that a causal relationship between a trial medication and an AE is at least
a reasonable possibility, i.e. the relationship cannot be ruled out i.e. the
relationship is definitely, probably, possibly or unlikely to be related (see
below).
All cases judged by either the reporting medically qualified professional
or the Sponsor as having a reasonable suspected causal relationship to
the trial medication qualify as adverse reactions.
Serious Adverse Event
(SAE)
A serious adverse event is any untoward medical occurrence that meets
below definition and per Section 9.1:

results in death

is life-threatening4

requires inpatient hospitalisation5 or prolongation of existing
hospitalisation

results in persistent or significant disability/incapacity

consists of a congenital anomaly or birth defect

Other ‘important medical event’.
Serious Adverse Reaction
(SAR)
This is an adverse event that is both serious and is considered a drug
reaction.
4 The term "life-threatening" in the definition of "serious" refers to an event in which the participant was at risk of death at the
time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.
5 Hospitalisation is defined as an unplanned, formal inpatient admission, even if the hospitalisation is a precautionary measure for
continued observation. The participant must be admitted overnight, a short stay of several hours to receive treatment is not
considered hospitalisation. If a patient is admitted overnight or longer for social/economic reasons and is otherwise medically
stable, this does not constitute a SAE. Other examples of visits to a hospital facility that are not considered hospitalisation are:
Emergency room visits, outpatient surgery and pre-planned or elective procedures for a pre-existing condition (as long as that
condition has not deteriorated while on trial treatment or brought forward because of worsening symptoms).

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Suspected Unexpected
Serious Adverse Reaction
(SUSAR)
A SUSAR is a SAR that is:

not listed in the summary of product characteristics (SmPC) for
that product or

has not been described in the published literature before
Expectedness
An expected AR or SAR is a drug reaction that is listed in the SmPC and
or has been described in the published literature before.
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”,
the following note of clarification is provided: “Severe” is often used to describe intensity of a specific
event, which may be of relatively minor medical significance. “Seriousness” is the regulatory definition
supplied above.
9.3. Causality
The relationship of each adverse event to the trial medication must be determined by a medically qualified
individual according to the following definitions:
Definitely related:
There is clear evidence to suggest a causal relationship and other possible
contributing factors can be ruled out.
Probably related:
There is evidence to suggest a causal relationship and the influence of other factors
is unlikely.
Possibly related:
There is some evidence to suggest a causal relationship (e.g. because the event
occurs within a reasonable time after administration of the trial medication).
However, the influence of other factors may have contributed to the event (e.g.
the patient’s clinical condition, other concomitant treatments).
Unlikely to be related: There is little evidence to suggest there is a causal relationship (e.g. the event did
not occur within a reasonable time after administration of the trial medication), or
there is another reasonable explanation for the event (e.g. the patient’s clinical
condition, other concomitant treatment).
Not related:
There is no evidence of any causal relationship.
9.4. Procedures for Recording Adverse Events
The severity of adverse events will be assessed following the Common Terminology Criteria for Adverse
Events (CTCAE) v5.0:
1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal.
AEs occurring in participants from enrolment and during trial participation (up until Day 150 for a sub-set
of participants with extended follow up) that are observed by the Investigator or reported by the
participant with severity grade of 2 (moderate) or higher will be recorded on the CRF, whether or not
attributed to trial medication.
The following information will be recorded: description, date of onset and end date, severity, assessment
of relatedness to trial medication, other suspect drug or device and action taken. Follow-up information
should be provided as necessary.

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AEs considered related to the trial medication as judged by a medically qualified investigator will be
followed either until resolution, or the event is considered stable.
It will be left to the Investigator’s clinical judgment to decide whether or not an AE is of sufficient severity
to require the participant’s removal from treatment. A participant may also voluntarily withdraw from
treatment due to what he or she perceives as an intolerable adverse event. If either of these occurs, the
participant must undergo an end of trial assessment and be given appropriate care under medical
supervision until symptoms cease, or the condition becomes stable.
9.5. Reporting Procedures for Serious Adverse Events
General reporting procedures for all SAEs are to be managed by the site PI via local / national ethics
committee and regulatory requirements.
In addition, the COPCOV safety team will monitor events and communicate with the study Data Safety and
Monitoring Board (DSMB, see Section 9.7). The safety team can be contacted via COPCOV-
Safety@tropmedres.ac
SAEs relating to acquisition of COVID-19, and morbidity and mortality associated with this, do not need to
be reported to the COPCOV safety team immediately, but should be reported no less than monthly in order
to be included in scheduled Safety Monitoring Committee meetings.
All other SAEs detected by the site investigator should be reported to the COPCOV safety team within 24
hours of site awareness. The safety team and the local PI will gather any additional relevant information.
The COPCOV safety team will inform the DSMB within 10 days of initial notification of the SAE and keep
the DSMB updated as needed.
Treatment codes will be unblinded for specific participants after discussion with the study co-PI.
9.6. Reporting Procedures for Pregnancy
If a female participant becomes pregnant after enrolment she should be instructed to discontinue study
drug. The site study team is to notify the COPCOV safety team within 24 hours of site awareness through
completion of the pregnancy notification form and submission to: COPCOV-Safety@tropmedres.ac
Pregnant participants will be asked to return unused study medication at their next visit and will continue
remaining follow up visits and procedures per protocol.
9.7. Data Safety and Monitoring Board
An independent Data Safety and Monitoring Board (DSMB) will be set up consisting of qualified volunteers
with the necessary knowledge of clinical trials. The DSMB will receive summary reports, prior to each
meeting.
The DSMB will consider a formal interim analysis/analyses if the study exceeds certain time periods. The
safety and the statistical considerations in the interim analyses such as the stopping rules for trial efficacy
including the type 1 error probability, and futility for no treatment benefit have been clearly detailed in
the DSMB charter and the statistical analysis plan.
All data reviewed by the DSMB will be in the strictest confidence. A DSMB charter will outline its
responsibilities, number of interim reports and how it will operate. Interim reports will be prepared by the
Trial Statistician.

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All DSMB recommendations will be communicated to site PIs. The site PI will be responsible for submitting
the written DSMB summary reports with recommendations as applicable to local/ national ethics
committees and other applicable groups.
STATISTICS AND ANALYSIS
10.1. Description of Statistical Methods
All participant data will be included in the Intention-To-Treat (ITT) analysis according to the arm they were
randomised to, irrespective of the actual study drug that they took. This ITT analysis will be the main
strategy for the primary outcome and will be followed by a per protocol (PP) analysis. A per protocol (PP)
analysis will be conducted to adjust for non-compliance to study protocols. Under an assumption of no
post-randomisation confounding, this is a form of sensitivity analysis of the intention to treat analysis. In
the PP analysis, participants who did not take their pills, or those who took extra chloroquine/
hydroxychloroquine (in both cases as determined by PK analyses), no final outcome assessed and losses
to follow-up prior to the assessment of the final outcome, and any major protocol violations will be
excluded. A detailed Analysis plan will be written by the trial statistician.
10.2. The Number of Participants
A large and definitive study is needed to characterise the benefit of prophylaxis with chloroquine or
hydroxychloroquine in protecting heath care workers (and other persons defined at risk of contracting
COVID-19) from COVID-19 illness. Power calculations are based on an assumption of 3% incidence of
symptomatic COVID-19 during the trial period (1% per month). This is a conservative estimate and
although some sites may have more or less cases, due to the unpredictability of numbers of cases in a site
and a country, this assumption remains valid. Expert opinion considers that if chloroquine or
hydroxychloroquine is effective, it may decrease symptomatic COVID-19 by 23%, and therefore, the
chloroquine arm or hydroxychloroquine would have a 2.31% COVID-19 diagnosis. A 95% confidence
interval with 80% power would indicate 8,520 participants randomised to each arm. We will aim to enrol
10,000 participants in each arm in the two trials which allows for at least a 10% LTFU, withdrawal rate,
protocol deviation and non-adherence. Thus 20,000 would be randomised to chloroquine/ placebo and
20,000 to hydroxychloroquine/ placebo.
10.3. Analysis of Outcome Measures
A mixed effects Negative Binomial model will be used to model the incidence of symptomatic COVID-19
infection to obtain incidence rate ratios comparing the chloroquine arm with the placebo. Repeated
measures and hospital clustering effect will be taken to account in the mixed effects model. Incidence rate
ratios and the corresponding 95% confidence intervals will be obtained and reported. As much as possible
graphical methods will be used to show trends in the incidence of symptomatic COVID-19 over time and
by arm. In the event that the Negative Binomial models fail to converge, as is the characteristic of these
models when the outcome is rare, a Binomial regression model will be considered to model the risk/ odds
of symptomatic COVID-19 infection to obtain risk differences/ odds ratios as appropriate comparing the
chloroquine/ hydroxychloroquine arm with placebo. Survival methods will be used to estimate the time to
resolution and also as a method of handling missing data in case of dropouts. In this approach, participants
without outcomes will be censored at their longest observed time.
A continuous severity score (see Appendix A for example) will be used to assess severity of symptomatic
COVID-19 and ARIs of those who acquire these, and these will be captured longitudinally over time. A rank-
based mixed model approach will be used to analyse these scores, to compare the two groups in order to
discriminate between severities at the lower end of the spectrum.

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Normally distributed continuous baseline characteristics will be summarised using means and standard
deviations while skewed continuous baseline characteristics will be summarised medians and interquartile
ranges. Categorical data will be summarised using counts and percentages. A Fisher’s exact test will be
used to compare binary outcome data between groups. Statistical significance will be determined at 5%
significance level.
DATA MANAGEMENT
11.1. Access to Data
Direct access will be granted to authorised representatives from the University of Oxford, local ethics
committees and regulatory authorities, and any host institution for monitoring and/or audit of the study
to ensure compliance with regulations.
11.2. Data Handling and Record Keeping
Clinical study data will be recorded on CRFs and entered on to a password-protected database by the local
study PI, a research nurse or designee. The study database will be built in a clinical data management
system that is compliant with ICH GCP and FDA 21 CFR Part 11 and will be hosted in a secure, access-
restricted server. A system for recording electronic patient reported outcomes (ePRO) will be built and
integrated with the study database. The study database and ePRO system will include internal quality
checks to identify data that appear inconsistent, incomplete, or inaccurate.
Measures will be taken to ensure non-disclosure of information that is potentially harmful to participants.
Paper records (for example, patient identifiable information for the purposes of follow-up, the screening
logs and signed ICFs) will be kept in locked cabinets; electronic data will only be accessible to staff with
user accounts and passwords. The database contains an audit trail that keeps record of changes to data
and user activity within the database. All electronic data will be stored on secure servers that are backed
up daily, with weekly off-site storage.
Participant records at site will, taking into account the ability of the sites, be stored in binders in the
secured access-limited room or scanned and stored electronically. The records will be retained for five
years following completion of the study, or according to local site regulation. The study database will be
retained indefinitely.
With participant’s consent, clinical data and results from blood analyses stored in the database may be
shared according to the terms defined in the MORU data sharing policy with other researchers to use in
the future.
Data generated from this study will adhere to the 2016 “Statement on data sharing in public health
emergencies”(https://wellcome.ac.uk/press-release/statement-data-sharing-public-health-
emergencies).
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES
The study will be conducted in accordance with relevant regulations and standard operating procedures.
The study will be conducted in compliance with this protocol, International Conference on Harmonization
(ICH) Guidelines for Good Clinical Practice (GCP) and any applicable regulatory requirement(s). Monitoring
will be overseen by the MORU Clinical Trials Support Group (CTSG) according to a prespecified risk-based
monitoring plan to ensure compliance to the study protocol and applicable guidelines and regulations.
Blood samples will be processed, stored and shipped in accordance with MORU SOPs.

Protocol version 6.0 dated 13 January 2021
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Data validation will be performed to identify errors or discrepancies and thus ensure completeness,
validity and accuracy of data.
ETHICAL AND REGULATORY CONSIDERATIONS
13.1. Declaration of Helsinki
The Investigator will ensure that this study is conducted in accordance with the principles of the
Declaration of Helsinki.
13.2. Guidelines for Good Clinical Practice
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with
Good Clinical Practice.
13.3. Approvals
The protocol, informed consent form, participant information sheet and any proposed advertising material
(if applicable) will be submitted to OxTREC and applicable local/ national ethics committees and regulatory
agencies for written approval.
The Investigator will submit and, where necessary, obtain approval from the above parties for all
amendments to the original approved documents.
13.4. Participant Confidentiality
The study team will ensure that the participants’ anonymity is maintained.
The participants will be
identified only by a participant ID number on all study documents and any electronic database, with the
exception of the CRF, where participant initials may be added. All documents will be stored securely and
only accessible by study team and authorised personnel. The study will comply with the Data Protection
Act 2018, which requires that personal data must not be kept as identifiable data for longer than necessary
for the purposes concerned.
13.5. Expenses and Benefits
Participants will not be paid for their participation in the research. Reimbursement for costs incurred by
participants during study participation will be reimbursed per local allowed guidelines and ethics
committee policies.
13.6. Reporting
The PI will ensure that an Annual Progress Report is submitted to all applicable ethics committees and
regulatory agencies on the anniversary of the date of approval of the study, or as otherwise defined per
local requirement. In addition, the PI shall submit an End of Study Report to all applicable parties upon
completion of the study.
13.7. Other Ethical Considerations
The decision to include only participants with a smartphone potentially runs the risk of violating the “fair
subject principal” (28) i.e. introducing a socio-economic bias into the trial. Given the trial will be conducted
in employed workers in facilities providing care for COVID-19, we do not think there will be many who
would not be able to be enrolled on this basis. Additionally, as we have already selected a discrete group

Protocol version 6.0 dated 13 January 2021
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on whom to conduct the study we do not think excluding those without a smartphone will add any
additional meaningful bias which will affect the study objectives.
Given the urgency of the question which this trial aims to answer and the difficulty of collecting the same
information without the use of an app-enabled smartphone we believe that the prompt and definitive
answering of the trial question is in society’s best interests, and given the current equipoise between
chloroquine / hydroxychloroquine and placebo in prevention of COVID-19, does not disadvantage those
ineligible to enrol.
13.8. Community and public engagement
Given the current lack of evidence that chloroquine or hydroxychloroquine will be effective in the
prevention of COVID-19, there is currently scientific equipoise which justifies the use of placebo in this
study. Although chloroquine or hydroxychloroquine have both been shown to be very safe, the medication
is not without side-effects.
As part of our engagement initiative (also called “patient and public involvement”, MORU will be
conducting a series of workshops within Thailand with (1) potential participants e.g. hospital staff and (2)
members of the public via existing advisory groups such the Bangkok Health Research Interest Group and
community advisory boards, to embed their voices into the research design, implementation and
dissemination of findings) (see Appendix C).
Similar or additional activities may be implemented at sites outside Thailand.
FINANCE AND INSURANCE
14.1. Funding
This study is funded via the ACT-Accelerator Therapeutics Partnership.
14.2. Insurance
The University has a specialist insurance policy in place which would operate in the event of any participant
suffering harm as a result of their involvement in the research (Newline Underwriting Management Ltd, at
Lloyd’s of London).
PUBLICATION POLICY
All publications will abide by the International Committee of Medical Journal Editors (ICMJE)
recommendations of the role of authors and contributors.
The results of the study will be summarised in lay language, in both English and the language(s) commonly
spoken at the study sites, and disseminated to key stakeholders, user communities and caretakers of study
participants.

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McChesney EW, Banks WF, Jr., Fabian RJ. Tissue distribution of chloroquine, hydroxychloroquine,
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Hongchao Pan RP, Quarraisha Abdool Karim, Marissa Alejandria, Ana Maria Henao-Restrepo,
César Hernández García, Marie-Paule Kieny, Reza Malekzadeh, Srinivas Murthy, Marie-Pierre
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Watson JA, Tarning J, Hoglund RM, Baud FJ, Megarbane B, Clemessy JL, et al. Concentration-
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APPENDIX A: EXAMPLE OF SEVERITY OUTCOME MEASURES
Observation
Scale
Outpatient
Feels normal
Feels unwell
URTI Symptoms (coryza and/ or sore throat)
Muscle aches
Cough
Afebrile <37.5oC
Fever ≥37.5 and ≤38.5oC
High fever >38.6oC
Shortness of breath on exertion
Shortness of breath at rest
Mainly chair/ bed bound
Requires hospitalisation (based on clinical symptoms)
Inpatient: Hospitalisation
Hypoxia / Hypoxaemia 90-95% on air (if measured) or requiring supplemental O2 (not high-
flow)
Hypoxia < 90% on air (if measured) or on supplemental O2 (up to 15L on non-rebreather)
Tachypnoea RR 25-40
Tachypnoea RR ≥ 40 
ARDS
Non-invasive ventilation: high-flow or CPAP/ BiPAP
Mechanical ventilation
Organ support other than respiratory
ECMO criteria met
Death
The above observations form an example of what may be collected and form the severity outcome scale
for participants in the trial who have symptomatic COVID-19 and also for those with an ARI. Additionally,
data will be collected on the duration of symptoms and analysed to determine if a difference in severity
exists between the two arms. As part of our analysis plan we will explore grouping, weighting and
aggregation of the above observations. A more detailed analysis plan can be found in the statistical analysis
plan (SAP) document.

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APPENDIX B: SCHEDULE OF STUDY PROCEDURES
Procedures
Visits
Day 0
Enrolment
Day 30
(-3 / +1)
Day 60
(-3 / +1)
Day 90
(-3 / +7)
ARI
symptom
onset1
Outcome
follow-
up if
symptom
atic
(≤Day 
150)
Prior to
vaccine
(or within
3 days
after first
dose)
Day 28
(+/-3 days)
post first
vaccine
dose
1
2
3
4
As needed
during trial
period
5
Vaccinated participants
ONLY
Screening
X
Eligibility
assessment
X
Informed
consent
X
Demographics
X
Medical history
X
Randomisation
X
Set up mobile
app
X
Given
thermometer
X
Venous blood
test
Y
Z
Z2
Z3
Z3
Observed 1st
dose of study
medication
X
Dispensation
of study
medication
(unless
diagnosed as
COVID-19
before visit)
X
X
X
Compliance
assessment
X
X
X
X
DBS
X*
X
X
X*
X*
Adverse event
assessments
X
X
X
X
X
Questions
about well-
being, illness,
COVID-19
diagnosis and
X
X
X
X
X
X
X
X

Protocol version 6.0 dated 13 January 2021
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clinical severity
data
Nose and
throat swab
(+/- sputum)
X
1Can be repeated on multiple occasions if illness worsens or new ARI during trial period.
2 If not already collected at Day 90.
3 If these timepoints are collected in vaccinated participants then no sample will be collected at Day 90.
Y 10mls of venous blood
Z 5mls of venous blood
* This sample is expected to be obtained from the venous blood sample drawn at the same visit. If
necessary direct finger prick may be performed.

Protocol version 6.0 dated 13 January 2021
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APPENDIX C: EXAMPLE OF COMMUNITY AND PARTICIPANT ENGAGEMENT
We will conduct a series of “Patient & Public Involvement” workshops, interviews and group discussions
(virtual or face-to-face) with two different groups of stakeholders (i) potential participants e.g. hospital
staff and (ii) members of the public via e.g. existing advisory groups such the Bangkok Health Research
Interest Group and community advisory boards.
These activities will be conducted at various stages with the following objectives:
(1) protocol development stage and prior to study start:

to inform study design, procedures, participant information materials, develop frequently asked
questions (FAQs)

to seek general attitudes about the study, use of placebo and study procedures

to develop communication materials for dissemination to the wider public and media about the
study, how best to communicate the meaning and rationale of “placebo”, “blinding”, etc

to identify what could motivate and/or discourage those to meet eligibility criteria to join the
study

to determine to what extent is chloroquine is available from local pharmacies and/or informal
vendors
(2) soon after study start:

to identify any challenges in recruitment, study procedures, understanding of the study, and
potential solutions
(3) after study completion:

to disseminate the study results

to inform strategies for dissemination of study results to the wider public so that they can use
and find value in the research
In all stages, we will also be seeking the general attitudes about the epidemic e.g. fears, perception of
risks, measures taken by individuals to protect themselves, likelihood of chloroquine or other drug self-
medication, perception of public health measures (e.g. social distancing), and economic consequences.
Understanding these social factors will help us with communication with participants, their families and
the general public.

Protocol version 6.0 dated 13 January 2021
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APPENDIX D: POTENTIAL SITES
The Faculty of Tropical Medicine (FTM), Mahidol University, Bangkok, is affiliated and partnered with the
Mahidol Oxford Tropical Medicine Research Unit (MORU), which have successfully collaborated together
for more than 40 years in the management of Tropical diseases. FTM is the only faculty specialising in
tropical medicine in Thailand and runs the Hospital for Tropical Diseases in Bangkok. Both FTM and MORU
are fitted with state-of-the-art molecular diagnostic testing facilities.
Sunpasithiprasong Hospital, Ubon Ratchathani. Situated in the East of Thailand on the Laos border, this
long-term 1200 bed hospital and MORU collaborator for 34 years has dedicated on-site study nurses
currently conducting clinical trials.
Udon Thani Hospital, Udon Thani, (800 beds) is situated in the Northeast of Thailand adjacent to Lao’s
capital, Vientiane, and has been a study site for previous trials with successful collaboration.
Chiangrai Clinical Research Unit (CCRU) is a MORU-affiliated unit in the North of Thailand. It has a full-
time team of a clinician researcher, study nurses and laboratory staff, with a laboratory based in the
Prachanukroh Hospital (760 beds).
Shoklo Malaria Research Unit (SMRU), Mae Sot, based on the Thai-Myanmar border in the West of
Thailand is the largest of the MORU-affiliated sites. Originally set up to provide basic healthcare and
malaria treatment to Myanmar migrants fleeing civil war in Kayin (Karen) state, this unit now supports and
runs several in-patient clinics, has a fully accredited laboratory able to test for COVID-19 and other
respiratory pathogens and works closely with the Thai Governmental hospital in the city.
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), a clinical research unit
embedded in the 450 bed Mahosot Hospital in Lao PDR’s capital, Vientiane, conducts clinical research on
diseases of regional public health importance, and has recently developed capability for testing for SARS-
CoV-2, as well as other respiratory viruses and causes of febrile illness. Audrey Dubot-Pérès, the head of
Virology at LOMWRU and also works at the Institut de Recherche pour le Développement (IRD) in the Unit
of Emerging Viruses (Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille.
Additionally LOMWRU has excellent links, and is currently collaborating in, 5 provincial hospitals, which
could be potential study sites: Xieng Khuang; Luang Namtha; Salavan; Savannakhet; and Phonhong. These
provinces provide health care to the provinces which have porous borders with China, Myanmar and
several geographically distinct regions of Thailand and Vietnam.
Myanmar-Oxford Clinical Research Unit (MOCRU) is a MORU-affiliated unit in Yangon, Myanmar with
strong links to Medical Action Myanmar (MAM) a non-governmental organisation which runs a network of
2,000 health workers and 10 clinics as well as strong collaborative links with the Myanmar Ministry of
Health and several public hospitals in Yangon and Mandalay.
Cambodia-Oxford Medical Research Unit (COMRU) a collaboration between MORU and the Angkor
Hospital for Children (AHC) in Siem Reap, Cambodia. This collaboration started in 2006 and led by Professor
Paul Turner, head of COMRU, and Dr Claudia Turner, CEO of AHC, provides free, quality healthcare to
approximately 450 children a day, as well as high-quality research. The laboratory is equipped to do
respiratory virus testing, including COVID-19 as well as whole genome sequencing of isolates. Given the
volume of children presenting with respiratory illnesses, COVID-19 could quite easily spread to healthcare
providers and back out to the community.
Hospital of Tropical Diseases (HTD), Ho Chi Minh City, Vietnam The Oxford University Clinical Research
Unit (OUCRU), our sister unit based in the HTD, has a long history of conducting hospital-based clinical
trials and was at the forefront of the research response to Avian Influenza in 2004 led by Professor Jeremy
Farrar. HTD is a regional referral hospital serving a population of 38 million in the South of the country.
The Christian Medical College (CMC), Vellore, India. An institution currently collaborating with MORU,
Bangkok on the biggest scrub typhus trial ever conducted and the only trial on severe scrub typhus. CMC

Protocol version 6.0 dated 13 January 2021
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comprises 3,000 hospital beds across 6 campuses providing primary to quaternary care management of
patients. CMC consistently ranks as one of the top medical institutions in India.
Other potential sites will be located in, but are not limited to, the following countries:
Africa
Benin, Botswana, Burkina Faso, Cameroon, Côte
d’Ivoire, Democratic Republic of Congo, Egypt,
Ethiopia, Gambia, Ghana, Guinea, Kenya, Mali,
Mozambique,
Niger,
Nigeria,
Senegal,
Sierra
Leone, South Africa, Sudan, Tanzania, Tunisia,
Uganda, Zambia, Zimbabwe
Asia
Bangladesh, India, Indonesia, Malaysia, Maldives,
Nepal, Pakistan, Saudi Arabia, Vietnam
Europe
Croatia,
France,
Italy,
Netherlands,
Russian
Federation, Switzerland, Ukraine, United Kingdom
North / South America
Argentina, Brazil, Canada, Chile, Colombia, Cuba,
Dominican Republic, Guatemala, Jamaica, Peru,
Puerto Rico

Protocol version 6.0 dated 13 January 2021
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APPENDIX E: AMENDMENT HISTORY
Amendment
No.
Protocol
Version No.
Date
issued
Author(s) of changes
Details of Major Changes
1
2.0
23 Mar 2020
Dr Will Schilling, Dr Nick White
Study population increased to 40,000
Hydroxychloroquine added as study
drug for sites in Europe
2
3.0
06 Apr 2020
Dr Will Schilling, Dr Nick White
Co-primary objective related to symptom
severity now secondary
Study population clarified as healthcare
workers (other “high-risk” population
removed)
To ensure that the primary outcome
measures are clear, a table has been added:
Overview of primary endpoint ascertainment
Procedures for follow up of participants if
unwell clarified (multiple sections)
Provision added for sites to enrol up to 200
participants if agreed with MORU
Safety reporting procedures updated to
acknowledge local reporting requirements
AE capture clarified to Grade 2 or above (per
CTCAE scale)
The statistical analysis was clarified that 1)
randomisation will be stratified by site, 2) a
mixed effects negative binomial regression
model will be used for the primary outcome,
and 3) a rank-based mixed model approach
will be used to analyse these scores
Funding source clarified to Wellcome Trust
via COVID-19 Therapeutics Accelerator
Africa added as study location
3
4.0
06 Apr 2020
Dr Will Schilling, Dr Nick White
Tertiary outcome and procedures added
for EQ-5D-3L assessment, to assess the
potential impact of study drug
prophylaxis on work or behaviour during
the COVID-19 pandemic
Study population further clarified as
healthcare workers with direct patient
contact
4
5.0
30 Jun 2020
Dr Will Schilling, Dr Nick White
Participant inclusion has been
broadened to include individuals
working in healthcare facilities who are
not providing direct patient care
Additional exclusion criteria and
prohibited medications added after
regulatory discussions re pregnancy and
potential cardiotoxicity. Upper age for
participation clarified as <70 years old
Clarification added in study design for
participants to stop study medication if
they are hospitalized due to COVID-19
illness
Addition of possible interim analysis to
be completed by DSMB
Pregnancy reporting process added
Visit window expanded to 27-31 days
5
6.0
13 Jan 2021
Dr Will Schilling, Dr Nick White
Defined procedures for management of
participants who may receive COVID-19
vaccination after enrolment
Clarified potential exploratory
objectives which may be included in
analysis, e.g., pharmacokinetic analysis
of study medication and evaluation of

Protocol version 6.0 dated 13 January 2021
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antibody response in vaccinated
participants
Updated benefit and risk profile for
study medications and design
Participant inclusion has been further
broadened to include individuals
otherwise defined by site investigator as
at risk for COVID-19 infection
Exclusion criteria have been updated to
clarify that participants may not be
enrolled with prior COVID-19
vaccination or current use of
chloroquine or hydroxychloroquine
Study procedures updated to allow once
daily reporting of participant
temperature and symptoms
Further defined categories meeting
serious adverse events (SAEs)
Clarified management of participants
who discontinue study medication early
for follow up through D90
Note: The following additional changes have been implemented in each revision as necessary, and are not individually itemized:
1.
Updated background regarding COVID-19.
2.
Site list for potential participating countries.
3.
Minor formatting and consistency corrections.