Clinical trial NCT04328961
Conditions: COVID-19 Corona Virus Infection SARS (Severe Acute Respiratory Syndrome) SARS-CoV-2
Keywords: novel coronavirus post-exposure prophylaxis
Sponsor: University of Washington
Start date: 2020-03-31; Completion date: 2020-10-08
Enrollment: 943 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a clinical study for the prevention of SARS-CoV-2 infection in adults exposed to the virus. This study will enroll up to 2000 asymptomatic men and women 18 to 80 years of age (inclusive) who are close contacts of persons with laboratory confirmed SARS-CoV-2 or clinically suspected COVID-19. Eligible participants will be enrolled and randomized to receive the intervention or placebo at the level of the household (all eligible participants in one household will receive the same intervention).

Detailed description:
This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study of Hydroxychloroquine (HCQ) post-exposure prophylaxis (PEP) for the prevention of SARS-CoV-2 infection in adults exposed to the virus.The overarching goal of this study is to assess the effectiveness of HCQ PEP on the incidence of SARS-CoV-2 detection by polymerase chain reaction (PCR) to inform public health control strategies.This study will enroll up to 2000 asymptomatic men and women 18 to 80 years of age (inclusive) at baseline who are close contacts of persons with PCR-confirmed SARS-CoV-2 or clinically suspected COVID-19 and a pending SARS-CoV-2 PCR test. Eligible participants will be enrolled and randomized 1:1 to HCQ or ascorbic acid at the level of the household (all eligible participants in one household will receive the same intervention). Participants will be counseled about the preliminary in vitro data on HCQ activity against SARS CoV-2 and equipoise regarding efficacy in humans.The duration of study participation will be approximately 28 days.

Arms: arm 1: Ascorbic acid 500 mg orally daily for 3 days, then 250 mg orally daily for 11 days arm 2: Hydrochloroquine 400 mg orally daily for 3 days, then 200 mg orally daily for an additional 11 days
Interventions: intervention 1: Hydroxychloroquine Sulfate intervention 2: Ascorbic Acid
Intervention descriptions: intervention 1: Eligible participants in a household randomized to this study arm will receive hydrochloroquine therapy intervention 2: Eligible participants in a household randomized to this study arm will receive ascorbic acid therapy.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol Hydroxychloroquine for COVID-19 PEP, Version 1.2 
 
1 
About this Model Protocol 
This model document is a protocol template created to align institutions engaged in evaluating 
hydroxychloroquine (HCQ) therapy for coronavirus disease (COVID-19) post-exposure 
prophylaxis (PEP). It contains the following: 
• Sections written in black text are mandatory and must be consistent across the 
participating institutions to maintain scientific integrity of the project 
• Sections written in italics are optional and may be omitted as required (e.g., 
based on institutional needs and practices) 
• A site-specific protocol addendum template (Appendix 3) is provided to capture 
information that is specific to a given study site 
These materials are provided “AS IS” WITHOUT WARRANTY OF ANY KIND, EITHER 
EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED 
WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, OR 
NON-INFRINGEMENT. Authors and sponsors of this document do not accept any 
responsibility for any loss of any kind including loss of revenue, business, anticipated savings or 
profits, loss of goodwill or data, or for any indirect consequential loss whatsoever to any person 
using these materials or acting or refraining from action as a result of the information contained 
in these materials. Any party using these materials bears sole and complete responsibility for 
ensuring that the materials, whether modified or not, are suitable for the particular use and are 
accurate, current, commercially reasonable under the circumstances, and comply with all 
applicable laws and regulations. 
Nothing in this model document should be construed to represent or warrant that persons using 
this document have complied with all applicable laws and regulations. All individuals and 
organizations using this document bear responsibility for complying with the applicable laws and 
regulations for the relevant jurisdiction. 
 
 


CONFIDENTIAL 
Protocol Hydroxychloroquine for COVID-19 PEP, Version 1.2 
 
2 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
Efficacy of Hydroxychloroquine for Post-exposure Prophylaxis (PEP) to Prevent Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Among Adults Exposed to 
Coronavirus Disease (COVID-19): A Blinded, Randomized Study 
Compound: 
Hydroxychloroquine 
Short Title: 
Hydroxychloroquine for COVID-19 PEP 
Protocol Version and Approval Date: 
Version 1.2; 09 April 2020 
Protocol Registry Number: 
NCT04328961 
Regulatory Agency Identifying Number(s): 
Not applicable 
Sponsor Name and Legal Registered Address: 
University of Washington 
Roosevelt Way NE, Seattle, WA 98115 
Funding Agency and Legal Registered Address: 
Bill & Melinda Gates Foundation 
1300 I St NW, Washington, DC 20005 
Co-Principal Investigators: 
Dr. Ruanne V. Barnabas, University of Washington 
Phone: +1 206 520 3813; Email: rbarnaba@uw.edu 
Dr. Anna Bershteyn, NYU School of Medicine 
Phone: +1 408 309 9610; Email: anna.bershteyn@nyulangone.org 
Sponsor Signatory Name and Title: 
                                                                       09 April 2020 
Signature 
 
Date 
Medical Monitor name and contact information is provided separately for each site.  


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Protocol Hydroxychloroquine for COVID-19 PEP, Version 1.2 
 
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Table of Contents 
 
1. 
Synopsis ...........................................................................................................................6 
2. 
Schedule of Activities ....................................................................................................10 
3. 
Introduction ...................................................................................................................11 
3.1. 
Background .....................................................................................................................11 
3.2. 
Study Rationale ...............................................................................................................12 
3.2.1. 
COVID-19 and Antiviral Approaches ............................................................................12 
3.2.2. 
Antiviral Effects of Chloroquine Analogues Against COVID-19 ..................................13 
3.2.3. 
Rationale for Drug Selection ..........................................................................................13 
3.2.4. 
Rationale for Dosing Schedule .......................................................................................14 
3.2.5. 
Rationale for Ascorbic Acid Control as a Comparator ...................................................15 
3.2.6. 
Rationale for Enrolling the Index Case for the Index Case Sub-
study ................................................................................................................................15 
3.2.7. 
Rationale for Including Genetic Testing .........................................................................15 
3.3. 
Benefit/Risk Assessment ................................................................................................16 
4. 
Objectives and Endpoints ............................................................................................17 
5. 
Study Design ..................................................................................................................19 
5.1. 
Overall Design ................................................................................................................19 
5.2. 
Participant and Study Completion ..................................................................................20 
6. 
Study Population ...........................................................................................................21 
6.1. 
Close Contact Participants ..............................................................................................21 
6.1.1. 
Inclusion Criteria ............................................................................................................21 
6.1.2. 
Exclusion Criteria ...........................................................................................................21 
6.2. 
Index Cases .....................................................................................................................22 
6.2.1. 
Inclusion Criteria ............................................................................................................22 
6.2.2. 
Exclusion Criteria ...........................................................................................................22 
6.3. 
Screen Failures ................................................................................................................22 
6.4. 
Recruitment .....................................................................................................................22 
6.5. 
Co-enrollment Guidelines ...............................................................................................22 
7. 
Treatments .....................................................................................................................23 
7.1. 
Treatments Administered ................................................................................................23 
7.2. 
Risks to the Participants ..................................................................................................23 
7.2.1. 
Risks Associated with PEP Administration with HCQ ..................................................23 
7.2.2. 
Risks Associated with COVID-19 Surveillance and Quarantine ...................................24 
7.3. 
Strategies to Minimize Risk ............................................................................................24 
7.3.1. 
Dose Selection ................................................................................................................24 
7.3.2. 
Management of Participants to Limit Risks of SARS-CoV-2 
Transmission ...................................................................................................................24 
7.4. 
Dose Modification and Toxicity Management ...............................................................24 
7.5. 
Method of Treatment Assignment ..................................................................................26 
7.6. 
Blinding ..........................................................................................................................26 
7.7. 
Preparation/Handling/Storage/Accountability ................................................................26 


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7.8. 
Treatment Compliance ....................................................................................................26 
7.9. 
Concomitant Therapy .....................................................................................................27 
7.9.1. 
Prohibited Medications ...................................................................................................27 
7.9.2. 
Precautionary Medications ..............................................................................................27 
7.10. 
Treatment After the End of the Study .............................................................................27 
8. 
Discontinuation/Withdrawal Criteria .........................................................................27 
8.1. 
Discontinuation of Study Treatment ...............................................................................27 
8.2. 
Withdrawal from the Study .............................................................................................28 
8.3. 
Lost to Follow-up ...........................................................................................................28 
9. 
Study Encounters ..........................................................................................................28 
9.1. 
Close Contact Participants ..............................................................................................29 
9.1.1. 
Screening/Baseline Evaluation: Day 0/1 ........................................................................29 
9.1.2. 
Day 2 Through Day 13 ...................................................................................................29 
9.1.3. 
Day 14 .............................................................................................................................30 
9.1.4. 
Exit Contact (Day 28±3) .................................................................................................30 
9.1.5. 
Participants who Develop COVID-19 During the Study ................................................31 
9.2. 
Index Cases .....................................................................................................................31 
9.2.1. 
Baseline Evaluation: Day 1 .............................................................................................31 
9.2.2. 
Exit Contact (Day 28) .....................................................................................................31 
9.3. 
Participant Reimbursement .............................................................................................32 
10. 
Study Assessments and Procedures ............................................................................32 
10.1. 
Efficacy Assessments .....................................................................................................32 
10.1.1. Mid-nasal Swab ..............................................................................................................32 
10.1.2. Participant Survey ...........................................................................................................33 
10.2. 
Adverse Events ...............................................................................................................33 
10.2.1. Serious Adverse Events ..................................................................................................33 
10.2.2. AE and SAE Attribution to Study Medication ...............................................................34 
10.2.3. AE and SAE Reporting ...................................................................................................34 
• 
SAEs will be reported within 48 hours to the Sponsor. ..................................................34 
• 
Grade 3 and 4 AEs assessed as related to the study medication by 
the clinician will be reported to the Sponsor within 48 hours. .......................................34 
• 
Grade 1 and 2 AEs assessed as related to the study medication by 
the clinician will be reported to the Sponsor within 2 weeks of 
the participant’s Exit Contact. .........................................................................................34 
10.2.4. Reporting of Use During Pregnancy ...............................................................................34 
10.2.5. Reporting of Misuse of Drug ..........................................................................................34 
10.2.6. Treatment of Overdose ...................................................................................................34 
10.2.7. AEs Among Index Case Participants ..............................................................................34 
10.3. 
Safety and AE Assessments ............................................................................................34 
10.4. 
Dried Blood Spot Optional Sub-study ............................................................................35 
10.5. 
Genetic Testing ...............................................................................................................35 
10.5.1. Samples Used for Genetic Testing ..................................................................................35 
10.5.2. Genetic Testing Procedures ............................................................................................35 
10.5.3. Genetic Information That Will Be Obtained ..................................................................36 
10.6. 
Biohazard Containment ..................................................................................................36 


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11. 
Statistical Considerations .............................................................................................36 
11.1. 
Sample Size Determination ............................................................................................36 
11.2. 
Populations for Analyses ................................................................................................37 
11.3. 
Statistical Analyses .........................................................................................................37 
11.3.1. Efficacy Analyses ...........................................................................................................38 
11.3.2. Safety Analyses ...............................................................................................................38 
11.3.3. Pharmacokinetic Analysis ...............................................................................................38 
11.3.4. Exploratory Exposure-Response Analyses .....................................................................38 
11.3.5. Exploratory Transmission Analyses ...............................................................................38 
11.3.6. Combined Study Analysis ..............................................................................................39 
12. 
References ......................................................................................................................40 
13. 
Appendices .....................................................................................................................43 
Appendix 1: Abbreviations and Terms ..........................................................................................43 
Appendix 2: Study Governance Considerations ............................................................................44 
Appendix 3: Site-specific Protocol Addendum Template .............................................................48 
Appendix 4: Hydroxychloroquine Label .......................................................................................51 
Appendix 5: Physiologically Based Pharmacokinetic Modeling of 
Hydroxychloroquine Used for Post-exposure Prophylaxis ............................................51 
Appendix 6: Pharmacokinetic Sample Collection and Analysis ...................................................51 
 


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Protocol Hydroxychloroquine for COVID-19 PEP, Version 1.2 
 
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1. 
Synopsis 
Protocol Title: 
Efficacy of Hydroxychloroquine for Post-exposure Prophylaxis (PEP) to Prevent Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Among Adults Exposed to 
Coronavirus Disease (COVID-19): A blinded, Randomized Study 
Short Title: 
Hydroxychloroquine for COVID-19 PEP 
Rationale: 
Post-exposure prophylaxis (PEP) is defined as taking antimicrobial medication after being 
exposed or potentially exposed to an infectious agent to prevent becoming infected. 
PEP is routinely used for prevention of a variety of viral, bacterial, and parasitic infections, 
including influenza and human immunodeficiency virus. Based on experience with PEP for other 
infections, therapy should be started as soon as possible after a recent possible exposure. 
Hydroxychloroquine (HCQ) is currently approved for the suppressive treatment and treatment of 
acute attacks of malaria due to several Plasmodium strains. It is also indicated for the treatment 
of discoid and systemic lupus erythematosus and rheumatoid arthritis. With the first Food and 
Drug Administration approval in 1955, safety and tolerability of HCQ are well described. 
In vitro, HCQ displays antiviral activity against coronaviruses, including severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2). Pharmacologic modeling based on observed drug 
concentrations and in vitro drug testing suggest that prophylaxis at approved doses could prevent 
SARS-CoV-2 infection and/or ameliorate viral shedding. Clinical trials of HCQ treatment for 
coronavirus disease (COVID-19) pneumonia are underway in China under separate protocol(s). 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To test the efficacy of HCQ (400 mg 
orally daily for 3 days then 200 mg 
orally daily for an additional 11 days, 
to complete 14 days) to prevent 
incident SARS-CoV-2 infection, 
compared to ascorbic acid among 
contacts of persons with SARS-CoV-2 
infection 
• Polymerase chain reaction 
(PCR)-confirmed SARS-CoV-2 
infection (self-collected samples 
collected daily Day 1 through Day 14) 


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Protocol Hydroxychloroquine for COVID-19 PEP, Version 1.2 
 
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Secondary 
• To determine the safety and tolerability 
of HCQ as SARS-CoV-2 PEP in adults 
• Adverse events 
• To test the efficacy of HCQ (400 mg 
orally daily for 3 days then 200 mg 
orally daily for an additional 11 days, 
to complete 14 days) to prevent 
incident SARS-CoV-2 infection 
2 weeks after completing therapy, 
compared to ascorbic acid among 
contacts of persons with SARS-CoV-2 
infection 
• PCR-confirmed SARS-CoV-2 infection 
(self-collected samples collected daily 
Day 1 through Day 14 and collected 
2 weeks after cessation of treatment 
[i.e., Day 28]) 
• To test the efficacy of HCQ to shorten 
the duration of SARS-CoV-2 shedding 
among those with SARS-CoV-2 
infection in the HCQ PEP group 
• SARS-CoV-2 viral shedding by PCR 
• To test the efficacy of HCQ to prevent 
incident COVID-19  
• PCR-confirmed COVID-19 diagnosis 
post start of HCQ therapy  
Exploratory 
• To conduct SARS-CoV-2 viral 
genotyping to assess the impact of 
HCQ on viral resistance to HCQ PEP 
• Viral genotyping of SARS-CoV-2 in a 
subset of treated study participants 
who develop infection 
• To assess adherence to HCQ PEP  
• Self-reported daily dosing and study 
therapy concentration (if in 
sub-study) in study participants 
• To evaluate the pharmacokinetics (PK) 
of HCQ by infection status  
• HCQ blood concentration 
• To assess if there is an association 
between PK of HCQ and the efficacy 
and safety endpoints evaluated 
• HCQ blood concentration, tolerability, 
and efficacy 
• To evaluate if SARS-CoV-2 viral load in 
the index case is associated with 
SARS-CoV-2 infection in the contact 
• SARS-CoV-2 semiquantitative PCR and 
genotyping 
• To test the efficacy of HCQ to shorten 
the magnitude of SARS-CoV-2 
shedding among those with SARS-
• Daily SARS-CoV-2 semiquantitative 
PCR 


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Protocol Hydroxychloroquine for COVID-19 PEP, Version 1.2 
 
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CoV-2 infection in the HCQ PEP 
group 
• To investigate the association of 
plausible genetic markers and 
susceptibility to SARS-CoV-2 infection 
and/or severity of COVID-19 
• Rational gene candidates associated 
with SARS-CoV-2 infection and/or 
COVID-19 severity 
COVID-19: coronavirus disease; HCQ: hydroxychloroquine; PEP: post-exposure prophylaxis; SARS-CoV-2: severe 
acute respiratory syndrome coronavirus 2. 
Overall Design: 
This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study 
of HCQ PEP for the prevention of SARS-CoV-2 infection in adults exposed to the virus. 
This study will enroll up to 2000 asymptomatic men and women 18 to 80 years of age (inclusive) 
at baseline who are close contacts of persons with polymerase chain reaction (PCR)-confirmed 
SARS-CoV-2 or clinically suspected COVID-19 and a pending SARS-CoV-2 PCR test. Eligible 
participants will be enrolled and randomized 1:1 to HCQ or ascorbic acid at the level of the 
household (all eligible participants in 1 household will receive the same intervention). 
Participants will be counseled about the preliminary in vitro data on HCQ activity against 
SARS-CoV-2 and equipoise regarding efficacy in humans. 
Participants may participate in a sub-study where they will be asked to provide a dried blood 
spot sample for therapy concentration and pharmacokinetics (PK) of HCQ as well as for 
SARS-CoV-2 antibody testing, if possible.  
The index cases will be invited to participate in the index case sub-study.  
An independent data and safety monitoring board (DSMB) will be convened for this study with 
expertise in COVID-19 or respiratory viruses, PEP, and emerging epidemics; DSMB will include 
a biostatistician. The purpose of the DSMB is to monitor the study for operational futility, social 
harms, and efficacy. 
If additional data emerge on alternative effective agents for SARS-CoV-2 prophylaxis and/or 
data about HCQ as PEP, the protocol could be modified through an amendment to evaluate an 
alternative therapy as PEP. Alternatively, this platform study could be modified through an 
adaptive design to test the efficacy of new potential agents for COVID-19 PEP. 
Number of Participants: 
Up to 2000 eligible participants will be randomly assigned (at the level of household) 1:1 to 
study treatment (HCQ or ascorbic acid). Up to 2000 index cases will be enrolled. 
Treatment Groups and Duration: 
The duration of study participation will be approximately 28 days. Households will be 
randomized 1:1 (at the level of household), with close contact participants receiving one of the 
following therapies: 


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• HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days 
• Ascorbic acid 500 mg orally daily for 3 days then 250 mg orally daily for 11 days 
After 14 days of treatment are completed, participants will be asked to participate in the study for 
an additional 14 (±3) days. 
Eligible index cases will be asked to provide a mid-nasal swab at baseline to determine the viral 
load and complete a questionnaire at baseline and on Day 28 to report their clinical course. 
 


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2. 
Schedule of Activities 
Procedure 
Screening 
Self-Quarantine 
Exit 
Contactb 
Treatment Period  
 
Day 0a 
Day 1a 
Day 2 
Day 3 
Days4
 to 7 
Day 8 
Days9
 to 13 
Day 14  
Day 28 
(±3 days) 
Informed consent 
X 
Xc 
 
 
 
 
 
 
 
Demography 
X 
Xc 
 
 
 
 
 
 
 
Past and current medical conditions, including known pregnancy 
and/or lactation status 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
Exposure to index case information 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
Xc 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Mid-nasal swab 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study therapy (HCQ or ascorbic acid) 
 
## 
## 
## 
# 
# 
# 
# 
 
Daily Survey (including dosing and swab adherence, concomitant 
medications, and symptoms review) 
 
X 
X 
X 
X 
X 
X 
X 
 
Exit Contact Survey (including concomitant medications, 
symptoms, etc.) 
 
 
 
 
 
 
 
 
X 
Adverse Event review 
 
X 
X 
X 
X 
X 
X 
X 
X 
If in sub-study: dried blood spot sample for HCQ concentration 
and anti-SARS-CoV-2 antibodies (if possible) 
 
X 
1 to 5 samples (no more than 1 per day)  
after dosing start 
X 
Index case participant mid-nasal swab 
 
X 
 
 
Index case participant questionnaire 
 
X 
 
X 
EOS: end of study; HCQ: hydroxychloroquine; HIPAA: Health Insurance Portability and Accountability Act; SARS-CoV-2: severe acute respiratory 
syndrome coronavirus 2. 
Note: ## denotes either 400 mg dose HCQ or 500 mg dose of ascorbic acid (depending on group assignment); # denotes either 200 mg dose HCQ or 250 mg 
dose of ascorbic acid (depending on group assignment). 
a Screening and Day 1 evaluations will be conducted through a web-based screening tool, HIPAA-compliant video conference (Telehealth), telephone, or text 
messaging. Screening and Day 1 evaluations may occur on the same day. 
b These evaluations will be conducted by telephone, text messaging, or through Telehealth. 
c Index case sub-study participants only.  
 


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3. 
Introduction 
This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study 
of the efficacy of hydroxychloroquine (HCQ) post-exposure prophylaxis (PEP) for the 
prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults 
exposed to the virus. 
Evaluations include safety and tolerability, SARS-CoV-2 viral shedding, and coronavirus disease 
(COVID-19) diagnosis. Two study groups (one active and one receiving ascorbic acid 
[vitamin C], to serve as a placebo-equivalent comparator) will be enrolled to assess a daily 
dosing regimen administered for 14 days, which appears to be the approximate incubation period 
of SARS-CoV-2 infection. 
Up to 2000 eligible participants 18 to 80 years of age will be randomized (at the level of 
household) 1:1 to receive one of the following therapies: 
• HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days 
• Ascorbic acid 500 orally daily for 3 days then 250 mg orally daily for 11 days 
HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be 
bitter and ascorbic acid will be sour. 
During the study participants will perform the following: 
• Collect mid-nasal swabs for viral detection for the primary trial endpoint 
• Complete Surveys that will include questions about symptoms from both the drug 
regimen and virus infection, review of concomitant medications, and other pertinent 
topics 
Note: Participants who report respiratory or other febrile illness will be referred for 
assessment to their primary care provider. 
During the first 14 study days, participants take medication, complete Surveys, and collect 
mid-nasal swab to assess symptoms and virus exposure. On Day 28, a final swab is collected and 
Survey completed. The duration of study participation will be approximately 28 days. 
Up to 2000 eligible index cases for the COVID-19 PEP study will be invited to participate and 
asked to provide a baseline mid-nasal swab for SARS-CoV-2 testing and complete a 
questionnaire at baseline and on Day 28 to report the clinical course of their illness. 
3.1. 
Background 
SARS-CoV-2 is a coronavirus novel to the human population discovered in December 2019; it is 
currently the cause of a global pandemic [1,2,3]. The World Health Organization (WHO) named 
the novel coronavirus SARS-CoV-2 and the disease caused by SARS-CoV-2 COVID-19. 
As of 08 March 2020, person-to-person transmission has occurred in China, across temperate 
Asia, Europe, and North America, and with sporadic cases in Africa and the southern 
hemisphere. Accurate reporting is limited by availability of diagnostic testing. The WHO 
declared the COVID-19 pandemic a Public Health Emergency of International Concern on 
30 January 2020 [4], and the United States declared a national emergency on 13 March 2020 [5]. 


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Most deaths and severe pneumonitis have occurred in the elderly or in persons with underlying 
pulmonary or cardiac comorbidities or diabetes. In healthy adults, including pregnant women, it 
can cause a febrile, self-limited pneumonia. Infection appears less symptomatic in children and 
younger adults [6]. Nevertheless, the burden of this pandemic to the global health and economic 
systems is expected to be substantial. No acquired immunity to this novel viral infection appears 
to exist in the human population globally, and no effective treatment or preventative agent is 
licensed at this time. 
As with many infectious epidemics, household contacts, first responders, caregivers, and medical 
personnel attending persons with COVID-19 are at high risk of infection. The incubation time 
requires 14 days of quarantine for exposed individuals not wearing personal protective 
equipment [7], and on 03 March 2020, WHO declared a global shortage of personal protective 
equipment leaving doctors, nurses, and other frontline workers dangerously ill-equipped to care 
for COVID-19 patients [8]. Extensive absences from the care network and health system will 
degrade the ability to care not only for those with COVID-19 but also for routine healthcare 
issues as well. 
PEP is defined as taking antimicrobial medication after potential exposure to an infectious agent 
to prevent becoming infected. PEP should be started as soon as possible after a recent possible 
exposure to the infectious agent [9]. At this time, there is no known effective prophylaxis for 
COVID-19 and thus there is equipoise for testing a non-active comparator (e.g., ascorbic acid) 
against a potentially active drug. 
3.2. 
Study Rationale 
3.2.1. 
COVID-19 and Antiviral Approaches 
SARS-CoV-2 is a novel betacoronavirus of zoonotic origin, similar to the coronaviruses severe 
acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome 
coronavirus (MERS). Based on current evidence, case fatality rate for SARS-CoV-2 is about 3%, 
which is significantly lower than SARS-CoV (10%) and MERS-CoV (40%) [10]. However, 
SARS-CoV-2 has potentially higher transmissibility (R0: 1.4-5.5) than both SARS-CoV 
(R0: 2-5) and MERS-CoV (R0: <1) [10]. 
Our understanding of the viral pathogenesis of SARS-CoV-2 remains limited. However, it 
appears that the virus cell entry depends on binding of the viral spike (S) proteins to cellular 
receptors and on S protein priming by host cell proteases. SARS-CoV-2, like SARS-CoV, uses 
the same receptor angiotensin converting enzyme 2 (ACE2) on pulmonary epithelial cells for 
entry and the transmembrane serine protease 2 for S protein priming [11]. The receptor binding 
domain of lineage B betacoronaviruses is a single, continuous domain that contains all of the 
structural information necessary to interact with the host receptor. Fusion is mediated at the cell 
membrane, delivering the viral nucleocapsid inside the cell for subsequent replication. ACE2 
expression is found in the lung epithelial cells, vascular endothelium, renal tubular epithelium, 
and epithelia of the small intestine. Viral shedding has been localized primarily to respiratory 
droplets and fecal samples [2]. 
Medications to treat and/or prevent SARS-CoV-2 need to inhibit aspects of the viral life cycle, 
ultimately blocking replication. Already-approved and available medications are ideal for 


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immediate evaluation for SARS-CoV-2 infection treatment and prevention. Two potential targets 
for anti-SARS-CoV-2 medications are viral polymerases and proteases [12]. Pilot clinical studies 
are already ongoing for SARS-CoV-2 using various repurposed antiviral medicines 
(https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-
coronavirus-2019-ncov). Similarities between SARS-CoV-2 with SARS-CoV and MERS 
suggest that antivirals with in vitro efficacy against SARS-CoV and MERS may be promising 
agents as SARS-CoV-2 PEP [12,13]. 
3.2.2. 
Antiviral Effects of Chloroquine Analogues Against COVID-19 
Chloroquine (CQ) was discovered in 1934 by Bayer and was used in 1945 as an antimalarial to 
become one of the most prescribed drugs globally, prior to the emergence of widespread drug 
resistance in Plasmodium falciparum [14]. CQ was found to be effective against rheumatoid 
tenosynovitis in 1951 [15]. HCQ was licensed in the United States in 1955 as an antimalarial and 
as a drug for rheumatoid arthritis, and it was widely marketed for the latter due to a favorable 
safety profile with chronic use [16]. The mechanisms of action for HCQ for treatment of 
rheumatoid arthritis and other autoimmune diseases are still not fully understood despite 
widespread use over the past 60 years [17]. 
CQ and HCQ have been proposed as potential agents for treatment and prevention against other 
infectious agents beyond malaria [18,19]. The mechanism of action differs according to the 
pathogen: against intracellular bacteria and fungi by alkalinizing vacuoles containing the 
microorganisms, restoring the activity of other antibiotics, and against viral replication through 
alkalization of acidic organelles, namely endosomes, lysosomes, and Golgi vesicles. 
CQ is effective in vitro against SARS-CoV coronavirus in Vero E6 cells with the EC50 ~8 µM 
[20] and had shown evidence of prevention activity in vivo [21]. Hence, these re-purposed drugs 
were obvious hits for testing against SARS-CoV-2. In vitro inhibition in Vero E6 cells against 
the novel coronavirus, SARS-CoV-2, has been published in recent weeks. Wang et al (2020) 
showed that the EC50 and EC90 for CQ in Vero E6 cells is 1.13 µM and 6.90 µM, respectively 
[22]. Yao et al (2020) showed that the EC50 for CQ treatment of infected cells at 48 hours was 
5.47 µM, whereas HCQ appeared slightly more potent, with EC50 of 0.72 µM at 48 hours [23]. 
These levels appear to be within the range of exposures that could be achieved with standard 
HCQ treatment, and likely prophylaxis, due to concentrations of the drug achieved in the lung 
tissue [23]. No in vitro data in the lung epithelial cells are available nor are any animal model 
data. 
Multiple observational and small Investigator-initiated COVID-19 pneumonia treatment trials 
using CQ, HCQ, and variety of other medications are ongoing in China 
(https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-
coronavirus-2019-ncov). Gao et al reported anecdotal efficacy of CQ as treatment for 
COVID-19–associated pneumonia [24]. 
3.2.3. 
Rationale for Drug Selection 
The trial will test a daily regimen of HCQ for 14 days after exposure to SARS-CoV-2 (package 
insert Appendix 4). Daily dosing has the highest likelihood to achieve sustained required drug 
levels for viral inhibition, as shown in the physiologically based PK (PBPK) modeling 


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(Appendix 5). HCQ is commonly used daily in doses up to 600 mg of HCQ sulfate (465 mg 
base) per day for rheumatoid arthritis or systemic lupus erythematosus initially, with a usual 
maintenance dose 200 mg (155 mg base) for maintenance therapy. HCQ and CQ are both 
commonly used in a weekly dosing schedule for malaria chemoprophylaxis. 
HCQ is associated with a better safety profile for daily and chronic use than CQ, including 
5 decades of experience with use in these dose ranges in adults and the elderly. It is on the WHO 
Essential Medicines List for use in rheumatic disorders and is widely prescribed as an 
anti-inflammatory for rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune 
syndromes. Based on the limited in vitro data available, HCQ appears to be slightly more potent 
than CQ against SARS-CoV-2 [23]. 
As the COVID-19 epidemic remains very fluid and new data are emerging from observational 
and clinical trials daily, this protocol is written to allow adaptation to incorporate additional 
medications beyond HCQ to be tested as PEP. 
3.2.4. 
Rationale for Dosing Schedule 
HQC is a long-acting drug with a terminal half-life of approximately 40 days. It is well absorbed, 
moderately protein bound, and will accumulate in tissues including the lung, heart, liver, and 
kidneys. It is typically given with a loading dose of approximately 2-fold the standard dose to 
accelerate achieving steady state drug concentrations [25]. Since the drug will be used in those 
with a recent high-risk exposure to SARS-CoV-2, it is desirable to achieve adequate drug levels 
quickly. 
A PBPK model was built (SIMCYP simulator v.18) using physical and chemical parameters of 
HCQ obtained from the literature [26]; PK parameters (liver intrinsic clearance, fa, ka) were 
determined from clinical data [27]. This PBPK model was used to simulate HCQ concentrations 
in plasma and lung fluid following 5 proposed dosing regimens in order to select an optimal 
regimen for the Peking University Third Hospital’s ongoing trial of HCQ in China. The 
combination of in vitro antiviral concentration-effect and predicted drug concentrations in this 
study were used to propose a loading dose of 400 mg HCQ twice a day on Day 1, followed by 
HCQ 200 mg twice a day on Day 2 through Day 5. 
A second study (BYSY-DCTC-CPPO-HCQ-PBPKAR) was undertaken to simulate HCQ 
concentration-time profiles in plasma, whole blood, and lung in Chinese healthy populations. 
Since elderly patients have reduced glomerular filtration rate (GFR), simulations were conducted 
using a healthy Caucasian healthy population with renal injury (GFR 30 to 60 mL/min) and 
compared to a population with normal renal function to support the study design of prophylactic 
use of HCQ. In this analysis, 3 dosing regimens were simulated. Modeling suggests a loading 
dose of 400 mg for 3 days followed by 200 mg daily for 2 weeks should result in a shorter time 
to PK steady-state (Appendix 5). The 2-week treatment duration represents coverage for the 
duration of viral incubation time. 
This protocol will investigate a single dosage of HCQ. Participants will receive a loading dose of 
400 mg for 3 days followed by 200 mg daily for 11 days. Subsequent investigations will be 
encouraged to undertake a more rigorous exposure-response assessment to define optimal 
dosing, including exploration of the lowest possible effective dose, and possible alternate dosing 
schedules (i.e., weekly instead of daily). 


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3.2.5. 
Rationale for Ascorbic Acid Control as a Comparator 
In healthy adults, COVID-19 infection is likely to express as a febrile disease with cough and 
fatigue, but variability in symptomatology (to include oligosymptomatic infection) is a 
possibility [28]. Study participants will have already been exposed to SARS-CoV-2, likely with 
quarantine as a result, so randomization is unlikely to affect future risk behavior with respect to 
SARS-CoV-2. Symptom reporting may vary based on participants’ perception as to whether they 
are taking HCQ or ascorbic acid [29], but the primary study endpoints of infection and viral 
shedding are not affected. 
Therefore, use of a control is acceptable and ethical both for participants’ health and safety as 
well as ensuring the most rigorous trial design to evaluate PEP for SARS-CoV-2. Participants 
will be blinded to their allocation to the extent possible, with a comparator of ascorbic acid used 
to provide a similar taste as HCQ. Specifically, tablets will not be labeled as either HCQ or 
ascorbic acid, and an ascorbic acid tablet that is comparable in size and shape to HCQ will be 
used. All participants from the same household will be assigned the same regimen, so that 
comparisons cannot be made between the medications and to minimize crossover through drug 
sharing by household members. 
The dose of ascorbic acid (500 mg for 3 days, then 250 mg daily for 11 days) is safe. All 
participants, regardless of assigned group, will be able to take additional ascorbic acid (e.g., over 
the counter vitamins, or through food) should they choose, as there is no known maximum daily 
safe dose of ascorbic acid. Clinical trial evidence has demonstrated that ascorbic acid, alone or in 
combination with other micronutrients, does not substantially reduce the risk of upper respiratory 
infections or severe consequences of infectious processes [30,31]; thus, ascorbic acid is not 
expected to have a prevention effect for SARS-CoV-19 and is considered a placebo-equivalent 
product for this study [32]. 
3.2.6. 
Rationale for Enrolling the Index Case for the Index Case Sub-study 
The quantity of the virus shed by an individual frequently predicts transmissibility, and thus may 
relate to the likelihood of SARS-CoV-2 transmission. Index cases will be enrolled, and a nasal 
swab collected for SARS-CoV-2 testing to ascertain whether the index case was shedding virus 
and the level of viral shedding. The genotype of the virus shed will be investigated in a subset of 
participants. Evaluation of the paired samples (index case and contact) will provide evidence on 
whether the level of shedding is associated with SARS-CoV-2 transmission and whether 
subsequent infections among contacts were acquired within households. 
3.2.7. 
Rationale for Including Genetic Testing 
Genetic markers may be plausibly associated with SARS-CoV-2 acquisition. Recent studies 
indicate that ACE2 could be the host receptor for SARS-CoV-2. A number of ACE2 variants 
could reduce the association between ACE2 and SARS-CoV-2. Therefore, the expression of 
human ACE2 might be important for the susceptibility, symptoms, and outcome of SARS-CoV-2 
infection [33]. The association between plausible genetic markers and SARS-CoV-2 infection 
and disease will be assessed in this study. 


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3.3. 
Benefit/Risk Assessment 
COVID-19 can be unpredictable in its severity, but a 3.4% mortality rate has been observed 
among clinical pneumonia cases. The elderly (>60 years) and those with medical comorbidities 
are at highest risk of poor outcomes [1,2,3]. Moreover, transmission in younger persons 
amplifies infection in communities, putting susceptible persons at risk. There is no proven 
preventive drug other than transmission avoidance through barrier and droplet precautions, and 
in those likely exposed, quarantine for 14 days (beyond the viral incubation period) is currently 
recommended. HCQ has an excellent safety record at the proposed doses for 60 years and potent 
viral suppression in vitro. There is equipoise as to whether the in vitro efficacy of HCQ, or any 
other drug, will translate into preventive efficacy from disease or even a reduction in viral 
shedding. Thus, the potential benefit-to-risk ratio for testing HCQ as PEP is favorable in this 
population. 


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4. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To test the efficacy of HCQ (400 mg 
orally daily for 3 days then 200 mg 
orally daily for an additional 11 days, 
to complete 14 days) to prevent 
incident SARS-CoV-2 infection, 
compared to ascorbic acid among 
contacts of persons with SARS-CoV-2 
infection 
• Polymerase chain reaction 
(PCR)-confirmed SARS-CoV-2 
infection (self-collected samples 
collected daily Day 1 through Day 14) 
Secondary 
• To determine the safety and tolerability 
of HCQ as SARS-CoV-2 PEP in adults 
• Adverse events 
• To test the efficacy of HCQ (400 mg 
orally daily for 3 days then 200 mg 
orally daily for an additional 11 days, 
to complete 14 days) to prevent 
incident SARS-CoV-2 infection 
2 weeks after completing therapy, 
compared to ascorbic acid among 
contacts of persons with SARS-CoV-2 
infection 
• PCR-confirmed SARS-CoV-2 infection 
(self-collected samples collected daily 
Day 1 through Day 14 and collected 
2 weeks after cessation of treatment 
[i.e., Day 28]) 
• To test the efficacy of HCQ to shorten 
the duration of SARS-CoV-2 shedding 
among those with SARS-CoV-2 
infection in the HCQ PEP group 
• SARS-CoV-2 viral shedding by PCR 
• To test the efficacy of HCQ to prevent 
incident COVID-19  
• PCR-confirmed COVID-19 diagnosis 
post start of HCQ therapy  
Exploratory 
• To conduct SARS-CoV-2 viral 
genotyping to assess the impact of 
HCQ on viral resistance to HCQ PEP 
• Viral genotyping of SARS-CoV-2 in a 
subset of treated study participants 
who develop infection 
• To assess adherence to HCQ PEP  
• Self-reported daily dosing and study 
therapy concentration (if in sub-
study) in study participants 


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• To evaluate the pharmacokinetics (PK) 
of HCQ by infection status  
• HCQ blood concentration 
• To assess if there is an association 
between PK of HCQ and the efficacy 
and safety endpoints evaluated  
• HCQ blood concentration, tolerability, 
and efficacy 
• To evaluate if SARS-CoV-2 viral load in 
the index case is associated with 
SARS-CoV-2 infection in the contact 
• SARS-CoV-2 semiquantitative PCR and 
genotyping 
• To test the efficacy of HCQ to shorten 
the magnitude of SARS-CoV-2 
shedding among those with SARS-
CoV-2 infection in the HCQ PEP 
group 
• Daily SARS-CoV-2 semiquantitative 
PCR 
• To investigate the association of 
plausible genetic markers and 
susceptibility to SARS-CoV-2 infection 
and/or severity of COVID-19 
• Rational gene candidates associated 
with SARS-CoV-2 infection and/or 
COVID-19 severity 
COVID-19: coronavirus disease; HCQ: hydroxychloroquine; PEP: post-exposure prophylaxis; SARS-CoV-2: severe 
acute respiratory syndrome coronavirus 2. 


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5. 
Study Design 
5.1. 
Overall Design 
The overarching goal of this study is to assess the effectiveness of HCQ PEP on the incidence of 
SARS-CoV-2 detection by polymerase chain reaction (PCR) to inform public health control 
strategies. 
This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study 
of the efficacy of HCQ PEP for the prevention of SARS-CoV-2 infection in adults exposed to the 
virus. 
This study will enroll up to 2000 asymptomatic men and women 18 to 80 years of age (inclusive) 
at baseline who are close contacts of persons with PCR-confirmed SARS-CoV-2 or clinically 
suspected COVID-19 and a pending SARS-CoV-2 PCR test. Eligible participants will be 
enrolled and randomized 1:1 to HCQ or ascorbic acid at the level of the household (all eligible 
participants in 1 household will receive the same intervention). 
Participants will be counseled about the preliminary in vitro data on HCQ activity against 
SARS-CoV-2 and equipoise regarding efficacy in humans. 
Participants may participate in a sub-study where they will be asked to provide a dried blood 
spot (DBS) sample for therapy concentration and PK of HCQ as well as for SARS-CoV-2 
antibody testing, if possible. 
Index cases will be invited to participate in a sub-study where they will be asked to provide a 
mid-nasal swab at baseline and complete questionnaires at baseline and Day 28 to assess the 
extent to which SARS-CoV-2 transmission occurs within household contacts and whether that is 
dependent on the quantity of the virus shed. 
An independent data and safety monitoring board (DSMB) will be convened for this study with 
expertise in COVID-19 or respiratory viruses, PEP, and emerging epidemics; DSMB will include 
a biostatistician. The purpose of the DSMB is to monitor the study for operational futility, social 
harms, and efficacy. 
This multi-center study will be conducted in high COVID-19 incidence areas in the United 
States. At the time of the writing of this document, the sites are expected to be western 
Washington (Snohomish, King, and Pierce counties) and New York, NY. As of 13 March 2020, 
there are 328 cases and 32 deaths in King County, most of them in Seattle. As of 13 March 2020, 
there are 158 cases in New York City. Both setting are urban areas; Seattle has a population of 
3.5 million and New York has 8.6 million. 
If additional data emerge on alternative effective agents for SARS-CoV-2 prophylaxis and/or 
data about HCQ as PEP, the protocol could be modified through an amendment to alter its 
sample size and evaluate an alternative therapy as PEP. Alternatively, this platform study could 
be modified through an adaptive design to test the efficacy of new potential agents for 
COVID-19 PEP. 


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5.2. 
Participant and Study Completion 
Up to 2000 participants will be randomly assigned to study treatment. Up to 2000 index cases 
will be enrolled. 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Activities (SoA). 
This study will be considered completed when sufficient number of participants complete the 
study to enable appropriate evaluation of the primary endpoint. 


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6. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1. 
Close Contact Participants 
6.1.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Men or women 18 to 80 years of age inclusive, at the time of signing the informed 
consent 
2. Willing and able to provide informed consent 
3. Had a close contact of a person (index) with known PCR-confirmed SARS-CoV-2 
infection or index who is currently being assessed for COVID-19 
Close contact is defined as: 
a. Household contact (i.e., residing with the index case in the 14 days prior to index 
diagnosis or prolonged exposure within a residence/vehicle/enclosed space 
without maintaining social distance) 
b. Medical staff, first responders, or other care persons who cared for the index case 
without personal protection (mask and gloves) 
4. Less than 4 days since last exposure (close contact with a person with SARS-CoV-2 
infection) to the index case 
5. Access to device and internet for Telehealth visits 
6. Not planning to take HCQ in addition to the study medication  
6.1.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Known hypersensitivity to HCQ or other 4-aminoquinoline compounds 
2. Currently hospitalized 
3. Symptomatic with subjective fever, cough, or shortness of breath 
4. Current medications exclude concomitant use of HCQ 
5. Concomitant use of other anti-malarial treatment or chemoprophylaxis, including 
chloroquine, mefloquine, artemether, or lumefantrine.  
6. History of retinopathy of any etiology 
7. Psoriasis 
8. Porphyria 
9. Known bone marrow disorders with significant neutropenia 
(polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K) 
10. Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen 
11. Known moderate or severe liver disease 
12. Known long QT syndrome 
13. Severe renal impairment 


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14. Use of any investigational or non-registered drug or vaccine within 30 days preceding the 
first dose of the study drugs or planned use during the study period 
6.2. 
Index Cases 
6.2.1. 
Inclusion Criteria 
1. Men or women ³18 years of age inclusive, at the time of signing the informed consent 
2. Willing and able to provide informed consent 
3. Currently diagnosed with known PCR-confirmed SARS-CoV-2 infection or is currently 
being assessed for COVID-19 
4. A close contact is enrolled in the study 
6.2.2. 
Exclusion Criteria  
1. Currently hospitalized 
6.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened if there is a change in their eligibility. 
6.4. 
Recruitment 
Each site will establish local recruitment and screening methods that operationalize 
protocol-specified requirements for eligibility determination in a manner that is tailored to and 
most efficient for the local study setting and target study population. Each site will use a variety 
of recruitment approaches, including direct recruitment at clinics, referrals from other providers 
and SARS-CoV-2 testing sites and laboratories, and use of online and social networking websites 
and apps. Recruitment materials will educate participants about COVID-19, transmission within 
households, epidemiology in the community, and the in vitro data on HCQ limiting 
SARS-CoV-2 cell entry. 
Initially, the study will enroll from 2 clinical sites: western Washington and New York, which 
have established track records of high quality clinical research integrated into clinical care 
settings; annual retention rates in clinical trials conducted in these sites exceed 80% to 90%. The 
sites have large COVID-19 epidemics with regulation limiting contact to reduce infectious 
spread. 
6.5. 
Co-enrollment Guidelines 
Close contact participants may be co-enrolled in other research studies, provided that these are 
observational studies only. Any other exception requires approval of the Co-Principal 


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Investigators. The study team should be consulted for co-enrollment in studies that do not meet 
this guidance or if there are questions about eligibility for co-enrollment. For any co-enrolled 
study, combined blood draws should not exceed current Red Cross phlebotomy guidance. 
Index case participants may enroll at any point in another study. 
7. 
Treatments 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
7.1. 
Treatments Administered 
Study Treatment 
Name 
Hydroxychloroquine sulfate 
Ascorbic acid 
Dosage Formulation 
200 mg (155 mg base) tablets 
250 mg tablets 
Route of 
Administration 
Oral 
Dosing Instructions 
Take 2 tablets for the first 3 days and 1 tablet for the subsequent 
11 days, for a total of 14 days of treatment. Take at approximately 
the same time of the day with a meal or a glass of milk. If a dose 
is missed, it should be taken as soon as possible. If it is less than 
4 hours before the next dose, the dose should be skipped. 
Packaging and 
Labeling 
The medication for home delivery will be dispensed in an 
unmarked container with the study label. The container will be 
labeled with a unique identifier. The container will be packed in a 
standard box used for mail delivery of medications as needed. 
Manufacturer 
To be determined 
To be determined 
7.2. 
Risks to the Participants 
7.2.1. 
Risks Associated with PEP Administration with HCQ 
The risks associated with PEP reflect the adverse events (AEs) related to HCQ administration. 
With tens of millions of doses administrated for malaria and autoimmune diseases, the side effect 
profile of HCQ is well described and the drug is generally well tolerated. With short-term 
administration (as opposed to chronic/year-long use in rheumatologic disease management), the 
major AEs are gastrointestinal (nausea, vomiting, dyspepsia, abdominal cramps, and diarrhea) 
and transient skin rashes. The gastrointestinal symptoms may vary by specific generic 
manufacturer of HCQ [35] and are best managed by taking the drug with food or a glass of milk 
(Appendix 6). A transient rash, most commonly morbilliform or psoriasiform, can develop in 
10% of participants, often with a sustained loading dose, and is often managed by lowering the 
dose. To avoid this potential side effect, this protocol is using a short loading dose, not a 
sustained one. Uncommonly, idiosyncratic leukopenia/thrombocytopenia can occur and the drug 


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should not be given to those with underlying bone marrow disorders. Lastly, hypoglycemia can 
occur and those taking insulin or glucose-lowering drugs are at risk; blood glucose should be 
monitored. 
Minor blurry vision may occur with acute HCQ use, is reversible, dose-related, and is generally 
not severe. It may also be associated with mild headaches. It is caused by deposition of HCQ in 
the cornea or ocular muscle weakness, and is not a predictor of long-term toxicity. Participants 
experiencing minor blurry vision may adjust to it with counselling and reassurance that it is 
reversible and not progressive.   
More severe rashes, including drug-related eosinophilia with systemic symptoms and Stevens-
Johnson syndrome occur rarely.  
Long-term manifestations of HCQ, including retinitis, renal and hepatic disease, and 
cardiomyopathy (Appendix 4), are not likely in this 2-week PEP exposure. 
7.2.2. 
Risks Associated with COVID-19 Surveillance and Quarantine 
Enrollment in this protocol will not impact the public health department’s advice for 
self-quarantine. That said, quarantine is known to be stressful, especially for healthcare workers. 
Enrollment may improve morale during public health quarantine. Since there is clinical 
equipoise regarding HCQ efficacy on viral shedding, participants will be counseled to follow 
recommendations for self-quarantine. 
7.3. 
Strategies to Minimize Risk 
7.3.1. 
Dose Selection 
The recommended dose of HCQ for chronic use in lupus erythematosus is 200 mg to 400 mg 
daily—a dose that is safely taken for years including among elderly patients (≥65 years). The 
selection of 400 mg for 3 days then 200 mg daily for 11 days is likely to be safe with transient 
AEs (gastrointestinal symptoms and rashes) that are self-remitting. 
7.3.2. 
Management of Participants to Limit Risks of SARS-CoV-2 Transmission 
To limit the transmission of SARS-CoV-2, participants will receive visits via secure Telehealth 
in order to limit the movement of persons with potential SARS-CoV-2 and leave clinical space 
free for patients seeking care. Also, to limit exposure in waiting rooms and pharmacies, clinical 
specimens will be self-collected and medications delivered to homes. 
7.4. 
Dose Modification and Toxicity Management 
If a study therapy dose is missed, it should be taken as soon as possible. If it is less than 4 hours 
before the next dose, the dose should be skipped. 
Modification for toxicities is discussed below. Only toxicities related to study medications 
provided through the study will be considered in the toxicity management section. 
Grade 1 or 2 
Participants who develop Grade 1 or 2 toxicity (per division of acquired immunodeficiency 
syndrome [DAIDS] adverse event [AE] Grading Table; see: https://rsc.tech-


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res.com/docs/default-source/safety/division-of-aids-(daids)-table-for-grading-the-severity-of-
adult-and-pediatric-adverse-events-corrected-v-2-1.pdf) that is considered to be related to study 
medication may continue study treatment at the discretion of the site Investigator with close 
follow-up. If a participant chooses to discontinue study treatment, the site should notify the study 
protocol team within 7 days. These participants will remain on study, off study treatment, and 
have all evaluations performed. 
Grade 3 
• Participants who develop a Grade 3 symptomatic toxicity thought by the site Investigator 
to be related to study drug should have HCQ PEP withheld, and the site should consult 
with the Core Protocol team. The participant should be reevaluated every 2 days until the 
AE returns to Grade ≤2, at which time study drug may be reintroduced at the discretion 
of the site Investigator in consultation with the protocol team. 
• Participants experiencing Grade 3 toxicity requiring permanent discontinuation of study 
medication should be followed up weekly until resolution of the toxicity. Participants will 
have premature study treatment discontinuation evaluations performed. These 
participants will remain on study, off study treatment, and have all evaluations performed 
per the SoA. 
Grade 4 
• Participants who develop a Grade 4 symptomatic toxicity will have study medication 
permanently discontinued, and the site should notify study team within 48 hours. 
• Participants experiencing Grade 4 toxicity requiring permanent discontinuation of HCQ 
PEP should be followed up weekly until resolution of the AE or return to baseline. These 
participants will remain on study, off study treatment, and have all evaluations performed 
per the SoA. 
Specific Management of Toxicities Related to Study-Provided Drugs 
Gastrointestinal disturbance 
Gastrointestinal disturbance (nausea, vomiting, diarrhea) is a common known possible side effect 
of HCQ. Dividing doses by 6 hours and taking with food or milk may improve tolerability. 
Visual disturbances 
Suspected visual changes should be evaluated for possible etiologies. Participants experiencing 
Grade 1 or Grade 2 vision changes may continue use, at the discretion of the site Investigator. 
Participants who develop a Grade 3 symptomatic toxicity thought by the site Investigator to be 
related to study drug should have HCQ PEP withheld, and the site should consult with the Core 
Protocol team. The participant should be reevaluated every 2 days until the AE returns to 
Grade ≤2, at which time study drug may be reintroduced at the discretion of the site Investigator 
in consultation with the protocol team. 


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Allergic reactions 
HCQ should be discontinued permanently if a serious allergic reaction is suspected. These 
participants will remain on study, off study treatment, and have all evaluations performed per the 
standard operating procedure(s). 
7.5. 
Method of Treatment Assignment 
Participants will be randomized in a 1:1 ratio to HCQ or ascorbic acid at the level of the 
household (all eligible participants in 1 household will receive the same intervention). The 
randomization plan will be written by the Study Statistician. 
The randomization code and resulting allocation list will be generated and maintained by the 
Study Statistician. The list will be blocked and stratified by site and contact type (household 
versus healthcare worker). 
7.6. 
Blinding 
This is a blinded study. Eligible participants will receive one of the following therapies: 
• HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days 
• Ascorbic acid 500 mg orally daily for 3 days then 250 mg orally daily for 11 days 
HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be 
bitter and ascorbic acid will be sour. 
The participants will be blinded to their randomization group once assigned. Within 24 to 
48 hours of enrollment, the unblinded Study Pharmacist will use the randomization code 
revealed at the point of randomization to provide the participant with their group assignment and 
dispense the allocated study medication in a bottle marked with the study label. The medication 
and medication information, mid-nasal swabs sufficient to complete the study procedures, DBS 
sampling kit, if within the sub-study, and study instructions will be delivered to the participant. 
7.7. 
Preparation/Handling/Storage/Accountability 
Drugs should be stored at room temperature, as per package insert. Records must be maintained 
that document receipt, release for dosing, disposal, or return to the sponsor. 
7.8. 
Treatment Compliance 
The participant will be contacted to ensure that they received the box of study supplies; were 
able to collect the first mid-nasal swab and store it appropriately; and took their first day of 
medication. Participants will be asked to complete a Survey that includes information regarding 
treatment administration. In a sub-study, HCQ concentration via a DBS will also be evaluated. 
Consultation via Telehealth, text messaging, or telephone will be available to provide support to 
the participant to complete study procedures. 


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7.9. 
Concomitant Therapy 
Participants will be asked about concomitant medications at the screening/baseline evaluation 
visit. During the study, participants will be asked to complete Surveys (Daily Survey and Exit 
Contact Survey) that include information regarding any medication or vaccine (including 
over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the 
participant receives during the study. At each contact, the Investigator or designee should 
question the participant about any medication taken. 
7.9.1. 
Prohibited Medications 
Prohibited medications include digoxin, cyclosporin, cimetidine, amiodarone, tamoxifen, and 
antimalarial medications (including chloroquine, artemether, lumefantrine, mefloquine). 
7.9.2. 
Precautionary Medications 
Use of medications classified as precautionary is not study prohibitory but will be discussed with 
the study clinician and the participant. These medications include androgens, antidiabetic agents, 
phenothiazines, beta-blockers, cardiac glycosides, citalopram, dapsone, escitalopram, 
haloperidol, herbs, maitake, monoamine oxidase inhibitors, pegvisomant, prothionamide, 
quinolones, salicylates, and selective serotonin reuptake inhibitors. 
7.10. 
Treatment After the End of the Study 
No additional treatment will be provided at the end of the study. 
8. 
Discontinuation/Withdrawal Criteria 
8.1. 
Discontinuation of Study Treatment 
Study treatment will be discontinued for the following reasons: 
• Requirement for prohibited concomitant medications or other contraindication to HCQ 
• Occurrence of an AE requiring discontinuation of study medication 
• Request by participant to terminate study treatment 
• Clinical reasons believed to be life-threatening by the physician, even if not addressed in 
Section 7.2 
Participants who stop study treatment should continue study participation off study medication 
with continued evaluations as per the SoA. The reason for study medication discontinuation 
should be recorded. 
Participants who are identified as SARS-CoV-2 positive by PCR at baseline should continue 
study therapy and study participation. 
Participants with a clinical diagnosis of COVID-19 should continue on study therapy unless they 
are started on COVID-19 treatment outside of the study.  


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8.2. 
Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time for the following reasons: 
o At the request of the primary care provider if he/she thinks the study is no longer in 
the best interest of the participant 
o Participant is judged by the Investigator to be at significant risk of failing to comply 
with the provisions of the protocol as to cause harm to self or seriously interfere with 
the validity of the study results 
o At the discretion of the Institutional Review Board/Ethics Committee or government 
agencies as part of their duties, Investigator, or industry supporter 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
• See SoA for data to be collected at the time of study discontinuation and follow-up and 
for any further evaluations that need to be completed. 
8.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she is unable to be contacted by the study 
site. 
The following actions must be taken if a participant fails to comply with required study 
procedures: 
• The site must attempt to contact the participant as soon as possible and counsel the 
participant on the importance of maintaining the assigned procedure schedule and 
ascertain whether or not the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9. 
Study Encounters 
The current COVID-19 pandemic has placed a significant burden on the healthcare system. For 
this study, specimen and data collection will be conducted to minimize impact of non-ill 
participants within the healthcare system. If the participant is assessed as eligible, contact 
between study participants and study personnel will occur via a Health Insurance Portability and 
Accountability Act (HIPAA)-compliant video conference (Telehealth), although in-person visits 
either at the participant’s home or at a research center are permitted. 


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Participants will be instructed to seek clinical care should they manifest any signs or symptoms 
of COVID-19. 
9.1. 
Close Contact Participants 
9.1.1. 
Screening/Baseline Evaluation: Day 0/1 
Participants will be assessed for study eligibility through a screening conducted through a 
web-based screening tool, HIPAA-compliant video conference (Telehealth), telephone, or text 
messaging. 
Day 0 evaluations are as follows: 
• Informed consent 
• Collection of demographic information 
• Collection of past and current medical conditions, including known pregnancy and/or 
lactation status 
• Collection of concomitant medication information 
• Collection of information regarding exposure to the index case 
• Check of inclusion and exclusion criteria 
Eligible participants will be randomized with all members of a household assigned to the same 
arm. Participants will receive a swab kit either via courier or mail, which includes a Quick Start 
Instruction Card, swabs, plastic tubes for swab collection, and a return box with affixed 
Category B UN3373 label, as required by International Air Transport Association (IATA) 
guidelines [36]. 
The participant will do the following on Day 1: 
• Collect mid-nasal swab for PCR  
• Take study therapy (HCQ or ascorbic acid, as assigned) 
• Complete Daily Survey (online, Telehealth, telephone, or text messaging). This Survey 
will include confirmation of adherence to study therapy dosing and daily swab collection, 
concomitant medication review, and symptoms review. 
• If in DBS Sub-study, collect DBS samples for analysis of anti-SARS-CoV-2 antibodies (if 
possible). 
Instructions for skin puncture and DBS sample preparation are provided in Appendix 6. A study 
team member will be available via Telehealth, telephone, or text messaging to provide support 
for completion of this study procedure. 
Screening/Day 0 and Day 1 procedures may occur on the same day. 
The index case SARS-CoV-2 positive test results will be confirmed through self-report of the 
contact participant. If in the index case sub-study, shedding of SARS-CoV-2 will be assessed by 
PCR of a mid-nasal swab (Section 9.2). 
9.1.2. 
Day 2 Through Day 13 
The participant will do the following every day from Day 1 through Day 13, inclusive: 


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• Collect mid-nasal swab for PCR 
• Take study therapy (HCQ or ascorbic acid, as assigned) 
• Complete Daily Survey (online, telephone, or text messaging). This Survey will include 
confirmation of adherence to study therapy dosing and daily swab collection, 
concomitant medication review, and symptoms review. 
• If in DBS Sub-study, collect DBS samples for analysis of HCQ concentration at any time 
during this period (1 to 5 times) after study drug dosing has commenced. No more than 
1 sample per day should be collected. 
A study team member will be available via Telehealth, text messaging, or telephone to provide 
support for completion of study procedures. The courier will collect the swabs at minimum 
within 1 or 2 days of Day 7 and Day 13 and potentially as frequently as daily. 
9.1.3. 
Day 14 
The participant will do the following on Day 14: 
• Collect mid-nasal swab for PCR 
• Take study therapy (HCQ or ascorbic acid, as assigned) 
• Complete Daily Survey (online, telephone, or text messaging). This Survey will include 
confirmation of adherence to study therapy dosing and daily swab collection, 
concomitant medication review, and symptoms review. 
• If in DBS Sub-study, collect DBS samples for analysis of HCQ concentration, if not 
already collected. 
A study team member will be available via Telehealth, text messaging, or telephone to provide 
support for completion of study procedures. 
Participants are instructed to place their self-collected nasal swabs directly into the plastic tube 
that is pre-labeled with a unique barcode. Next, participants are instructed to place the plastic 
tube containing the self-collected nasal swab into a specimen bag, pre-packaged with an 
absorbent sheet, and then place the specimen bag into the provided return shipping box. Category 
B UN3373 stickers are affixed to the outside of the return box. Previous testing has demonstrated 
that respiratory viral ribonucleic acid (RNA) is stable in room temperature for up to 1 week. The 
courier will collect the swabs at minimum within 1 or 2 days of Day 14. 
9.1.4. 
Exit Contact (Day 28±3) 
The Exit Contact will be conducted through Telehealth, online, by telephone, or by text 
messaging. 
Exit Contact evaluations are as follows: 
• Collect mid-nasal swab for PCR 
• Review AEs 
• Complete Exit Contact Survey (online, Telehealth, telephone, or text messaging). This 
Survey will include concomitant medication review and symptoms review. 
• The Exit Contact Survey will include evaluation for SARS-CoV-2 infection and/or 
COVID-19 and associated testing and medical care. 


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• If in DBS Sub-study, collect DBS samples for analysis of anti-SARS-CoV-2 antibodies (if 
possible). 
Clinical outcomes will be confirmed through the electronic health record, if possible. 
The final swab will be collected by the courier or returned via the postal service. 
9.1.5. 
Participants who Develop COVID-19 During the Study 
Participants who develop symptoms concerning for COVID-19 will be instructed to contact their 
provider for clinical care and testing. Study results will be available to participants after study 
completion as they are not tested in real-time for clinical diagnosis. 
Participants who develop SARS-CoV-2 infection may be sent a home pulse oximeter to measure 
the oxygen saturation to provide direct information for clinical assessment.  
Participants with a clinical diagnosis of COVID-19 should continue on study therapy unless they 
are started on COVID-19 treatment outside this study. Other study procedures will continue, 
with early exit possible to document COVID-19 diagnosis.  
9.2. 
Index Cases 
9.2.1. 
Baseline Evaluation: Day 1 
Participants will be assessed for study eligibility through a screening conducted through a 
web-based screening tool, Telehealth, telephone, or text messaging. 
Day 1 evaluations are as follows: 
• Informed consent 
• Collection of demographic information 
• Check of inclusion and exclusion criteria 
Eligible participants will receive a swab kit either via courier or mail, which includes a Quick 
Start Instruction Card, a swab, a plastic tube for swab collection, and a return container with 
affixed Category B UN3373 label, as required by International Air Transport Association (IATA) 
guidelines [36]. 
The participant will do the following on Day 1: 
• Collect mid-nasal swab for PCR  
• Complete Survey (online, Telehealth, telephone, or text messaging). This Survey will 
include assessment of risk for COVID-19 acquisition, engagement with testing and 
treatment, and symptom review. 
9.2.2. 
Exit Contact (Day 28) 
The Exit Contact will be conducted through Telehealth, online, by telephone, or by text 
messaging. 


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Exit Contact evaluations are as follows: 
• Complete Exit Contact Survey (online, Telehealth, telephone, or text messaging). This 
Survey will include assessment of risk for COVID-19 acquisition, engagement with 
testing and treatment, and symptom review. 
Clinical outcomes will be confirmed through the electronic health record, if possible. 
9.3. 
Participant Reimbursement 
Participants will be reimbursed on Day 14 and Day 28. Index cases enrolled in the index case 
sub-study will receive a reimbursement on Day 28. No reimbursement will be provided to index 
cases for referral of their close contacts. No reimbursement will be provided for unscheduled 
Telehealth visits requested by the participants for support with study procedures. 
10. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. 
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
treatment. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All baseline evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management and obtained 
before signing of the informed consent form may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• Blood samples will only be collected as a part of a sub-study. The maximum amount of blood 
collected from each participant over the duration of the study, including any extra 
assessments that may be required, will not exceed 10 mL. 
10.1. 
Efficacy Assessments 
10.1.1. 
Mid-nasal Swab 
Participants will collect daily mid-nasal swabs for the initial 14 days and again at the Exit 
Contact for viral detection. 
Index case participants in the index case sub-study will submit their baseline nasal swab for 
SARS-CoV-2 testing by PCR. 


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Participants will receive a swab kit either via courier or mail, which includes a Quick Start 
Instruction Card, swabs, plastic tubes for swab collection, and a return box with affixed 
Category B UN3373 label, as required by IATA guidelines [36]. 
Participants will collect and store their nasal swabs in a box for return. 
The used swabs will be collected by the courier or returned via the postal service. 
Swabs will be subjected to RNA amplification and tested for SARS-CoV-2, as applicable. 
10.1.2. 
Participant Survey 
Participants will be asked to complete Surveys (Daily Survey and Exit Contact Survey) that will 
include questions about symptoms from both the drug regimen and virus infection, review of 
concomitant medications, and other pertinent topics include information on any symptoms that 
may be associated with COVID-19. 
10.2. 
Adverse Events 
AE information will only be collected on close contact participants. For information regarding 
AEs in index case participants see Section 10.2.7.  
Participants will be asked to complete Surveys (Daily Survey and Exit Contact Survey) that 
include information on any symptoms that they are experiencing. In addition, AE review by a 
staff member (via telephone, Telehealth, or text messaging) will be performed. 
All AEs must be recorded on electronic case report forms (eCRFs) if any of the following criteria 
have been met: 
• All AEs meeting SAE definition 
• All AEs judged by participant or clinician to be associated with study medication 
10.2.1. 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above 
All AEs that are recorded will have their severity graded. To grade AEs, sites should refer to the 
DAIDS AE Grading Table, corrected Version 2.1, July 2017, which can be found on the DAIDS 
Regulatory Support Center website at https://rsc.tech-res.com/docs/default-
source/safety/division-of-aids-(daids)-table-for-grading-the-severity-of-adult-and-pediatric-
adverse-events-corrected-v-2-1.pdf. 


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10.2.2. 
AE and SAE Attribution to Study Medication 
All AEs and SAEs should have attribution recorded as related or not related to study medication, 
in the judgment of the site Investigator. 
10.2.3. 
AE and SAE Reporting 
• SAEs will be reported within 48 hours to the Sponsor.  
• Grade 3 and 4 AEs assessed as related to the study medication by the clinician will be 
reported to the Sponsor within 48 hours.  
• Grade 1 and 2 AEs assessed as related to the study medication by the clinician will be 
reported to the Sponsor within 2 weeks of the participant’s Exit Contact.  
10.2.4. 
Reporting of Use During Pregnancy 
• Medication exposure during pregnancy will be reported to the Sponsor within 2 weeks of 
the participant’s Exit Contact. 
10.2.5. 
Reporting of Misuse of Drug  
• Misuse and abuse of medication outside the protocol will be reported to the Sponsor 
within 2 weeks of the participant’s Exit Contact. 
10.2.6. 
Treatment of Overdose 
Overdose of HCQ should be managed according to the labeling information (see Appendix 4). 
Ascorbic acid exhibits low toxicity; risks from overdose are expected to be minimal. 
Overdose of study medication should be reported to the Sponsor within 48 hours. 
10.2.7. 
AEs Among Index Case Participants  
AEs among the index case participants in the index case sub-study will not be collected or 
reported as index cases are not receiving study medication or interventions. 
10.3. 
Safety and AE Assessments 
Safety will be assessed via participant Surveys, as shown in the SoA. 
Participants will be asked to complete Surveys (Daily Survey and Exit Contact Survey) that 
include questions about their health, healthcare seeking, symptoms, illness within their 
household, contact, and mobility. Qualifying events will be recorded on the eCRF and reported 
as AEs, as described in Section 10.2. 
Social harms will be assessed throughout the study, reported using the Social Harms form, and 
reported to the Sponsor within 48 hours. 


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10.4. 
Dried Blood Spot Optional Sub-study 
Up to 1800 participants will be enrolled in the DBS Sub-study. DBS will be requested, but not 
required, of all participants. For those study sites not wishing to participate in the DBS 
Sub-study, this will not be considered a protocol deviation. 
Participants will receive instructions for DBS self-collection in writing, with telephone, 
Telehealth, and text messaging options as support. Once cards have been dried, they will be 
collected by the study courier and returned to the laboratory. 
The aim of the DBS Sub-study is to evaluate HCQ drug concentrations as an adherence measure 
and the PK of HCQ. If serological assays for SARS-CoV-2 are available, DBS may be tested for 
SARS-CoV-2 antibodies. 
Pharmacokinetics 
The exposure-response relationship of HCQ in the PEP of participants exposed to SARS-CoV-2 
has not been established. Population PK analyses can be used to further inform dose selection in 
other populations and support concentration-response investigations with efficacy and safety 
outcomes. 
To accomplish this, sparse PK sampling techniques can be employed. This would involve 
collection of whole blood at 1 to 5 times after dosing has commenced. The time of collection 
post-dose can be random; however, no more than 1 sample per day should be collected. 
Given the long half-life of HCQ, samples for several weeks after the last dose are also 
informative to the population PK model development. 
The basic requirements for PK sampling are as follows: 
1. Accurate record of time of the dose prior to the blood sampling (dd:mm:yy; hh:mm) 
2. Accurate recording of time of blood sampling (dd:mm:yy; hh:mm) for each blood 
sampling. 
3. Whole blood can be obtained by venipuncture or capillary blood by skin puncture using a 
lancet. 
4. Approximately 100 µL of blood is then applied to filter paper as outlined in Appendix 6. 
Anti-SARS-CoV-2 Antibody Testing 
DBS sample for serology will be collected at Day 1 and Day 28 and tested for SARS-CoV-2 
antibodies provided that an appropriate test is available. 
10.5. 
Genetic Testing 
10.5.1. 
Samples Used for Genetic Testing 
Dried blood spot and mid-nasal swab samples collected in the study could be used potentially for 
genetic studies. During the consent process, participants can opt out of genetic testing.  
10.5.2. 
Genetic Testing Procedures  
Studies conducted on stored samples will investigate genes that may play a role in susceptibility 
to SARS-CoV-2 infection or other respiratory viruses and/or severity of COVID-19. The samples 


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will not be used to study genes related to diseases other than SARS-CoV-2 or other respiratory 
viruses. 
10.5.3. 
Genetic Information That Will Be Obtained 
Samples will be tested for the presence of genetic markers, which the investigators believe, on 
the basis of available medical literature, to possibly be rationally associated with susceptibility 
to SARS-CoV-2 infection and/or the severity of COVID-19. Genome-wide screening (such as 
“SNP screening”) is not planned.  
10.6. 
Biohazard Containment 
As the transmission of SARS-CoV-2 and other respiratory droplet pathogens can occur through 
contact with respiratory droplets and contaminated surfaces, precautions will be employed by all 
personnel in the handling of all specimens for this study, as currently recommended by the 
Centers for Disease Control and Prevention and the National Institutes of Health. 
All dangerous goods and materials, including diagnostic specimens and infectious substances, 
must be transported using packaging mandated by Code of Federal Regulations 42 Part 72. 
Please refer to instructions detailed in the IATA Dangerous Goods Regulations. 
11. 
Statistical Considerations 
11.1. 
Sample Size Determination 
Not all individuals exposed to COVID-19 will become infected, and early estimates place family 
members at a 3% to 15% risk of infection after likely exposure [32, 33]. The sample size 
required to show a 50% protective efficacy of PEP is entirely dependent on that attack rate. 
Sample size calculations used an estimated 6% attack rate. 
A sample size will be chosen for each group (HCQ and ascorbic acid) to achieve 80% power 
with 0.05 two-sided Type 1 error for the endpoint of any laboratory-detected incident 
SARS-CoV-2, exclusion of participants with positive SARS-CoV-2 at baseline, an attack rate of 
6%, 50% efficacy of HCQ in reducing SARS-CoV-2 incidence, and randomizing the first 
household member enrolled and subsequent household members to the same intervention. With 
these assumptions, a cohort of 1498 households (749 in the control and 749 in the intervention 
for each cohort) will provide at least 80% power to detect a decrease in SARS-CoV-2 incidence 
from 6% to 3%. As household size increases, power will increase. 
Household members will be randomized as a unit but analyzed as individuals. 
The table below estimates power assuming that households are randomized until either 
1498 households are randomized or 1498 individuals are randomized. Each row shows the 
distribution of the numbers of individuals within a household who are randomized. Individual risk 
is assumed to be independent. Power may be lower depending on correlation in risk within and 
between households (Table 1). 


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Table 1 
Power to Detect a Decrease from 6% to 3% Under Hypothetical 
Distributions of Number of Household Contacts 
 
Distribution of Number 
Randomized Within 
Household 
Number of 
Households is the 
Target 
Number of 
Participants is the 
Target 
Number 
in 
Household 
1 
2 
3 
4 
5 
NHH 
Np 
Power 
NHH 
Np 
Power 
A 
0.8 
0.1 
0.06 0.03 0.01 1498 
2022 89% 
1108 
1498 78% 
B 
0.75 0.15 0.06 0.03 0.01 1498 
2097 90% 
1070 
1498 78% 
C 
0.25 0.35 0.16 0.13 0.11 1498 
3745 99% 
600 
1498 76% 
NHH: number of households; Np: number of participants. 
These power calculations indicate that final power will depend heavily on the population 
enrolled. To mitigate the potential loss in power from lack of information about cluster size, the 
final target sample size will be estimated midway through the study based on the observed 
distribution of the number of household contacts. The procedure for redetermining sample size 
will be described in an Interim Monitoring Plan approved by the DSMB. 
11.2. 
Populations for Analyses 
For analysis purposes, the following populations are defined: 
Population 
Description 
Intention to Treat 
All enrolled participants who are contacts 
Modified Intention to 
Treat (MITT) 
Contacts who are SARS-CoV-2 negative by PCR at the baseline 
visit and whose corresponding index case is SARS-CoV-2 
positive by report or PCR 
PK evaluable 
Participants from the DBS Sub-study with at least 1 interpretable 
PK sample  
DBS: dried blood spot; PK: pharmacokinetic; PCR: polymerase chain reaction; SARS-CoV-2: severe acute 
respiratory syndrome coronavirus 2.  
Note: All PCR negative household contacts will be included in the MITT analyses. 
11.3. 
Statistical Analyses 
The Statistical Analysis Plan will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints (these are listed in Section 4). 


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11.3.1. 
Efficacy Analyses 
Demographic characteristics (age, sex, race) of each study group will be tabulated. 
The mean age (plus range and standard deviation) by sex of the enrolled participants, as a whole 
and per group, will be calculated. 
The primary analysis will be performed using the modified Intention-to-Treat population. If the 
participant is not SARS-CoV-2 positive by laboratory test, their infection time will be censored 
at the last negative swab test date at or before the Day 14 swab. A logistic model stratified by site 
and accounting for within-household correlation will be used to assess the efficacy of the HCQ 
group compared to control. To aid understanding of the results from the logistic model, 
cumulative incidence Kaplan-Meier curves of time to infection will be presented by site and 
treatment arm.  
Subgroup Analyses 
All subgroup analyses will be pre-specified in the Statistical Analysis Plan. Any further 
subgroups will be considered ad hoc. 
Missing Data 
Due to the design of the study and retention activities, we expect to be able to categorize all 
infections as either incident or prevalent at baseline. However, in the unlikely event of a missing 
test result, the missing data will be imputed. 
Additional analyses will be described in the Statistical Analysis Plan finalized before database 
lock. 
11.3.2. 
Safety Analyses 
All safety analyses will be performed on the Intention-to-Treat population. AEs and social harms 
will be compared by study group. 
11.3.3. 
Pharmacokinetic Analysis 
Sparse PK from DBS will be analyzed using standard population PK analysis methodologies 
using standard software such as NONMEM® V7.4 or Phoenix NLME V8.2. 
11.3.4. 
Exploratory Exposure-Response Analyses 
PK-evaluable participants will have post-hoc individual concentration profiles and exposure 
estimates determined for exploratory exposure-response analyses against primary and 
secondary efficacy and safety endpoints. Exploratory PK/pharmacodynamic analyses will be 
performed as the data allow. 
11.3.5. 
Exploratory Transmission Analyses 
The index case sub-study will assess the risk of SARS-CoV-2 transmission and the association 
with the semi-quantitative PCR results. Also, the risk of transmission between close contacts will 
be assessed by determining whether the viruses are a genetic match among household members 
through SARS-CoV-2 sequencing.  


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11.3.6. 
Combined Study Analysis 
This protocol is being published as a model protocol for other institutions to consider as they 
undertake studying PEP of SARS-CoV-2 infection. It is hoped that individual patient data from 
similar studies can be pooled into a combined study analysis. De-identified data from the present 
study will be made available for these purposes in accordance with the funder’s open access 
policy (https://www.gatesfoundation.org/how-we-work/general-information/open-access-policy). 


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12. 
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2. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in 
China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. 
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3. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 
2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 
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6. Cai J, Xu J, Lin D, et al. A Case Series of children with 2019 novel coronavirus infection: 
clinical and epidemiological features. Clin Infect Dis. 2020 Feb 28. pii: ciaa198. doi: 
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7. Linton NM, Kobayashi T, Yang Y, et al. Incubation Period and Other Epidemiological 
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8. WHO News Release. Shortage of personal protective equipment endangering health 
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10.1186/s12879-019-3980-9. 
14.Slater AF. Chloroquine: mechanism of drug action and resistance in Plasmodium 
falciparum. Pharmacol Ther. 1993 Feb-Mar;57(2-3):203-235. 
15.Mackenzie AH. An appraisal of chloroquine. Arthritis Rheum. 1970 May-Jun;13(3):280-
291. 


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16.Shippey EA, Wagler VD, Collamer AN. Hydroxychloroquine: an old drug with new 
relevance. Cleve Clin J Med. 2018 Jun;85(6):459-467. doi: 10.3949/ccjm.85a.17034 
17. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: 
implications for rheumatology. Nat Rev Rheumatol. 2020 Mar;16(3):155-166. doi: 
10.1038/s41584-020-0372-x.  
18.Rolain JM, Colson P, Raoult D. Recycling of chloroquine and its hydroxyl analogue to face 
bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents. 
2007 Oct;30(4):297-308.  
19.Savarino A, Shytaj IL. Chloroquine and beyond: exploring anti-rheumatic drugs to reduce 
immune hyperactivation in HIV/AIDS. Retrovirology. 2015 Jun 18;12:51. doi: 
10.1186/s12977-015-0178-0. 
20.Keyaerts E, Vijgen L, Maes P, et al. In vitro inhibition of severe acute respiratory syndrome 
coronavirus by chloroquine. Biochem Biophys Res Commun. 2004 Oct;323(1):264-268. 
21.Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS 
coronavirus infection and spread. Virol J. 2005 Aug;2:69-78. 
22.Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently 
emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271. doi: 
10.1038/s41422-020-0282-0. Epub 2020 Feb 04. 
23.Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing 
design of hydroxychloroquine for the treatment of severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2). Clin Inf Dis. 2020 Mar 09. pii: ciaa237. doi: 
10.1093/cid/ciaa237. [Epub ahead of print]. 
24.Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy 
in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 
2020 Feb 19. doi: 10.5582/bst.2020.01047. [Epub ahead of print]. 
25.Furst DE, Lindsley H, Baethge B, et al. Dose-loading with hydroxychloroquine improves 
the rate of response in early, active rheumatoid arthritis: a randomized, double-blind 
six-week trial with eighteen-week extension. Arthritis Rheum. 1999 Feb;42(2):357-365. 
26.Collins K, Jackson K, Gustafson D. Hydroxychloroquine: a physiologically based 
pharmacokinetic model in the context of cancer-related autophagy modulation. J Pharmacol 
Exp Ther. 2018;365(3):447-459. 
27.Tett SE, Cutler DJ, Day RO, Brown KF. Bioavailability of hydroxychloroquine tablets in 
healthy volunteers. Br J Clin Pharmacol. 1989;27(6): 771-779. 
28.Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with 
COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci. 
2020 Mar 04. doi: 10.1007/s11427-020-1661-4. [Epub ahead of print]. 
29.Barrett B, Brown R, Rakel D, et al. Placebo effects and the common cold: a randomized 
controlled trial. Ann Fam Med. 2011 Jul-Aug;9(4):312-322. doi: 10.1370/afm.1250. 
30.Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs 
hydrocortisone alone on time alive and free of vasopressor support among patients with 
septic shock: the VITAMINS randomized clinical trial. JAMA. 2020 Jan 17. 
doi: 10.1001/jama.2019.22176. [Epub ahead of print]. 
31.Graat J, Schouten E, Kok F. Effect of daily vitamin E and multivitamin-mineral 
supplementation on acute respiratory tract infections in elderly persons: a randomized 
controlled trial. JAMA. 2002 Aug 14;288(6):715-721. 


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32. WHO. Report of the WHO-China joint mission on coronavirus disease 2019 (COVID-19). 
2020 Feb 16-24.  
33.Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. Comparative genetic analysis of the 
novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell 
Discovery. 2020; 6(1):11.  
34.Bi Q, Yongsheng W, Shujiang M, et al. Epidemiology and transmission of COVID-19 in 
Shenzhen, China: analysis of 391 cases and 1286 of their close contacts. medRxiv. 2020. 
https://doi.org/10.1101/2020.03.03.20028423. 
35.Srinivasa A, Tosounidou S, Gordon C. Increased Incidence of Gastrointestinal Side Effects 
in Patients Taking Hydroxychloroquine: A Brand-related Issue? J Rheumatol. 
2017 Mar;44(3):398. doi: 10.3899/jrheum.161063. 
36.UN3373 Medical Packaging. Biological Substance Category B. Available at: 
https://www.un3373.com/category-biological-substances/category-b. Updated 2018 Jun. 
Accessed 2020 Mar 01. 
 


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13. 
Appendices 
Appendix 1: Abbreviations and Terms 
Term 
Definition 
ACE2 
Angiotensin converting enzyme 2 
AE 
Adverse event 
COVID-19 
Coronavirus disease 
CQ 
Chloroquine 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DAIDS 
Division of acquired immunodeficiency syndrome  
DBS 
Dried blood spot 
DSMB 
Data and safety monitoring board 
EC50 
Half-maximal effective concentration 
eCRFs 
Electronic case report forms 
Eligible 
Qualified for enrollment into the study based upon adherence to 
inclusion/exclusion criteria 
GFR 
Glomerular filtration rate 
HCQ 
Hydroxychloroquine 
HIPAA 
Health Insurance Portability and Accountability Act 
IATA 
International Air Transport Association 
ICF 
Informed consent form 
Index case 
Term used throughout the protocol to denote the person with confirmed or 
suspected SARS-CoV-2 infection to whom the study participant was exposed 
IRB 
Institutional Review Board 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
Participant(s) 
Term used throughout the protocol to denote the enrolled individual(s) 
PCR 
Polymerase chain reaction 
PEP 
Post-exposure prophylaxis 
PK 
Pharmacokinetic 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SARS-CoV 
Severe acute respiratory syndrome coronavirus 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of Activities 
WHO 
World Health Organization 
WIRB 
Western Institutional Review Board 
 


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Appendix 2: Study Governance Considerations 
Investigators and Institutional Affiliations 
The following Investigators and Institutional Affiliations were established at the time of protocol 
authoring. Designees may be provided, as appropriate. Other institutions may utilize this model 
protocol with permission from a Co-Principal Investigator.  
Name 
Role  
Institution 
Contact Information 
Dr. Ruanne V. 
Barnabas 
Principal 
Investigator 
University of 
Washington 
Phone: +1 206 520 3813 
Email: rbarnaba@uw.edu 
Dr. Anna Bershteyn 
Co-Principal 
Investigator 
New York 
University 
Phone: +1 408 309 9610 
Email: 
Anna.Bershteyn@nyulangone.org 
University of Washington Coordinating Center 
Dr. Elizabeth 
Brown 
Study 
Statistician 
Fred 
Hutchinson 
Cancer 
Research Center 
Phone: +1 206 667-1731 
Email: erbrown@fredhutch.org  
Dr. Jared Baeten 
Co-
Investigator 
University of 
Washington 
Phone: +1 206 520-3808 
Email: jbaeten@uw.edu 
Dr. Connie Celum 
Co-
Investigator 
University of 
Washington 
Phone: +1 206 520-3800 
Email: ccelum@uw.edu 
Dr. Mark Wener 
Co-
Investigator 
University of 
Washington 
Phone: +1 206 598-6152 
Email: wener@uw.edu 
Dr. Anna Wald 
Co-
Investigator 
University of 
Washington 
Phone: +1 206 520-4340 
Email: annawald@uw.edu 
Dr. Helen Y. Chu 
Co-
Investigator 
University of 
Washington 
Phone: +1 206 685-5386 
Email: helenchu@uw.edu 
Collaborators from Bill & Melinda Gates Foundation 
Name 
Contact Information 
Steve Kern, PhD 
Phone: +1-206-770-2496 
E-mail: steven.kern@gatesfoundation.org 
Scott Miller, MD 
Phone: +1-206-409-7757 
E-mail: scott.miller@gatesfoundation.org 
Peter Dull, MD 
Phone: +1-206-770-2465 
E-mail: peter.dull@gatesfoundation.org 


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Committees Structure 
Study Team Monitoring 
The study team will monitor the conduct of the study through monthly summary reports of arms 
of accrual and baseline characteristics and quarterly reports of data pooled over treatment arms 
of data completeness, specimen collection, and adverse events (AEs). The study will review 
individual participant-level safety data frequently to assess the relation of all reported AEs to 
study treatment. On a weekly basis, the study team will review by-arm summaries of premature 
study discontinuations and premature study treatment discontinuations (and reasons) and AEs. 
Independent Monitor 
Study conduct will be monitored by an independent monitor. Monitors will visit participating 
clinical research sites to review the individual participant records, including consent forms, 
electronic case report forms, supporting data, laboratory specimen records, and endpoints 
through laboratory and medical records (physicians’ progress notes, nurses’ notes, individuals’ 
hospital charts), to ensure protection of study participants, compliance with the protocol, and 
accuracy and completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to review product 
storage and management. 
Data and Safety Monitoring Board 
An independent data and safety monitoring board (DSMB) will be convened for this study with 
expertise in coronavirus disease (COVID-19) or respiratory viruses, post-exposure prophylaxis 
(PEP), and emerging epidemics and a biostatistician. The purpose of the DSMB is to monitor the 
study for operational futility, social harms, and efficacy. The DSMB will evaluate the progress of 
the project, including periodic assessments of accrual, retention, safety, performance and 
variation of the project sites, and other factors that can affect project implementation. 
The target number of households (index cases) and their contacts enrolled into the study will be 
re-assessed according to the distribution of cluster (household/institution) sizes seen in the study. 
The DSMB will review and approve modifications to the overall enrollment target. The DSMB 
will review the study after half to two-thirds of follow-up time with pre-specified stopping rules 
for efficacy and futility in terms of the efficacy of hydroxychloroquine (HCQ) PEP in reducing 
the incidence of SARS-CoV-2 infection overall and the ability of the study to meet its objectives. 
The DSMB will review severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
endpoints. The DSMB will consider factors external to the project when relevant information 
becomes available, such as policy changes or scientific developments that may have an impact 
on project implementation, safety, and integration of COVID-19 PEP into community-based 
disease prevention. 
The DSMB will conduct interim reviews when adequate data have been accrued and convene by 
teleconference. Open reports containing accrual and retention rates, participant characteristics, 
and serious adverse events will be sent to the protocol team and DSMB members the week prior 
to the DSMB meeting. Only the DSMB members and the unblinded biostatistician will receive 
password-protected closed reports of SARS-CoV-2 endpoints by randomization arm. 


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Regulatory and Ethical Considerations 
The study will be conducted according to Good Clinical Practice, the Belmont Report, and the 
Declaration of Helsinki. The study protocol, site-specific informed consent forms (ICFs), 
participant education and recruitment materials, and other requested documents—including any 
subsequent modifications—will be reviewed and approved by Western Institutional Review 
Board (WIRB), as the single IRB of record, responsible for oversight of research conducted at 
the study sites. Subsequent to initial review and approval, the WIRB will review the study at 
least annually.  
Informed Consent Process 
The principles of informed consent in the current edition of the Declaration of Helsinki will be 
implemented in each clinical study before any protocol-specified procedures or interventions are 
carried out. The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. A copy of the consent form will be given to 
the participant, and this fact will be documented in the participant’s record. 
A participant who is rescreened is not required to sign another ICF; eligibility for the study must 
be re-checked prior to enrollment. 
Study Records  
Each study site will establish a standard operating procedure for confidentiality protection. Each 
site will ensure that study records including administrative documentation and regulatory 
documentation as well as documentation related to each participant enrolled in the study, 
including ICFs, locator forms, case report forms, notations of all contacts with the participant, 
and all other source documents are stored in a secure manner. 
Confidentiality  
Participants’ study information will not be released without their written permission, except as 
necessary for oversight by: 
- 
The protocol Co-Principal Investigators or designees 
- 
Study funders 
- 
WIRB 
- 
New York University IRB 
- 
University of Washington IRB 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by coded number only to maintain participant confidentiality. The exceptions are 
SARS-CoV-2 testing results which are subject to local and state reporting which is names-based. 
Local public health may contact participants diagnosed with SARS-CoV-2 for the purpose of 
surveillance and contact notification. Participants will be informed prior to SARS-CoV-2 testing 
that results are reportable and may lead to contact by local public health if results are positive for 
infection. 
All records will be kept locked. All computer entry and networking programs will be done with 
coded numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the IRB, Office for Human Research 


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Protections, other local, United States, and international regulatory entities as part of their duties, 
or the industry supporters or designees.  
 
 


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Appendix 3: Site-specific Protocol Addendum Template 
PURPOSE: The use of this site-specific protocol addendum is recommended with a multi-site 
study. 
The purpose of this site-specific protocol addendum is to obtain information describing the local 
site-specific elements for conduct of the Core Protocol. The descriptions should focus on who, 
what, and where of the local study activities. 
INSTRUCTIONS: 
1. Add the Name of the study site to the Title of the Protocol in the header of the document. 
2. Please complete each section below. If general description language already appears in 
the Core Protocol, which adequately describes the local activity at the study site, a 
notation can be inserted in the given section that reads, “As described in the Core 
Protocol.” 
3. Please identify the completed addendum document using a version number and date. 
4. Please note: the site-specific protocol addendum will require review and approval by the 
local Institutional Review Board (IRB)/Ethics Committee (EC) of record for the study 
site. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Site Information:  
Name of Institution/Company:  
Address:  
 
Study Site Information for the Site Investigator: 
Name of Site Investigator:  
Title:  
Institution/Affiliation:  
Address:  
Telephone Number:  
Cell/Other Number:  
Fax Number:  
 
Study Site Number: 
 
Assurance Information: 
United States Department of Health and Human Services Office for Human Research Protections 
Assurance Federal Wide Assurance number:  


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Expiration Date: 
 
IRB/Ethics Committee Information: 
Name of Human Subjects Protection oversight office for study site:  
Name and number of reviewing IRB/EC:  
Telephone Number at Office:  
Fax Number at Office:  
If Available, Point of Contact at IRB/EC:  
Name:  
Telephone Number:  
 
Local Site-Specific Information: 
1. Identify key study personnel (include name, title, address, point of contact information). 
2. Description of key study personnel roles and responsibilities. 
3. Describe the local recruiting procedures and strategies. Provide copy of any site-specific 
recruitment material. Identification of personnel responsible for completing tasks. 
4. Describe the local consenting process. Provide a copy of the site-specific consent form(s). 
If an Ombudsman is named for the study site, provide name, title, and point of contact 
information. 
5. Identify local study collaborations at the site such as pharmacy, laboratories, and other 
institutional departments. 
6. Describe the local specimen/sampling procedures in place. Include acquisition, 
disposition, storage, and unique coding. If samples will be kept for future use, describe 
procedures and the security measures for short-term and long-term management. Provide 
name of repository. 
7. Describe the plan for on-site management of study records and data, and participant study 
records. Explain procedures and security measures in place for short-term and long-term 
management. Declare who will have access to data. 
8. Describe the local measures in place to promote privacy and confidentiality. 
9. Describe the local procedures in place for provision of care for the participant regarding 
research-related injuries. 
10. Identify who the participant can contact locally should the participant have any questions 
regarding the research. Identify who the participant can contact should the participant 
have questions regarding their rights as a study participant. Include the points of contact 
information (name, title, and telephone number). 
11. Describe the procedures in place to address Health Insurance Portability and 
Accountability Act requirements. If a separate authorization form will be used at the 


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study site, provide a copy or ensure appropriate language has been included in the 
consent document(s). 
12. Describe any unique site-specific study procedures or supplemental activities. 
13. Declare any unique study population/cultural influences, socioeconomic conditions, etc. 
14. Declare any other site-specific reporting obligations and procedures. Name any additional 
oversight boards or committees. 
15. Define abbreviations that may apply to the specific study site. 
 


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Appendix 4: Hydroxychloroquine Label 
Generic hydroxychloroquine label (current as of June 2018) is available online at 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b82bbda6-64f2-4426-b4ec-
254eeea895ae and provided below. 
Appendix 5: Physiologically Based Pharmacokinetic Modeling of 
Hydroxychloroquine Used for Post-exposure Prophylaxis 
Appendix 6: Pharmacokinetic Sample Collection and Analysis 
Collection of Blood 
Skin puncture 
1. Before skin puncture, the participant should warm his/her hands. The finger is massaged 
anterogradely to enrich the blood flow toward the puncture site. 
2. Clean the skin of the palmar side of the tip of the distal phalanx of the third or fourth 
finger of the non-writing hand with a suitable disinfectant, for example, 70% isopropyl 
alcohol. Puncture the skin by a single-use safety lancet. The finger should be held in such 
a position that the gravity facilitates the collection of blood from the fingertip. 
3. When collection of capillary blood by skin puncture is complete, place a bandage on the 
fingertip. 
Preparation of Blood Spots 
Preparation from blood collected by skin puncture 
1. Wipe off the first drop of blood with a gauze pad because it may contain excess tissue 
fluids. Massage the finger again to increase blood flow at the puncture site. Transfer the 
following drop to one of the circles of a filter card without touching the surface directly 
with the fingertip. Allow the blood to be soaked into the texture of the filter by capillary 
forces only. 
2. Let the next large drop of capillary blood form on the fingertip and collect it in the next 
circle. Continue this procedure until all necessary circles are filled or blood flow stops. 
3. Do not squeeze or “milk” the finger excessively if the blood flow is not sufficient to fill 
all the required circles of the filter card. If blood flow stops, place a bandage on the 
fingertip. Perform a second skin puncture on another finger if more blood is needed for 
the examination. 
4. For blood obtained by venipuncture, use syringe to apply approximately 100 µL of blood 
on the filter paper. 
Drying of Blood Spots 
To dry the blood spots, put the filter cards on a clean paper towel and let them dry, preferably 
overnight (but for at least 4 hours), at room temperature in the absence of any external source of 
heat. When the drying process is complete, the blood spots have a uniformly dark brownish color 
and no red areas are visible anymore. 


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Storage and Transportation of Dried Blood Spots (DBS) 
NOTE: Processing of the blood spots can be interrupted after drying. The filter cards can now be 
stored. 
1. For storage, put the filter paper card in a single, gas-impermeable zipper bag, containing 
1 to 2 desiccant sachets to protect the specimens from moisture. Optionally, add a 
humidity indicator card. 
2. Store at ambient temperature until the DBS card is collected. 
On the filter paper, the participant should record the following: 
1. Date and time of sample 
2. Date and time of last dose 
Samples that appear to be collected according to the schedule of activities, which have the 
required amount of blood for a 5- to 6-mm punch and have the minimal required information 
(1 through 2 above), will be processed for hydroxychloroquine (and metabolite) concentration. 

SAP_001.pdf: 
 
 
 
 
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STATISTICAL ANALYSIS PLAN  
 
 
Efficacy of Hydroxychloroquine for Post-exposure Prophylaxis (PEP) to Prevent Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Among Adults Exposed to 
Coronavirus Disease (COVID-19): A Blinded, Randomized Study 
 
Protocol Registry Number: 
NCT04328961 
 
 Effective Date: August 22, 2020 
Version: 1.0 
 
 
 
 
 
 
 
 
 
 


 
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1. LIST OF ABBREVIATIONS AND ACRONYMS  
A list of abbreviations used in the SAP. 
Term/Abbreviation 
Definition 
HCQ 
hydroxychloroquine 
PEP 
post-exposure prophylaxis 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
2. INTRODUCTION 
This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study of 
the efficacy of hydroxychloroquine (HCQ) post-exposure prophylaxis (PEP) for the prevention of 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults exposed to 
the virus. 
2.1. GENERAL DESIGN CONSIDERATIONS 
Evaluations include safety and tolerability, SARS-CoV-2 detection, SARS-CoV-2 viral shedding, 
and coronavirus disease (COVID-19) diagnosis. Two study groups (one active and one receiving 
ascorbic acid [vitamin C], to serve as a placebo-equivalent comparator) will be enrolled to assess 
a daily dosing regimen administered for 14 days, which appears to be the upper limit of the 
incubation period of SARS-CoV-2 infection. 
Up to 2000 eligible participants 18 to 80 years of age will be randomized (at the level of household) 
1:1 to receive one of the following therapies: 
• 
HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days 
• 
Ascorbic acid 500 orally daily for 3 days then 250 mg orally daily for 11 days 
HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be bitter 
and ascorbic acid will be sour. 
During the study participants will perform the following: 
• 
Collect mid-nasal swabs for viral detection for the primary trial endpoint 
• 
Complete Surveys that will include questions about symptoms from both the drug regimen 
and virus infection, review of concomitant medications, and other pertinent topics 
Note: Participants who report respiratory or other febrile illness will be referred for assessment to 
their primary care provider. 


 
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During the first 14 study days, participants take medication, complete Surveys, and collect 
mid-nasal swab to assess symptoms and virus exposure. On Day 28, a final swab is collected 
and Survey completed. The duration of study participation will be approximately 28 days. 
2.2. STUDY OBJECTIVES AND ENDPOINTS 
This document focuses on the statistical procedures for the primary and secondary objectives 
and endpoints listed in the following table. 
Objectives 
Endpoints 
Primary 
To test the efficacy of HCQ (400 mg orally daily for 
3 days then 200 mg orally daily for an additional 11 
days, to complete 14 days) to prevent incident 
SARS-CoV-2 infection, compared to ascorbic acid 
among contacts of persons with SARS-CoV-2 
infection 
Polymerase 
chain 
reaction 
(PCR)-confirmed 
SARS-CoV-2 infection through Day 14 
Secondary 
To determine the safety and tolerability of HCQ as 
SARS-CoV-2 PEP in adults 
Adverse events 
To test the efficacy of HCQ (400 mg orally daily for 
3 days then 200 mg orally daily for an additional 11 
days, to complete 14 days) to prevent incident 
SARS-CoV-2 infection two weeks after completing 
therapy, compared to ascorbic acid among 
contacts of persons with SARS-CoV-2 infection 
Polymerase 
chain 
reaction 
(PCR)-confirmed 
SARS-CoV-2 infection through Day 28 
To test the efficacy of HCQ to shorten the duration 
of SARS-CoV-2 shedding among those with SARS-
CoV-2 infection in the HCQ PEP group 
SARS-CoV-2 viral shedding by PCR 
To test the efficacy of HCQ to prevent incident 
COVID-19  
PCR-confirmed COVID-19 diagnosis post start of 
HCQ therapy  
2.3. RANDOMIZATION 
Enrolled contacts were randomized 1:1 to receive either HCQ or ascorbic acid. Randomization 
tables were stratified by study site and contact type (household/social exposure or healthcare 
worker exposure) and blocked into groups of randomly varying size. The tables were programmed 
in R and allocation was performed via REDCap by site pharmacists or their designees. All other 
study staff were blinded to randomization group apart from the coordinating center's unblinded 
statistical team. 
2.4. SAMPLE SIZE AND POWER 
Since finalization of the protocol and at the recommendation of the DSMB, the study size has 
been recalculated as an event-driven design. The original study was designed under 80% power 
with a target number of households, assuming 1 infection per household, recognizing there would 


 
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likely be more than 1 per household and therefore power would be at least 80%. In the spirit of 
accounting for the within household correlation without any existing estimates of what it may be, 
we instead assume 90% power with 50% reduction and 4 interim analyses (for 5 total) and a one-
sided alpha = 0.025 and a hard futility boundary. Under these design assumptions, the design 
requires 93 events. Assuming a household attack rate of 10% in the placebo arm (higher than in 
protocol and based on emerging evidence (UM study and HH study from China that looked at 
masks and disinfecting), we would need to enroll 1240 participants who are negative at baseline. 
3. GENERAL DATA ANALYSIS CONSIDERATIONS 
3.1. ANALYSIS SET(S) 
This section describes the cohorts for the primary, secondary and exploratory analyses described 
in this document.  
Intention to Treat (ITT) Cohort: The ITT Cohort includes all contacts enrolled into the study. 
Modified Intention to Treat (mITT) Cohort: Contacts who are SARS-CoV-2 negative by PCR at 
the baseline visit. 
mITT Sensitivity Cohort: Contacts in the mITT cohort who are SARS-CoV-2 negative by PCR 
at the day 1-3 visits. Participants who are SARS-CoV-2 negative on two of the three days, without 
a SARS-CoV-2 positive result, will be included in this cohort. 
Seronegative Cohort: If a validated, sensitive and specific assay is available for antibody testing, 
this cohort will include all mITT cohort participants who are antibody negative at baseline. 
Infected Cohort: Contacts who are SARS-CoV-2 positive by PCR at the baseline visit. 
PK Cohort: Participants from the DBS Sub-study with at least 1 interpretable PK sample 
Household Cohort: All enrolled index cases and their household contacts. Enrolled indexes are 
enrolled in either the PEP Study or the companion Early Treatment Study. 
Index Cohort: All enrolled index cases. 
4. GENERAL ANALYSIS METHODS 
Descriptive statistics that will be used to summarize continuous variables are as follows: mean 
and standard deviation, median and interquartile range, quartiles, range, and number of missing 
data values. For categorical variables, descriptive statistics that will be used include the following: 
frequencies, relative frequencies, and the number of missing data values. Descriptive analyses 
summarizing baseline and follow-up data will be stratified by site. Line, scatter and box plots will 
be used, as appropriate, for longitudinal data representations. A two-sided alpha level of 0.05 will 
be used for all statistical tests unless otherwise specified. 


 
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5. TRIAL PARTICIPANT DISPOSITION 
5.1. DISPOSITION OF PARTICIPANTS 
Relevant to the analyses described in this SAP, a CONSORT flow diagram will be constructed to 
describe how all of the participants who entered the study are accounted for including the following 
measures, as applicable:  
The numbers of participants screened, screened out (with reasons for exclusion), enrolled, 
randomized, allocated to each study arm, received assigned intervention (with reasons for not 
receiving assigned intervention), reasons for discontinuation from follow-up (e.g., lost to follow-
up, adverse event, noncompliance, etc.), and the number of participants with available data for 
each assay.  
5.2. TREATMENT EXPOSURE 
Self-reported pill taking will be reported by prescribed dosing day stratified by arm and overall. 
The summary measures will be number of doses reported taken and number of doses reported 
taken divided by number prescribed. The number and proportion of adherent participants will be 
reported by day and overall time. 
6. BASELINE DATA  
Baseline variables will include age, sex at birth, race, number of people in household, number of 
people in household enrolled in the study as contacts, number of infected contacts, underlying 
medical conditions (see below), contact type (HCW or household), household type, presence and 
number of children, number of bedrooms, number of bathrooms, number of days since contact 
with index case, duration of exposure to index case, current smoker, quarantine status hours of 
contact with the index case and the impact of pandemic on the participant’s ability to work. 
The following list of variables will be included and condensed into the following categories: 
metabolic disease (hypertension, diabetes mellitus type 1 and 2, and cardiovascular disease 
including atherosclerosis), non-communicable diseases (NCDs) (chronic cardiac disease 
excluding hypertension, chronic kidney disease, liver disease, chronic neurological disorder, 
chronic hematologic disease, rheumatologic disorder, dementia, malnutrition) infectious diseases 
not HIV, immunosuppressive disease (HIV, autoimmune disease and malignancy), lung disease 
(COPD, asthma) and other: 
Chronic cardiac disease, including congenital heart disease and heart failure (not hypertension) 
Hypertension 
Diabetes mellitus: Type 1 
Diabetes mellitus: Type 2 
Chronic pulmonary disease, including COPD 
Asthma (physician diagnosed) 
Chronic kidney disease 


 
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Moderate or severe liver disease 
Mild liver disease 
Chronic neurological disorder 
Malignant neoplasm 
Chronic hematologic disease 
HIV 
Rheumatologic disorder 
Dementia 
Malnutrition 
Autoimmune disease 
7. EFFICACY/EFFECTIVENESS ANALYSES  
7.1. EFFICACY ANALYSES 
Final (as opposed to interim) efficacy analyses will be stratified (baseline hazard) for enrollment 
site and contact type and adjusted by baseline variables as noted in each section below.  
7.1.1. Primary efficacy analyses 
Objective: To estimate the efficacy of HCQ (400 mg orally daily for 3 days then 200 mg orally 
daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection, 
compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection. 
Outcome: Polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection through Day 14 
Cohorts: mITT Cohort, Sensitivity Cohort 
Definition of Endpoint: An endpoint defining PCR test is defined as one with either concordant 
results or Ct  40 and will be referred to as positive test for this analysis. PCR tests not meeting 
these criteria will be referred to as negative. A participant will be defined as having reached the 
endpoint on the midpoint between the days of collection of their first positive result and last 
negative result (prior to the positive result) in the first 13 days of follow-up. Participants who have 
confirmed COVID-19 through external evaluation in the first 13 days (e.g. hospital or clinical 
assessment) will be defined as having reached the endpoint at the midpoint between the last prior 
negative test and the day of the external diagnosis. Participants who do not reach the endpoint 
will have their follow-up censored at their last negative RNA test. Any uncertainty in final endpoint 
determination will be resolved by the blinded Endpoint Adjudication Committee. 
Analysis Details:  
The primary analysis will be performed on the mITT Cohort. A sensitivity analysis will be 
performed on the Sensitivity Cohort to account for potential missed infections at day 1. 


 
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We will use a Cox Proportional Hazards model with robust standard errors to estimate the hazard 
ratio and corresponding 95% confidence interval and Wald test statistic. Efficacy will be calculated 
as 1 minus the hazard ratio (treatment/control) from the treatment coefficient. Robust confidence 
intervals and p-values will be displayed. Per FDA guidance on prevention studies, the following 
variables will be included to increase precision: quarantine status, sex, and age of contact.  
The number of evaluable participants per arm will be displayed (defined as participants with at 
least one PCR test result or external diagnosis) by arm with person-days of follow-up and number 
of endpoints per arm and prevalence of endpoints (number reached endpoint/number evaluable) 
with a 95% confidence interval calculated using exact binomial confidence intervals.  
7.1.2. Secondary efficacy analyses 
Infection by day 28 
Objective: To test the efficacy of HCQ (400 mg orally daily for 3 days then 200 mg orally daily 
for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection two 
weeks after completing therapy, compared to ascorbic acid among contacts of persons with 
SARS-CoV-2 infection. 
Outcome: Polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection through Day 28 
Cohorts: mITT Cohort, Sensitivity Cohorts 
Definition of Endpoint: An endpoint defining PCR test is defined as one with either 
concordant results or Ct  40 and will be referred to as positive test for this analysis. PCR tests 
not meeting these criteria will be referred to as negative. A participant will be defined as having 
reached the endpoint on the midpoint between the days of collection of their first positive and 
last negative PCR tests (prior to a positive test). Participants who have confirmed COVID-19 
through external evaluation (e.g. hospital or clinical assessment) will be defined as having 
reached the endpoint at the midpoint between the last negative test (prior to external diagnosis) 
and the day of the external diagnosis. Participants who do not reach the endpoint will have 
their follow-up censored at their last negative test. Any uncertainty in final endpoint 
determination will be resolved by the blinded Endpoint Adjudication Committee. 
Analysis Details: The same analytical approaches will be applied as for the primary efficacy 
analysis, including a primary analysis on the mITT Cohort and a sensitivity analysis on the 
Sensitivity Cohort. 
 
Duration of shedding 
Objective: To test the efficacy of HCQ to shorten the duration of SARS-CoV-2 shedding 
among those with SARS-CoV-2 infection. 
Outcome: SARS-CoV-2 viral shedding by PCR 
Cohort(s): mITT Cohort 
Definition of Endpoint: For this analysis, a positive PCR test is defined as one where both 
targets are identified or one target is identified with Ct  40. 


 
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PCR tests not meeting these criteria will be referred to as negative. The endpoint will be defined 
as the number of days from the first positive test until virus is no longer detected (a negative 
test has been observed with no positive tests following).  Censoring will be indicated if the 
participant is still shedding on day 14. Participants who have a COVID-19 related 
hospitalization or death will be assumed to shed through day 14 and would have their days of 
shedding censored as if they had been observed through day 14. 
Analysis Details: We will use a Cox Proportional Hazards model with robust standard errors 
to estimate the hazard ratio and corresponding 95% confidence interval and Wald test statistic. 
Robust confidence intervals and p-values will be displayed. This analysis represents a subset 
selected post-randomization and therefore requires adjustment for confounders. Due to lack of 
known confounders early in the epidemic, we propose that the list of baseline descriptors be 
assessed individually for their association with the primary endpoint. Those associated 
univariably with p<0.10 will be included in this analysis. A hazard ratio greater than 1 
(treatment/control) indicates efficacy of the intervention in shortening shedding. 
 
Prevention of COVID-19 diagnosis 
Objective: To test the efficacy of HCQ to prevent incident COVID-19. 
Outcome: PCR-confirmed COVID-19 diagnosis post start of HCQ therapy through Day 14 
Cohort(s): ITT, mITT, Sensitivity, Seronegative, Infected 
Definition of Endpoint: COVID-19 is defined as symptomatic disease based on the following 
criteria with virologic confirmation (RNA PCR Ct  40):  
• 
At least TWO of the following symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, 
headache, sore throat, new olfactory and taste disorder(s), OR  
• 
At least ONE of the following symptoms: cough, shortness of breath or difficulty 
breathing, OR 
• 
Severe respiratory illness with at least 1 of the following:  
o Clinical or radiological evidence of pneumonia, OR 
o Acute respiratory distress syndrome (ARDS) 
 
A participant will be defined as having reached the endpoint if they have the diagnosis above. 
The time of the endpoint will be the onset of symptoms. Participants who do not have the 
endpoint will be censored at the last time they were known to be symptom-free. Death and 
hospitalization will be counted in the endpoint. 
 
Analysis Details: We will use a Cox Proportional Hazards model with robust standard errors 
to estimate the hazard ratio and corresponding 95% confidence interval and Wald test statistic. 
Efficacy will be calculated as 1 minus the hazard calculated from the treatment coefficient. 
Robust confidence intervals and p-values will be displayed. The following baseline variables 
will be included to increase precision: presence of metabolic disease (if present in at least 10% 
of the population), weight, sex, age, and type of contact. 
7.1.3. Sensitivity efficacy analyses 
The following sensitivity analysis will be performed including the one defined in Section 7.1.1. 


 
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Objective: To repeat the primary analysis redefining the endpoint to exclude inconclusive tests 
with Ct>38 from the definition of the endpoint.  
Outcome: Polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection (self-collected 
samples collected daily Day 1 through Day 14]) 
Cohorts: mITT Cohort 
Definition of Endpoint: A participant will be defined as having the endpoint if at least one of their 
PCR tests throughout follow-up is positive (both targets are identified or the Ct is <=38) or they 
develop confirmed COVID-19 through external evaluation (e.g. hospital or clinical assessment).  
Analysis Details:  
The same analytical approaches will be applied as for the primary efficacy analysis with a positive 
test now being defined as concordant results (positive) or a Ct <=38. Inconclusive tests will be 
treated as negative. 
7.1.4. Stratified Analyses 
All efficacy analyses will also be repeated within subgroups defined by contact type, site, 
symptomatic index case, household size, time to start intervention, quarantine status, duration of 
exposure to index case (8 hours or less vs more than 8 hours) and presence of children in 
household. These subgroup analyses will only be adjusted for the same baseline covariates as 
the primary analysis (excluding the variable used to define the subgroup). For each of these 
subgroups, the cumulative incidence of the primary endpoint of SARS-CoV-2 infection by 14 days 
will be estimated, including 95% confidence intervals within each strata and a 95% confidence 
interval of the difference in cumulative incidence at 14 days between strata. 
8. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
8.1. EFFICACY AND FUTILITY MONITORING 
Interim monitoring will be performed on the primary outcome after approximately 20%, 40%, 60% and 80% 
of expected events. Monitoring will be performed using asymmetric O’Brien-Fleming bounds for early 
stopping for efficacy (lower) and futility (upper). The Wald test statistic from the robust Cox model without 
adjustment for covariates will be using for monitoring the trial with fraction of planned households as the 
information fraction[1].  
 
Table 1 Monitoring bounds with 4 interim analyses. Expected events may vary and actual stopping bound will be based 
on number of events observed at the time of monitoring. 
Analysis 
Expected number of 
events 
Efficacy bound 
Futility bound (binding) 
1 
19 
-4.50 
2.7 
2 
37 
-3.18 
0.64 
3 
56 
-2.60 
-0.52 


 
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4 
74 
-2.25 
-1.35 
5 
93 
-2.01 
-2.01 
 
 
 
 
9. SAFETY ANALYSES  
All safety analyses will be conducted on the ITT Cohort. The total number of serious adverse 
events (SAEs) and adverse events (AEs) will be summarized for each randomization arm by 
severity grade as shown in Mock Table 1. A line listing of SAEs will be presented by randomization 
arm. Attribution for SAEs and AEs as related or not related to the study medication as assessed 
by the clinical monitor will be reported. Social harms will be summarized for each randomization 
arm.  
10. 
CHANGE HISTORY  
This section will Identify major changes, if any after version 1.0 approval. 
 
Version 
Activity Description 
0
20
40
60
80
-4
-2
0
2
Number of Events
COVIDPEPet90
Z statistic


 
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Number 
Effective 
Date 
Affected 
Section(s) 
 
 
 
 
 
 
 
 


 
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Mock Table 1.  
Total Number of Serious Adverse Events, by Severity Grade and Arm  
 
Randomized Arm 
 
 
HCQ 
Control 
Total 
Severity Grade 
n 
% 
n 
% 
n 
% 
Grade 1 / mild 
 
 
 
 
 
 
Grade 2 / moderate 
 
 
 
 
 
 
Grade 3 / severe 
 
 
 
 
 
 
Grade 4 / potentially life-threatening 
 
 
 
 
 
 
Grade 5 / death 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTE: The denominator for calculation of percentages is the number of SAEs at a given severity level with the exception 
of the 'Total' column, for which the denominator is the total number of SAEs.