Clinical trial NCT04333225
Conditions: COVID-19
Keywords: hydroxychloroquine
Sponsor: Baylor Research Institute
Start date: 2020-04-03; Completion date: 2020-06-30
Enrollment: 221 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In order to assess the efficacy of hydroxychloroquine treatment weekly for a total of 7 weeks in the prevention of COVID-19 infection, three hundred sixty (360) Healthcare workers with high risk exposure to patients infected with COVID-19 will be tested for COVID-19 infection via nasopharyngeal (NP) swab once weekly for 7 weeks. Of those, one hundred eighty (180) will receive weekly doses of hydroxychloroquine for the duration of the study. Subjects who opt not to receive the study drug will form the control group.

Detailed description:

Arms: arm 1: Subjects who chose to enter the HCQ arm received a loading dose of 800 mg HCQ on day 1 followed by two 200 mg tablets once a week for a total of 7 weeks arm 2: Subjects who declined taking HCQ were considered as controls
Interventions: intervention 1: Hydroxychloroquine
Intervention descriptions: intervention 1: Weekly treatment in individuals at high risk

Protocol documents:
Prot_000.pdf: 
 
A Prospective Clinical Study of Hydroxychloroquine in the 
Prevention of SARS-COV-2 (COVID-19) Infection in Health 
Care Workers after High-Risk Exposures 
 
Protocol Version 1.4 – 28-MAY-2020 
 
Protocol 
 
NCT04333225 
 
ClinicalTrials.gov Submission Date 02-AUG-2021 


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1. 
TITLE PAGE 
 
 
 
BSWRI--001 
 
US IND NUMBER: EXEMPT  
 
A PROSPECTIVE CLINICAL STUDY OF 
HYDROXYCHLOROQUINE IN THE PREVENTION OF 
SARS-COV-2 (COVID-19) INFECTION IN HEALTH 
CARE WORKERS AFTER HIGH-RISK EXPOSURES  
VERSION 1.4 – 28-MAY-2020 
 
 
 


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SPONSOR APPROVAL AND SIGNATURE PAGE 
 
Peter A. McCullough, MD, MPH 
 
 
Principal Investigator 
 
 
Date 
Mezgebe Berhe, MD 
 
 
Co-Principal Investigator 
 
 
Date 
Kevin R. Wheelan, MD 
 
 
Co-Principal Investigator 
 
 
Date 
John Eidt, MD 
 
 
Co-Principal Investigator 
 
 
Date 
Cristie Columbus, MD, MPH 
 
 
Co-Principal Investigator 
 
 
Date 
Nancy Vish, PhD 
 
 
Co-Principal Investigator 
 
Date 
 
 
 
Kristen Chionh, MS, RD 
 
 
Co-Principal Investigator 
 
 
Date 
Rema Thyagarajan, PharmD 
 
 
Co-Principal Investigator 
 
 
Date 
Preethi Ravindranathan, MS 
 
 
Co-Principal Investigator 
 
 
Date 
Felius Joost, PhD 
 
 
Co-Principal Investigator 
 
 
Date 
Robert Gottlieb, MD, PhD 
 
 
Co-Principal Investigator 
 
 
Date 
Gelareh Rahimighazikalayeh, PhD 
 
 
Co-Principal Investigator 
 
Gerard, Zurawski, PhD 
 
Date 
 
 
Co-Principal Investigator 
 
Taimur Safder, MD, MPH 
 
Date 
 
Co-Principal Investigator  
 
 
 
 
 
 
 
 
 
Date 
 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the package insert for hydroxychloroquine.  I have read the BRI-001 
clinical study protocol and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
Peter A. McCullough, MD, MPH  
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Medical and Scientific 
Leader 
 
 
Clinical Study 
Manager 
 
 
Medical Monitor 
 
 
SAE Reporting 
 
Safety Hotline: 
Safety Fax: 
E-mail 
  
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Baylor Scott and White Research Institute 
Name of Investigational Products: 
Hydroxychloroquine 200 mg tablets 
Title of Study:  
A PROSPECTIVE CLINICAL STUDY OF HYDROXYCHLOROQUINE IN THE PREVENTION 
OF SARS-COV-2 (COVID-19) INFECTION IN HEALTH CARE WORKERS AFTER HIGH-RISK 
EXPOSURES 
Study center(s): Single center  
Studied period: 4 months 
Estimated date first subject enrolled: March 2020 
Estimated date last subject completed: July 2020 
Phase of development:  
2 
Objectives:   
For Healthcare workers with 
 
One day or more of exposure to suspected and/or positive COVID-19 patients, including but 
not limited to those working in the Emergency Department or Intensive Care Unit.  
OR  
 
Unprotected exposure to a known positive COVID-19 patient within 72 hours of screening. 
Primary:   
 
To assess the efficacy of hydroxychloroquine 400 mg (two 200 mg tablets) twice a day on day 
1 followed by two 200 mg tablets once a week for a total of 7 weeks in the prevention of 
COVID-19 infection 
Secondary: 
 
To compare the rate of COVID-19 positive conversion among emergency department workers 
versus intensive care unit workers 
Endpoints: 
Primary Efficacy Endpoint: 
Rate of COVID-19 positive conversion on weekly nasopharyngeal (NP) sampling 
Secondary Efficacy Endpoint: 
Time-to-first clinical event consisting of a persistent change for any of the following: 
 
One positive NP sample 
 
Common clinical symptoms of COVID-19 infection including fever, cough, and shortness of 
breath 
 
Less common signs and symptoms of COVID-19 infection including headache, muscle pain, 
abdominal pain, sputum production, and sore throat 
Exploratory Efficacy Endpoint: 
Time-to-first clinical worsening event consisting of any of the following: 
 
Hospitalization for COVID-19 infection 
 
Intensive care unit admission for COVID-19 infection 
 
All cause death 


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Safety: 
Participants will be closely monitored for any occurrence of adverse events or serious adverse events 
during the trial. Weekly in-person visits will be scheduled to capture the frequency, intensity, and 
relationship to study drug of (serious) adverse events. Body temperature will also be collected in all 
follow-up visits. 
Methodology:  
This prospective open label trial will study the safety, tolerability, and efficacy of hydroxychloroquine 
400 mg po in qualified health care workers. 
Qualified individuals will be prescribed oral hydroxychloroquine 400 mg twice a day (two 200 mg 
tablets twice a day) on day 1 followed by two 200 mg tablets once a week for a total of 7 weeks. Dose 
de-escalation is permitted during the study if indicated clinically.  Please refer to Section 7.3.1 for 
additional details on dose escalation and dose de-escalation. 
All study individuals will follow the same visit and assessment schedule.  Following study recruitment, 
participants will be scheduled to be assessed in person during treatment at days 7, 14, 21, 28, 35, 42 
and 49.  
Healthcare workers who are qualified for the trial but decline participation in receiving the treatment 
will form the control group and will be offered an observational registry where the same NP COVID-
19 sampling schedule and other assessments will be followed with the exception of blood testing.  The 
clinical outcomes will be captured in the same manner and with the same definitions as the clinical 
arm.  
Number of Subjects (planned):  
360 individuals will be enrolled into the study with half enrolling in the active treatment study and the 
other half, those who refuse to get the study treatment, will be entering an observational registry 
considered as the control group. 
Main criteria for inclusion: 
1. Adult male and female healthcare workers ≥ 18 to ≤ 75 years of age upon study consent 
2. Healthcare workers with  
 
One day or more of exposure to suspected and/or positive COVID-19 patients, 
including but not limited to those working in the Emergency Department or Intensive 
Care Unit.  
OR  
 
Unprotected exposure to a known positive COVID-19 patient within 72 hours of 
screening. 
3. Afebrile with no constitutional symptoms  
4. Willing and able to comply with scheduled visits, treatment plan, and other study procedures 
5. Evidence of a personally signed and dated informed consent document indicating that the 
subject (or a legally acceptable representative) has been informed of all pertinent aspects of the 
study prior to initiation of any subject-mandated procedures 
 


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Major exclusion criteria: 
1. Participation in other investigational clinical trials for the treatment or prevention of SARS-
COV-2 infection within 30days 
2. Unwilling to practice acceptable methods of birth control (both males who have partners of 
childbearing potential and females of childbearing potential) during Screening, while taking 
study drug, and for at least 30 days after the last dose of study drug is ingested  
Note: the following criteria follow standard clinical practice for FDA approved indications of this 
medication 
3. Having  a prior history of blood disorders such as aplastic anemia, agranulocytosis, 
leukopenia, or thrombocytopenia 
4. Having a prior history of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency 
5. Having dermatitis, psoriasis or porphyria 
6. Taking Digoxin, Mefloquine, methotrexate, cyclosporine, praziquantel, antacids and kaolin, 
cimetidine, ampicillin, Insulin or antidiabetic drugs, arrhythmogenic drugs, antiepileptic 
drugs, loop, thiazide, and related diuretics, laxatives and enemas, amphotericin B, high 
dose corticosteroids, and proton pump inhibitors, neostigmine, praziquantel, 
Pyridostigmine, tamoxifen citrate 
7. Allergies: 4-Aminoquinolines  
8. Pre-existing retinopathy of the eye  
9. Has a chronic liver disease or cirrhosis, including hepatitis B and/or untreated hepatitis  
10. Untreated or uncontrolled active bacterial, fungal infection 
11. Known or suspected active drug or alcohol abuse, per investigator judgment 
12. Women who are pregnant or breastfeeding 
13. Known hypersensitivity to any component of the study drug 
14. A known history of prolonged QT syndrome or history of additional risk factors for torsades de 
pointe (e.g., heart failure, requires a lab test , family history of Long QT Syndrome), or the use 
of concomitant medications that prolong the QT/QTc interval 
Investigational product, dosage and mode of administration:  
Oral hydroxychloroquine 400 mg twice a day (two 200 mg tabs twice a day) on day 1 followed by two 
200 mg tablets once a week for a total of 7 weeks.  
Duration of treatment:  
Study drug will be administered for 7 weeks. 
Criteria for evaluation: 
Efficacy: Rate of COVID-19 positive conversion on weekly nasopharyngeal (NP) sampling 
Safety: Body temperature measurements, adverse events, and serious adverse events. 
 
Statistical methods: 


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Sample size: A total sample of 360 individuals (180 in each arm) would provide at least 80% power to 
detect a relative risk reduction of 40% in the rate of positive NP samples when the anticipated rate of 
positive conversion among those taking hydroxychloroquine is approximately 30%.  
The power calculation, which was based on  Pearson Chi Square test, assumes the following: 
 
One-sided Type I error rate of 0.05 
 
Anticipated positive NP samples rate of 30% in the clinical arm 
 
A 40% lower risk of a positive NP sample comparing the hydroxychloroquine  group vs the 
controls 
 
Loss to follow-up rate of 15% 
Primary analysis of efficacy:   
The proportion of individuals who tested positive at least once during the study period will be 
compared between the clinical and the control arms. In addition, the potential effect of 
hydroxychloroquine on COVID-19 free survival time will also be explored by utilizing appropriate 
statistical methods. An intent-to-treat approach will be used throughout the analysis with the control 
group as the referent. A p-value < 0.05 will be considered statistically significant and a risk reduction 
of 5% will be considered as of smallest clinical importance. 
 
Study Rationale 
It is clear that close interaction of health care workers with patients put them at higher risk of getting 
exposed to infectious diseases. Failing to provide a safe environment for health care workers could cripple 
the medical system especially during an Epidemic outbreak like COVID-19. It is imperative to make sure 
that doctors and nurses do not get sick in high numbers; not only because that will contribute to spreading 
the virus among vulnerable patients but also due to their subsequent role in reducing the number of 
responding personnel. As a result, it is of utmost importance to provide effective prophylaxis to 
healthcare workers who are exposed to COVID-19.  
 
Schema for Study of Prophylactic Therapies for COVID-19 Exposure 
The trial design is initially for a 7 week treatment period which can be divided into 7 bins of time to allow 
a flexible design.  Given the fluid nature of information flow in this pandemic that for example, new 
information comes forward clearly showing that 6 days is a sufficient period of time for proven 
prophylaxis, this trial design can be altered.  Conversely if each subsequent qualifying exposure calls for 
another 6-day bin of time, the protocol can flex to the maximum 7 week period as stated for resource 
planning.   
Once subject’s eligibility is approved they may choose to either receive hydroxychloroquine or enter the 
observational registry. In both cases subjects will be tested for COVID-19 positive conversions on weekly 
nasopharyngeal (NP) sampling. The swab samples will be collected by trained personnel. Nasopharyngeal 
swab will be collected in a VCM medium tube or equivalent (UTM) or E-swabs/Amies medium (minitip-
NP swab) or M4, M4RT, M5 and M6 transport media. The Roche Cobas test will be utilized for detecting 
nucleic acids from SARS-CoV-2 in nasopharyngeal swab samples collected from study participants.  
The safety of the study participants will be ensured by closely monitoring the (serious) adverse events 
occurring during the trial.  In addition, we will comply with the standard of care for regular prescribing of 
hydroxychloroquine which does not require a routine assessment of subject’s health status especially for 
short-term use. However, since the package insert for hydroxychloroquine cautions on using antimalarial 


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compounds for individuals with hepatic disease, alcoholism, G-6-PD and severe blood disorder we will 
not include individuals having those diseases in our study.   
Subjects who choose to enter the clinical arm of the study will receive hydroxychloroquine for a total of 7 
weeks. The study drug supply will be maintained either through Baylor Scott & White pharmacies or 
directly from a manufacturer. 
The logistics of drug dispensing will be specified based on the availability of drug supplies and also the 
mechanism through which the drug would be accessed. If there is enough supply of hydroxychloroquine 
we will dispense the drug as feasible in advance for future visits, otherwise a weekly supply would be 
provided to participants at each visit. 
At the end of the study, after the last subject visit is completed. All collected data will be analyzed with 
the study population being those who either received hydroxychloroquine or entered the observational 
registry.  


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3. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Clinical Experience with Hydroxychloroquine ..........................................................21 
5.1.1. 
Safety and Tolerability ...............................................................................................21 
5.1.2. 
Clinical Experience with hydroxychloroquine ...........................................................21 
5.1.3. 
Transaminase and GGT Elevations ............................................................................21 
5.1.4. 
Muscle Discomfort .....................................................................................................22 
5.1.5. 
Anemia ........................................................................................................................22 
5.1.6. 
Prolonged QT and Risk for Arrythmias......................................................................22 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................23 
6.1. 
Objectives ...................................................................................................................23 
6.1.1. 
Primary Objective .......................................................................................................23 
6.1.2. 
Secondary Objective ...................................................................................................23 
6.2. 
Endpoints ....................................................................................................................23 
6.2.1. 
Primary Efficacy Endpoint .........................................................................................23 
6.2.2. 
Secondary Efficacy Endpoints ....................................................................................23 
6.2.3. 
Exploratory Efficacy Endpoints .................................................................................23 
6.2.4. 
Safety Endpoints .........................................................................................................24 
7. 
INVESTIGATIONAL PLAN .....................................................................................25 
7.1. 
Overall Study Design ..................................................................................................25 
7.2. 
Number of Subjects ....................................................................................................25 
7.3. 
Treatment Assignment ................................................................................................25 
7.3.1. 
Dose and Dose De-Escalation ....................................................................................25 
7.4. 
Criteria for Study Termination ...................................................................................25 
7.5. 
Schedule of Assessments ............................................................................................25 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................27 


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8.1. 
Subject Inclusion Criteria ...........................................................................................27 
8.2. 
Subject Exclusion Criteria ..........................................................................................27 
8.3. 
Subject Re-Screening ..................................................................................................28 
8.4. 
Subject Discontinuation and Termination ..................................................................28 
8.4.1. 
Subject Discontinuation Criteria .................................................................................28 
8.4.2. 
Subject Termination Criteria ......................................................................................28 
9. 
TREATMENT OF SUBJECTS ..................................................................................30 
9.1. 
Select Management Guidelines ..................................................................................30 
9.1.1. 
Management of Ongoing Exposures ..........................................................................30 
9.1.2. 
Management of Muscle Discomfort ...........................................................................30 
9.1.3. 
Diarrhea ......................................................................................................................30 
9.1.4. 
Nausea .........................................................................................................................30 
9.1.5. 
Management of COVID-19 positive test ....................................................................30 
9.2. 
Description of Study Drug ..........................................................................................30 
9.3. 
Concomitant Medications ...........................................................................................31 
9.3.1. 
Excluded Medications ................................................................................................31 
9.3.2. 
Permitted Medications ................................................................................................31 
9.4. 
Treatment Compliance ................................................................................................31 
9.4.1. 
Study Monitoring Committee .....................................................................................31 
9.5. 
Unscheduled Visits .....................................................................................................32 
9.6. 
Pregnancy ...................................................................................................................32 
9.6.1. 
Women of Childbearing Potential ..............................................................................32 
9.6.2. 
Methods of Birth Control............................................................................................32 
9.6.3. 
Suspected Pregnancy ..................................................................................................33 
9.7. 
Serious Toxicities .......................................................................................................34 
9.8. 
Study Procedures ........................................................................................................34 
9.8.1. 
Informed Consent .......................................................................................................34 
9.8.2. 
Informed Consent For Optional Viral Serology Sub-Study .......................................34 
9.8.3. 
Inclusion/Exclusion ....................................................................................................34 
9.8.4. 
Demographics and Baseline Disease Characteristics .................................................34 
9.8.5. 
Prior and Current Concomitant Medications ..............................................................34 
9.8.6. 
Current Background Medications ...............................................................................35 
9.8.7. 
Medical History ..........................................................................................................35 


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9.8.8. 
Height .........................................................................................................................35 
9.8.9. 
Weight .........................................................................................................................35 
9.8.10. 
Body Temperature Measurements ..............................................................................35 
9.8.11. 
Cough Visual Analog Scale ........................................................................................35 
9.8.12. 
Exposure Assessment .................................................................................................35 
9.8.13. 
Pregnancy Test ............................................................................................................35 
9.8.14. 
Study Drug Administration.........................................................................................35 
9.8.15. 
Study Drug Dispensation and Collection ...................................................................36 
9.8.16. 
Adverse Event Collection ...........................................................................................36 
9.8.17. 
Optional Viral Serology Study ...................................................................................36 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
10.1. 
Study Drug ..................................................................................................................39 
10.2. 
Study Drug Packaging and Labeling ..........................................................................39 
10.3. 
Study Drug Storage .....................................................................................................39 
10.4. 
Study Drug Administration.........................................................................................39 
10.5. 
Study Drug Accountability .........................................................................................39 
10.6. 
Study Drug Handling and Disposal ............................................................................40 
11. 
SAFETY ASSESSMENTS ........................................................................................41 
11.1. 
Safety Parameters .......................................................................................................41 
11.2. 
Adverse and Serious Adverse Events .........................................................................41 
11.2.1. 
Definition of Adverse Events .....................................................................................41 
11.2.1.1. 
Adverse Event .............................................................................................................41 
11.2.1.2. 
Serious Adverse Event ................................................................................................41 
11.3. 
Eliciting Adverse Event Information ..........................................................................42 
11.4. 
Assessment of Causality .............................................................................................42 
11.5. 
Assessment of Severity ...............................................................................................43 
11.6. 
Recording Adverse Events .........................................................................................43 
11.7. 
Reporting Serious Adverse Events .............................................................................44 
12. 
STATISTICS ..............................................................................................................46 
12.1. 
Sample Size ................................................................................................................46 
12.1.1. 
Efficacy Variables ......................................................................................................46 
12.1.2. 
Safety Variables ..........................................................................................................46 
12.2. 
Statistical Analyses .....................................................................................................46 


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12.2.1. 
Primary Analysis of Efficacy ......................................................................................46 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................48 
13.1. 
Audits and Inspections ................................................................................................48 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................49 
14.1. 
Quality Assurance .......................................................................................................49 
14.2. 
Financial Disclosure ...................................................................................................49 
14.3. 
Sponsor Obligations....................................................................................................49 
14.4. 
Investigator Documentation ........................................................................................49 
14.5. 
Clinical Study Insurance .............................................................................................50 
14.6. 
Use of Information ......................................................................................................50 
15. 
ETHICS ......................................................................................................................51 
15.1. 
Institutional Review Board (IRB) or Ethics Committee Review ...............................51 
15.2. 
Ethical Conduct of the Study ......................................................................................51 
15.3. 
Written Informed Consent ..........................................................................................51 
15.4. 
Confidentiality ............................................................................................................52 
15.5. 
Modification of the Protocol .......................................................................................52 
15.6. 
Protocol Deviations ....................................................................................................53 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................54 
16.1. 
Retention of Records ..................................................................................................54 
16.2. 
Case Report Forms .....................................................................................................54 
17. 
PUBLICATION POLICY ..........................................................................................55 
18 
APPENDICES ............................................................................................................56 
18.1 
Appendix I: Registry for Screened and Not Randomized ..........................................56 
18.2 
Appendix II: Cough Visual Analog Scale ..................................................................57 
18.3 
Appendix III: Exposure Assessment Questionnaire ...................................................58 
19 
REFERENCES ...........................................................................................................60 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 3: 
Schedule of Assessments ............................................................................................26 
Table 4: 
Study Drug Product Information ................................................................................30 
Table 6: 
SAE Reporting Contact Information ..........................................................................45 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
ATS 
American Thoracic Society 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
BP 
Blood Pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations (US) 
CK 
Creatine kinase 
CKD 
Chronic kidney disease 
Cmax 
Maximum drug concentration in plasma 
CT 
Computed tomography 
DSMB 
Data safety monitoring board 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
ICH 
International Conference on Harmonization 
INR 
International normalized ratio 
IRB 
Institutional Review Board 


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Abbreviation or Specialist Term 
Explanation 
IWRS 
Interactive Web Response System 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MMRM 
Mixed model repeated measures 
PK 
Pharmacokinetic 
RBC 
Red blood cell 
ROS 
Reactive oxygen species 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-36 
36-item short form survey 
SRC 
Sample size re-calculation committee  
TBL 
Total bilirubin 
Tmax 
Time when maximum drug concentration in plasma is achieved 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 


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5. 
INTRODUCTION 
New major epidemic foci of coronavirus disease 2019 (COVID-19), have been identified and are 
rapidly expanding in Europe, North America, Asia, and the Middle East, with the first confirmed 
cases being identified in African and Latin American countries.1 By March 16, 2020, the number 
of cases of COVID-19 outside China had increased drastically and the number of affected 
countries, states, or territories reporting infections to WHO was 143.1 On the basis of”alarming 
levels of spread and severity, and by the alarming levels of inaction”, on March 11, 2020, the 
Director-General of WHO characterized the COVID-19 situation as a pandemic. 
The WHO Strategic and Technical Advisory Group for Infectious Hazards (STAG-IH) regularly 
reviews and updates its risk assessment of COVID-19 to make recommendations to the WHO 
health emergencies programme.2 STAG-IH's most recent formal meeting on March 12, 2020, 
included an update of the global COVID-19 situation and an overview of the research priorities 
established by the WHO Research and Development Blueprint Scientific Advisory Group that 
met on March 2, 2020, in Geneva, Switzerland, to prioritize the recommendations of an earlier 
meeting on COVID-19 research held in early February, 2020.  
To respond to COVID-19, many countries are using a combination of containment and 
mitigation activities with the intention of delaying major surges of patients and levelling the 
demand for hospital beds, while protecting the most vulnerable from infection, including elderly 
people and those with comorbidities. Activities to accomplish these goals vary and are based on 
national risk assessments that many times include estimated numbers of patients requiring 
hospitalization and availability of hospital beds and ventilation support. Most national response 
strategies include varying levels of contact tracing and self-isolation or quarantine; promotion of 
public health measures, including handwashing, respiratory etiquette, and social distancing; 
preparation of health systems for a surge of severely ill patients who require isolation, oxygen, 
and mechanical ventilation; strengthening health facility infection prevention and control, with 
special attention to nursing home facilities; and postponement or cancellation of large-scale 
public gatherings. 
Based on more than 500 genetic sequences submitted to GISAID (the Global Initiative on 
Sharing All Influenza Data), the virus has not drifted to significant strain difference and changes 
in sequence are minimal. There is no evidence to link sequence information with transmissibility 
or virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that 
causes COVID-19. 
SARS-CoV-2, like other emerging high-threat pathogens, has infected health-care workers in 
China and several other countries. To date, however, in China, where infection prevention and 
control was taken seriously, nosocomial transmission has not been a major amplifier of 
transmission in this epidemic. Epidemiological records in China suggest that up to 85% of 
human-to-human transmission has occurred in family clusters and that 2055 health-care workers 
have become infected, demonstrating that patient to healthcare worker is tractable.   However, 
there have been no major nosocomial outbreaks and some supporting evidence that some health-
care workers may have acquired infection or transmitted the infection to their families. These 
findings suggest that close and unprotected exposure is required for transmission by direct 
contact or by contact with fomites in the immediate environment of those with infection. 
Continuing reports from outside China suggest the same means of transmission to close contacts 


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and persons who attended the same social events or were in circumscribed areas such as office 
spaces or cruise ships. It has been suggested that a healthcare worker that had 15-30 min of 
exposure within 6 feet of an infected patient without PEP could acquire the infection. 
Intensified case finding and contact tracing are considered crucial by most countries and are 
being undertaken to attempt to locate cases and to stop onward transmission. Confirmation of 
infection at present consists of PCR for acute infection, and although many serological tests to 
identify convalescent antibodies which confer potential immunity are being developed they 
require validation with well characterized sera before they are reliable for general use. 
From studies of viral shedding in patients with mild and more severe infections, shedding seems 
to be greatest during the early phase of disease. The role, if any, of asymptomatic carriers in 
transmitting infection is not yet completely understood.  Pre-symptomatic infectiousness is a 
concern among healthcare workers and many countries are now using 1–2 days of symptom 
onset as the start day for contact identification. 
A comprehensive report published by the Chinese Center for Disease Control and Prevention on 
the epidemiological characteristics of 72,314 patients with COVID-19 confirmed previous 
understanding that most known infections cause mild disease, with a case fatality ratio that 
ranged from 2·9% in Hubei province to 0·4% in the other Chinese provinces. This report also 
suggested that elderly people, particularly those older than 80 years, and people with 
comorbidities, such as cardiac disease, respiratory disease, and diabetes, are at greatest risk of 
serious disease and death. The case definition used in China changed several times as COVID-19 
progressed, making it difficult to completely characterize the natural history of infection, 
including the mortality ratio.  Information on mortality and contributing factors from outbreak 
sites in other countries varies greatly, and seems to be influenced by such factors as age of 
patients, associated comorbidities, availability of isolation facilities for acute care for patients 
who need respiratory support, and surge capacity of the health-care system. Individuals in care 
facilities for older people are at particular risk of serious disease as shown in the report of a 
series of deaths in an elderly care facility in Washington State. 
The pandemic of COVID-19 has clearly entered a new stage with rapid spread in countries 
outside China and all members of society must understand and practice measures for self-
protection and for prevention of transmission of infection to others. STAG-IH makes the 
following recommendations. 
First, countries need to rapidly and robustly increase their preparedness, readiness, and response 
actions based on their national risk assessment and the four WHO transmission scenarios for 
countries with no cases, first cases, first clusters, and community transmission and spread (4Cs). 
Second, all countries should consider a combination of response measures: case and contact 
finding; containment or other measures that aim to delay the onset of patient surges where 
feasible; and measures such as public awareness, promotion of personal protective hygiene, 
preparation of health systems for a surge of severely ill patients, stronger infection prevention 
and control in health facilities, nursing homes, and long-term care facilities, and postponement or 
cancellation of large-scale public gatherings. 
Third, countries with no or a few first cases of COVID-19 should consider active surveillance for 
timely case finding; isolate, test, and trace every contact in containment; practice social 
distancing; and ready their health-care systems and populations for spread of infection. 


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None of these suggested by STAG-IH address the issue of healthcare workers with concern over 
high-risk exposures such as those who would qualify for this trial. 
Azithromycin may have direct and indirect antiviral effects on human cells infected with 
pathogenic strains of viruses that could apply in COVID-19 infection.3 4 5 6 7 8 
Hydroxychloroquine and chloroquine are antimalarial agents that have been used for decades for 
both active treatment and prophylaxis.  Several sources of data and rationale have been 
developed to support the notion that hydroxychloroquine may have activity against COVID-19.9 
10 11 12 13 
A prospective open-label trial from France evaluated the efficacy of hydroxychloroquine alone 
and in combination with azithromycin in symptomatic, hospitalized patients with positive 
COVID-19. The study composed of 36 patients, out of which 20 received 600 mg of 
hydroxychloroquine daily for 10 days. The remaining 16 patients who either refused the 
treatment or were not eligible to receive it because they were at other centers in France were 
considered as the control group.  The primary endpoint was virological clearance of NP sampling 
at six days.  Six patients who received hydroxychloroquine contributed incomplete NP sampling 
to the analysis because three worsened and were transferred to the intensive care unit, one patient 
died, one patient left the hospital, and one patient could not tolerate the study medication due to 
nausea.  At day 6, 70% of hydroxychloroquine-treated patients were virologically cured 
comparing with 12.5% in the control group (p= 0.001). The investigators found the rate of 
recovery in patients taking hydroxychloroquine to be approximately 5 times more than that of 
patients in the control group.  Six patients were additionally treated with Azithromycin for 
presumed superimposed bacterial infection. The figure below, demonstrates the efficacy of 
hydroxychloroquine alone and in combination with azithromycin according to the French 
study14: 


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Finally, research gaps about COVID-19 should be addressed in prospective, clinical trials as 
proposed in this study.  The present study will leverage information concerning the infectious 
curve associated with COVID-19 exposure as illustrated in the figure. 
 


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5.1. 
Clinical Experience with Hydroxychloroquine 
Please refer to the package insert. 
5.1.1. 
Safety and Tolerability 
Please refer to the package insert for a detailed discussion of safety findings for studies in 
healthy subjects, rheumatology, infectious diseases, and other illnesses patients with 
hydroxychloroquine. 
5.1.2. 
Clinical Experience with hydroxychloroquine 
Please refer to the package insert for a detailed discussion of clinical experience and efficacy 
findings for studies in healthy subjects, rheumatology, infectious diseases, and patients with 
other illnesses 
5.1.3. 
Transaminase and GGT Elevations  
In clinical studies of hydroxychloroquine, patients may have increases of transaminase enzymes 
above baseline upon initiation of treatment, please refer to the package insert for a detailed 
discussion. 
.  


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5.1.4. 
Muscle Discomfort 
In clinical studies of hydroxychloroquine, patients may have increases in muscle discomfort 
above baseline upon initiation of treatment, please refer to the package insert for a detailed 
discussion. 
   
5.1.5. 
Anemia 
Clinical studies of hydroxychloroquine, patients may have reductions in hemoglobin from 
baseline upon initiation of treatment, please refer to the package insert for a detailed discussion. 
 
5.1.6. 
Prolonged QT and Risk for Arrythmias 
Hydroxychloroquine may prolong the QT interval. Please refer to the package insert for a 
detailed discussions.  


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
For healthcare workers with 
• 
One day or more of exposure to suspected and/or positive COVID-19 patients, including but 
not limited to those working in the Emergency Department or Intensive Care Unit. 
OR 
• 
Unprotected exposure to a known positive COVID-19 patient within 72 hours of screening. 
6.1.1. 
Primary Objective 
To assess the efficacy of hydroxychloroquine 400 mg twice a day (two 200 mg tablets twice a 
day) on day 1 followed by two 200 mg tablets once a week for a total of 7 weeks in the 
prevention of COVID-19 infection  
6.1.2. 
Secondary Objective 
To compare the rate of COVID-19 positive conversion among emergency department workers 
versus intensive care unit workers 
 
6.2. 
Endpoints 
6.2.1. 
Primary Efficacy Endpoint 
Rate of COVID-19 positive conversion on weekly nasopharyngeal (NP) sampling 
6.2.2. 
Secondary Efficacy Endpoints 
Time-to-first clinical event consisting of a persistent change for any of the following: 
 One positive NP sample 
 Common clinical symptoms of COVID-19 infection including fever, cough, and 
shortness of breath 
 Less common signs and symptoms of COVID-19 infection including headache, muscle 
pain, abdominal pain, sputum production, and sore throat 
  
6.2.3. 
Exploratory Efficacy Endpoints 
Time-to-first clinical worsening event consisting of any of the following: 
1) Hospitalization for COVID-19 infection 
2) Intensive care unit admission for COVID-19 infection 
3) All cause death 


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6.2.4. 
Safety Endpoints 
 
Frequency, intensity, and relationship to study drug of adverse events and serious adverse events, 
change from baseline in body temperature. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This prospective open label trial will study the safety, tolerability, and efficacy of 
hydroxychloroquine in qualified health care workers.  
Qualified individuals will be administered hydroxychloroquine twice a day on day 1 (two 200 
mg twice a day) and once a week (two 200 mg) afterwards for a total of 7 weeks. Dose de-
escalation is permitted during the study if indicated clinically.  Please refer to Section 7.3.1 for 
additional details on dose de-escalation.  
All study individuals will follow the same visit and assessment schedule.  Following study 
enrollment, participants will be scheduled to be assessed in person at Days 7, 14, 21, 28, 35, 42 
and 49. 
7.2. 
Number of Subjects 
A total of 360 subjects will be enrolled 
7.3. 
Treatment Assignment 
Qualified individuals may choose which group they want to be in. Subjects in the treatment 
group will receive hydroxychloroquine for 7 weeks. Those who decide to opt out of receiving 
treatments will compose the control group. 
7.3.1. 
Dose and Dose De-Escalation  
Subjects receiving hydroxychloroquine will start at fixed doses unless contraindicated clinically.  
The investigator may choose to decrease the subject’s dose to one-half of the prior doses if 
clinically indicated.  Dose de-escalation can occur more than once, but the minimum dose 
permitted is 200 mg of hydroxychloroquine.  Reasons for dose de-escalation should be discussed 
with the medical monitor prior to changing dose.   
Unscheduled visits due to dose de-escalation should include assessments detailed in Section 9.5.  
7.4. 
Criteria for Study Termination 
Although the Sponsor intends to complete the study, the Sponsor reserves the right to 
discontinue the study at any time for clinical or administrative reasons, or if required by 
regulatory agencies.  If the Sponsor discontinues the study, all study drug will be discontinued 
and the investigator will be responsible for securing any alternative therapy to be administered, 
as appropriate. 
7.5. 
Schedule of Assessments 
Table 3 lists the overall schedule of assessments for the study. 


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Table 3: 
Schedule of Assessments  
Study Day  
(Day) 
Assessment 
Screen 
Aa 
Day 
1b 
Day 7 
Day 7±3 
Day 14 
Day 14±3 
Day 21 
Day 21±3 
Day 28 
Day 28±3 
Day 35 
Day 35±3
 
 
Day 42 
Day 42±3 
Day 49j 
Day 49±3 
(End of study visit) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
X 
Xc 
 
 
 
 
 
 
 
Self-reported Pregnancy Statusd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics and baseline disease 
characteristics 
X 
 
 
 
 
 
 
 
 
Prior and Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current background medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
Self-reported Height 
X 
 
 
 
 
 
 
 
 
Self-reported Weight 
X 
 
 
 
 
 
 
 
 
Body temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study druge 
 
X 
X 
X 
X 
X 
X 
X 
 
Collect study drugf 
 
 
X 
X 
X 
X 
X 
X 
X 
nasopharyngeal (NP) sampling 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event collection 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
Visual analogue scale (VAS) for cough 
severity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exposure assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Virus serologyh 
X 
 
 
X 
 
X 
 
Xj 
 
 
a Total Screening period should not exceed 30 days.  Screening and Day 1 can be completed in the same visit.   
b Day 1 is the day of administration of the first dose.  On Day 1, all procedures should be performed before study drug 
administration. 
c Screening eligibility procedures do not need to be repeated on Day 1; however, a review of any changes in eligibility criteria 
should be evaluated prior to Day 1 procedures 
d Female participants will be asked with respect to their pregnancy as a verbal check 
e Depending on the availability of the drug supply, the schedule of drug dispensing might change  
   f If the schedule for drug dispensing changes, the arrangements for drug collection will change accordingly 
    g AE assessments on Day 1 should be performed following study drug administration 
    h Only applicable to those who choose to participate in the optional viral serology study 
i Individuals who terminate from the study prior to the Day 49 study visit should return to the clinic as soon as possible for 
early termination assessments (i.e., Day 49 Day Prior and end-of-treatment visits).  Participants should complete the end-of-
treatment procedures, including assessments, prior to any adjustments being made to their treatment regimen. 
j If final serology draw not collected at Day 42, it can be collected at day 49 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
1. Adult male and female healthcare workers ≥ 18 to ≤ 75 years of age upon study consent 
2. Healthcare workers with 
• 
One day or more of exposure to suspect and/or positive COVID-19 patients, including 
but not limited to those working in the Emergency Department or Intensive Care Unit. 
OR 
• 
Unprotected exposure to a known positive COVID-19 patient within 72 hours of 
screening. 
3. Afebrile with no constitutional symptoms  
4. Willing and able to comply with scheduled visits, treatment plan, and other study procedures 
5. Evidence of a personally signed and dated informed consent document indicating that the 
subject (or a legally acceptable representative) has been informed of all pertinent aspects of the 
study prior to initiation of any subject-mandated procedures 
 
8.2. 
Subject Exclusion Criteria 
1.  Participation in other investigational clinical trials for the treatment or prevention of 
SARS-COV-2 infection within 30days 
2. Unwilling to practice acceptable methods of birth control (both males who have partners 
of childbearing potential and females of childbearing potential) during Screening, while 
taking study drug, and for at least 30 days after the last dose of study drug is ingested  
Note: the following criteria follow standard clinical practice for FDA approved indications of 
this medication 
3. Having  a prior history of blood disorders such as aplastic anemia, agranulocytosis, 
leukopenia, or thrombocytopenia 
4. Having a prior history of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency 
5. Having dermatitis, psoriasis or porphyria 
6. Taking Digoxin, Mefloquine, methotrexate, cyclosporine, praziquantel, antacids and 
kaolin, cimetidine, ampicillin, Insulin or antidiabetic drugs, arrhythmogenic drugs, 
antiepileptic drugs, loop, thiazide, and related diuretics, laxatives and enemas, 
amphotericin B, high dose corticosteroids, and proton pump inhibitors, neostigmine, 
praziquantel, Pyridostigmine, tamoxifen citrate 
7. Allergies: 4-Aminoquinolines  
8. Pre-existing retinopathy of the eye  
9. Has a chronic liver disease or cirrhosis, including hepatitis B and/or untreated hepatitis  


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10. Untreated or uncontrolled active bacterial, fungal infection 
11. Known or suspected active drug or alcohol abuse, per investigator judgment 
12. Women who are pregnant or breastfeeding 
13. Known hypersensitivity to any component of the study drug 
14. A known history of prolonged QT syndrome or history of additional risk factors for 
torsades de pointe (e.g., heart failure, requires a lab test , family history of Long QT 
Syndrome), or the use of concomitant medications that prolong the QT/QTc interval  
8.3. 
Subject Re-Screening 
Subjects may repeat the Screening procedures to qualify for the study with approval from the 
medical monitor. 
8.4. 
Subject Discontinuation and Termination 
Subjects have the right to discontinue study drug or withdraw from the study at any time for any 
reason, without prejudice to their medical care.  Furthermore, the investigator may discontinue a 
subject from study drug.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a subject from the study.  The reason for a subject’s 
discontinuation from study drug or study termination will be recorded in the electronic case 
report form (eCRF).  
8.4.1. 
Subject Discontinuation Criteria 
Discontinuation refers to a subject’s stopping administration of study drug.  Reasons for study 
drug discontinuation may include the following: 
 Confirmed clinical worsening event 
 Occurrence of an AE or change in medical status that leads the investigator to be 
concerned about the subject’s welfare 
 Administrative reasons (e.g., inability to continue) 
 Sponsor termination of the study 
 Voluntary withdrawal 
 Females who become pregnant during the study 
 A positive COVID-19 test 
Subjects who are discontinued from study drug should still continue in the study, completing all 
study visits and undergo all scheduled study assessments, if possible.   
8.4.2. 
Subject Termination Criteria 
Termination refers to a subject’s stopping study drug and all study assessments and visits.  
Reasons for study termination include the following: 
 Loss to follow-up 


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 Death 
 Withdrawal of consent 
Every reasonable effort should be made to contact individuals who do not return for a scheduled 
visit.  The investigator should inquire about the reason for withdrawal, request the subject return 
all unused investigational product, request the subject return for end-of-treatment and follow-up 
visits (if applicable), and follow up with the subject regarding any unresolved AEs.   


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Select Management Guidelines 
The following guidelines apply to the management of study participants:   
9.1.1. 
Management of Ongoing Exposures 
Study participants will continue to adhere to good clinical practice to avoid infection with 
COVID-19 according to the CDC and other applicable guidance.    
9.1.2. 
Management of Muscle Discomfort 
Basic symptomatic relief is the first step in managing muscle spasm, including walking, adequate 
hydration, wearing socks, and stretching before bedtime.  Assessment of levels of electrolytes 
such as magnesium, calcium and potassium may indicate the need for replacement.  If vitamin D 
levels are low, supplementation may be warranted.  Muscle relaxants may also help relieve 
symptoms. 
 
9.1.3. 
Diarrhea 
In instances where an individual experiences diarrhea consideration will be made with respect to 
the doses of the study medications as well as concomitant medications. 
9.1.4. 
Nausea 
Nausea may occur with higher doses of hydroxychloroquine..  Nausea adverse events are 
typically mild and reversible within a few Days after treatment initiation.  If symptoms do not 
resolve, dose de-escalation, with consultation of the medical monitor, may be necessary.   
9.1.5. 
Management of COVID-19 positive test 
If the result of an NP swab test demonstrates the presence of SARS-CoV-2, the subject will be 
directed to immediately receive appropriate medical care and will discontinue study treatment and 
procedures, however the sponsor will continue to follow the subject until their condition is resolved or 
death. Patient management following a positive test during the study will not be directed by study 
procedures and will be at the discretion of the subject’s physician.  
 
9.2. 
Description of Study Drug 
Hydroxychloroquine (BRI-001) drug product information is shown in Table 4.   
Table 4: 
Hydroxychloroquine Drug Product Information 
Description 
Hydroxychloroquine tablets 
Ingredients 
Hydroxychloroquine sulfate 
 
Route of Administration 
Oral 


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9.3. 
Concomitant Medications 
9.3.1. 
Excluded Medications 
Subjects taking these medications or treatments will be ineligible for enrollment: 
 Any other investigational drug or device as part of an interventional study; 
 Taking Digoxin, Mefloquine, methotrexate, cyclosporine, praziquantel, antacids and 
kaolin, cimetidine, ampicillin, Insulin or antidiabetic drugs, arrhythmogenic drugs, 
antiepileptic drugs, loop, thiazide, and related diuretics, laxatives and enemas, 
amphotericin B, high dose corticosteroids, and proton pump inhibitors, neostigmine, 
praziquantel, Pyridostigmine, tamoxifen citrate 
Subjects who take excluded medications during the study should not discontinue study drug 
solely on this basis.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a subject from the study. 
9.3.2. 
Permitted Medications 
Allowed concomitant medications include the following: 
 Daily multivitamins or recommended daily supplements; 
 Other medications intended to manage concurrent diseases, as authorized by the 
treating physician; 
 Oral, implantable, or injectable contraceptives. 
Subjects taking medication chronically should be maintained on those same doses and dose 
schedules throughout the study period and should not have additions or changes made to their 
medications, as medically feasible.   
The use of the other therapies which may affect walking distance, are permitted during the study, 
provided the subjects have been receiving a stable dosage for at least 30 days prior to Day 1.  
Unless medically indicated and discussed with the medical monitor, the doses of these agents 
should remain unchanged during the study. 
9.4. 
Treatment Compliance 
The investigator or his/her designated and qualified representatives will only dispense study drug 
to subjects enrolled in the study in accordance with the protocol.  The study drug must not be 
used for reasons other than that described in the protocol.  Subjects who miss more than 25% of 
the total number of expected doses will not be considered treatment-compliant.  
9.4.1. 
Study Monitoring Committee 
A study monitoring team including a qualified physician, a monitor from BSWRI, and a 
statistician will be responsible to monitor the safety and integrity of the study and to make 
recommendations as appropriate.  They will start reviewing the collected data approximately 4 


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weeks after the first subject is enrolled and will continue to do so quarterly until the last dose of 
the last subject enrolled.   
The study monitoring committee will be responsible for reviewing the progress of the study and 
the accumulating of the data while the study is ongoing. They may recommend that the study 
continue as is, be modified to protect subject safety, or be terminated.  However, investigators, 
will make decisions concerning the need for laboratory investigations, ECG, and intra-subject 
dose-escalation decisions throughout the study for each subject and may choose to decrease the 
subject’s dose (to one-half of the prior dose).   
 
  
9.5. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
 Management of an adverse event or serious adverse event; 
 Dose de-escalation; 
 Any time the investigator feels that it is clinically appropriate for subject safety. 
At a minimum, unscheduled visits should include collection of adverse events and vital signs.  
Additional conversations may be necessary with the medical monitor following an unscheduled 
visit to assess subject safety. 
9.6. 
Pregnancy 
9.6.1. 
Women of Childbearing Potential 
Women will be asked to self-report their pregnancy status at screening. We are relying on self-
reporting of pregnancy because we do not want to delay the preventive treatment for COVID-19 
to those who are working in a high-risk environment. The study investigators believe that the risk 
of contracting COVID-19 may be worse than taking hydroxychloroquine. 
 Women of childbearing potential (WOCBP) are those who are not surgically sterile (no history 
of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy) do not have 
fallopian inserts with confirmed blockage, have not had reproductive potential terminated by 
radiation, and are not postmenopausal for at least 1 year. 
9.6.2. 
Methods of Birth Control 
During Screening, while taking study drug and until 30 days following administration of the final 
dose of study medication, WOCBP must practice one of the following acceptable methods of 
birth control: 
 Use double barrier contraception method defined as male use of a condom and female 
use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, 
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 Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
90 days prior to start of study drug administration; 
 Use of an intrauterine device; 
 monogamous partner with a vasectomy; 
 Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
During Screening, while taking study drug and until 30 days after the final dose of study 
medication is taken, males who have female partners of childbearing potential must practice one 
of the following methods of birth control: 
 Have had a vasectomy (at least 6 months earlier); 
 Use double barrier contraception method, defined as male use of a condom and 
female use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, 
diaphragm [always use with spermicidal jelly/cream]); 
 Partner use of an intrauterine device; 
 Partner use of hormonal contraceptives (oral, parenteral, vaginal or transdermal) for 
at least 90 days prior to start of study drug administration; 
 Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
9.6.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., late or missed menstrual period).  Male subjects must be 
instructed to contact the investigator if a sexual partner suspects she may be pregnant. 
If a subject or investigator suspects that the subject may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If the serum pregnancy test 
confirms the pregnancy, the subject must permanently discontinue taking study drug.  The 
investigator must immediately report to the medical monitor a pregnancy associated with study 
drug exposure.  The early discontinuation protocol-required procedures outlined for End-of-
treatment and Follow-up visits must be performed on the subject.  
Pregnancy is not considered an AE; however, the investigator must follow a pregnant subject, or 
the pregnant female partner of a male subject (if consenting), and report follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome.  Infants 
resulting from such pregnancies should be followed for a minimum of 8 Days.  BSWRI or 
designee may contact the investigator to request additional information throughout the course of 
the pregnancy. 
The following pregnancy outcomes must be considered SAEs and will require additional 
reporting in the eCRF and reported as a serious adverse event: 


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 Congenital anomaly/birth defect; 
 Stillbirth; 
 Spontaneous miscarriage. 
9.7. 
Serious Toxicities 
In the case of serious toxicities, the investigator may choose to interrupt treatment with 
hydroxychloroquine.  Dose reductions are permitted to manage tolerability issues.  Once a 
subject’s dose has been reduced, that dose should be maintained until the Day 49 visit.  Subjects 
who resume therapy after an interruption will follow the originally planned study schedule.  
9.8. 
Study Procedures  
The following sections describe each assessment.  The timing of these assessments is noted in 
Table 3.  All Day 1 procedures, except AE assessments, should be completed prior to 
administration of first dose of study drug. 
9.8.1. 
Informed Consent 
Written informed consent (see Section 15.3) must be obtained from the subject before any 
study-related procedures are performed, and again if there is a change in the study procedures 
that would affect the subject’s willingness to participate. 
9.8.2. 
Informed Consent For Optional Viral Serology Sub-Study 
Individuals who are willing to participate in the viral serology sub-study, which is optional, will 
sign a separate consent form prior to the collection of samples. 
 
9.8.3. 
Inclusion/Exclusion 
Inclusion and exclusion criteria must be reviewed as indicated in Table 3.  Subjects must meet all 
of the inclusion and none of the exclusion criteria for entry in the study.  Investigators should 
contact the medical monitor with any questions regarding eligibility prior to enrolling the 
subjects on Day 1. 
9.8.4. 
Demographics and Baseline Disease Characteristics 
Demographic data including sex, age, race, and ethnicity, will be collected as indicated in  
Table 3.  Baseline disease characteristics will be collected as indicated in Table 3.   
9.8.5. 
Prior and Current Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the subject is taking.  
All allowed and excluded medications should be recorded including all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications.  Trade or generic drug names 
should be used where possible.  Concomitant medications will be reviewed as indicated in  
Table 3 and all changes will be recorded. 


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9.8.6. 
Current Background Medications 
The name, dose, and frequency must be recorded for all background medications that the subject 
is taking.  Trade or generic drug names should be used where possible.  Additional background 
PAH medications may only be prescribed after a clinical worsening event is confirmed.  
9.8.7. 
Medical History 
A complete medical history (e.g., per subject report) that includes all medical history within the 
past 5 years must be collected.  Medical history will be recorded as indicated in Table 3.   
9.8.8. 
Height 
Height will be self-reported as indicated in Table 3. 
9.8.9. 
Weight 
Weight will be self-reported as indicated in Table 3.    
9.8.10. 
Body Temperature Measurements 
Body temperature will be measured as indicated in Table 3.  
9.8.11. 
Cough Visual Analog Scale 
Cough visual analogue scale (VAS, 0–100 mm) will be recorded as indicated in Table 3 to assess 
cough severity in patients with chronic cough. Please refer to appendix II for cough visual 
analogue scale template.  
9.8.12. 
Exposure Assessment 
Subjects will be questioned about potential exposure to COVID-19 infection over the past 7 days 
as indicated in Table 3 to quantify ongoing risk of infection. Please refer to Appendix III for 
more details on exposure assessment questionnaire.  
9.8.13. 
Pregnancy Test 
WOCBP (see Section 9.6) will self-report on their pregnancy status. Any subject who becomes 
pregnant during the study must discontinue taking study drug immediately.  See Section 9.6.3 for 
a description of procedures to be followed in case of pregnancy. 
9.8.14. 
Study Drug Administration 
Subjects should self-administer two capsules on day 1 following by two capsules once a week 
after that (preferably in the morning) until the end of the study. A bottle of tablets will be 
included in each subject’s study drug kit.  
A vomited dose must not be replaced.  A double dose (e.g., missed dose from previous week and 
dose for current week) must not be taken. 


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9.8.15. 
Study Drug Dispensation and Collection 
Study drug will be dispensed to the subject and collected from the subject as indicated in Table 
3.  The dispensing schedule will be subject to availability. Dispensed treatment kits from each 
visit should be returned to the site for collection at the subsequent visit. 
9.8.16. 
Adverse Event Collection 
Subjects will be observed for general appearance, presence of illness or injury, or signs 
indicative of a concurrent illness as indicated in Table 3.  Subjects must be instructed to 
volunteer any information regarding AEs on or after the first dose of study drug or query the 
subjects with an open question regarding any AEs they may be experiencing (e.g., “How have 
you been feeling since your last visit?”).  Any findings are to be documented.  Subjects must be 
asked if they have been hospitalized, had any accidents, used any new medications, or changed 
concomitant medication regimens (including prescription drugs, over-the-counter medications, 
vitamins, herbal products, and minerals).  Responses must be documented in the source 
documents. 
9.8.17. 
Optional Viral Serology Study 
Infection with SARS-COVID-2 may range from asymptomatic to disease requiring 
hospitalization. Given a high number of asymptomatic or minimally symptomatic infections, it is 
possible that a proportion of the population could have been exposed and recovered, especially in 
the weeks before active testing and surveillance became available in the United States. 
Moreover, healthcare workers who work in the “frontline” or directly with patients infected with 
SARS-COVID-2, are at higher risk of infection.  
Another important aspect of finding detectable IgG antibody titers is the use of plasma from 
recovered patients with COVID-19 in a similar fashion as it  has previously been used to treat 
outbreaks other potentially lethal infectious diseases such as SARS, Ebola, diphtheria, measles, 
etc. before a vaccine was available. On March 24, 2020, the FDA announced a pathway to 
facilitate access to COVID-19 convalescent plasma for use in patients with serious or 
immediately life-threatening COVID-19 infections. This therapy relies on circulating serum 
antibodies that are able to, either prevent infection via blocking interaction of the virus with the 
host cell receptor, or that can potentiate antibody-dependent cell-mediated cytotoxicity (ADCC).  
Hypothesis: A proportion of healthcare workers have previously been exposed and recovered 
from SARS-COVID-2.  Detectable IgG antibodies against SARS-COVID-2 would indicate 
evidence of past infection. Moreover, the development of IgM or IgG antibodies during the study 
period would indicate exposure to the virus.  
Inclusion criteria:  
 All healthcare workers participating in the chemoprophylaxis trial will be offered 
participation.  
 
Accordingly, the Biotechnology Center within the Baylor Institute for Immunology Research has 
initiated a viral serology study to collect serum/plasma samples from those participating in the 
study that also agree to have blood samples obtained. The donors that have the highest titers of 


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antibodies directed to SARS-COV-2 proteins will have the highest potential for eliciting potent 
therapeutic benefit.  
Individuals who agree to participate in the viral serology sub-study will be required to sign a 
separate ICF before collection of the samples. Subjects are not required to participate in the viral 
serology sub-study in order to enroll in the primary study. Samples for viral serology sub-study 
should be collected on day 1/baseline (pre-dose) and on days 14, 28 and 42 as indicated in Table 
3.  
Healthcare worker blood sampling: Initial blood sampling for plasma collection will be planned 
via staff at the BSWRI BPM core laboratory, which is classified as a Bio Safety Level 2 lab 
(BSL-2). The Core will manage documentation, storage, and appropriate dispersal of the 
collected materials.  
Serology testing: Samples will be processed by the BPM Core staff for viral inactivation. 
Serology at the Biotechnology Center will be undertaken with read out of SARS-COV-2-specific 
plasm pan-Ig and/or or IgG. If needed for throughput, samples can be pooled and assayed to 
identify positive pools, followed by deconvolution.  
Biotechnology Center will run serology tests using either solid phase ELISA or bead-based 
Luminex™ multiplexed assay (the latter is ~10-fold more sensitive). Recombinant protein 
components of SARS-COV-2 are the basis of these assays, and these will either be purchase 
commercially (Sinobiologicals) or made in house. If commercial assay kits become available, 
then they will be used for testing or validation of in-house assays.  
Serology study Endpoints:  
 The primary endpoint is to determine the proportion of healthcare workers that have 
detectable SARS-COVID-2 IgG at baseline  
 Secondary endpoint: determine the proportion of healthcare workers who seroconvert as 
evidenced by detectable IgM and/or IgG levels throughout the study. 
Considerations/Interventions:  
 All serum samples will be paired with a Nasopharyngeal swab PCR as this is performed 
weekly.  
 Participants with detectable IgM and no detectable IgG against SARS-COVID-2 will be 
considered recently infected and will require further evaluation by Employee health.  
 Participants who have only detectable IgG will be considered previously exposed and 
with resolved infection.  
 Participants with detectable IgG and IgM will be considered to have been infected and on 
recovery phase.  
 
Study termination:  
 Participants may elect to stop participation at any time.  
 


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Management of COVID-19 positive cases:  
 Those who become infected during the trial will be encouraged to do the serology testing 
two weeks after they become positive, if feasible. 
Management of missed visits: 
Subjects who miss the Day 42 serology for any reason (subject availability, had to leave before 
completing visit, etc.) will be reminded during the Day 49 visit that they did not have their final 
serology draw done at Day 42. They will be asked if they wish to have the final draw done at the 
final visit (“today”). This will allow them to receive at least the “before and after” results of their 
antibodies during the study (all subjects consented to Day 1 serology draws and had at least 1 
sample collected) in addition to any samples they consented to have collected during the study, 
and they will be informed that this helps the researcher gather more data on the prevalence of 
antibodies in healthcare workers at high risk of COVID-19 infection. 
In all cases, this conversation will be documented on the Day 49 source documents, including 
that it was not done at Day 42 and why, and that the subject is agreeing or refusing to have it 
drawn at Day 49. For subjects that did have some procedures at Day 42 but were not able to 
complete the serology sample collection, this is additionally documented in the Day 42 source 
documents. For subjects who missed Day 42 entirely, there will be a notation in the subject file 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Hydroxychloroquine tablets will be used in this study. 
10.2. 
Study Drug Packaging and Labeling 
The study drug will be supplied in high-density polyethylene (HDPE) bottles. Each bottle will 
contain a desiccant insert that must not be ingested.  Labeling on each kit bottle will contain at 
minimum the following information: 
 Medication ID number; 
 Protocol BSWRI-001; 
 Caution Statement: Keep out of sight and reach of children; 
 Control or lot number 
 Store at 20° – 25°C (68° – 77°F), short term excursions allowed to 15° – 30°C (59° – 
86°F); 
 BSWRI, Dallas, TX. 
A double panel label will be presented on the treatment kit carton containing this and other 
information as well.  
10.3. 
Study Drug Storage 
The stability of the drug product has been and is currently being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location with room 
temperature conditions of 20° - 25°C (68° - 77°F), with brief excursions allowed to 15° – 30°C 
(59° – 86°F).   
10.4. 
Study Drug Administration 
Please refer to Section 9.8.14 for details on study drug administration.  Clear instructions will be 
provided to the subject regarding the number and type of capsules to be ingested at each study 
drug administration time point listed in Table 3.  Subjects must be instructed to continue taking 
study drug twice on day 1 (two 200 mg twice a day) and once weekly (two 200 mg) after that for 
a total of 7 weeks unless: (1) subject has been otherwise instructed by the investigator or (2) the 
subject has been formally discontinued from the study.    
10.5. 
Study Drug Accountability 
The investigator, or designee, will maintain a record of all study drug received, dispensed, and 
returned to the Sponsors’ designee.  No study drug shall be destroyed by the clinical site unless 
directed in writing to do so by the Sponsor’s quality assurance department.  Study drug bottles 
and any unused capsules should be returned to the study staff for eventual disposition by the 
Sponsor.  The number of capsules returned at each visit will be recorded for each bottle in the 
kit. 


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10.6. 
Study Drug Handling and Disposal 
At the conclusion of the study or in an instance of planned study drug replacement, the Sponsor 
or its designee will direct the site regarding the final disposition of study drug. 


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11. 
SAFETY ASSESSMENTS 
11.1. 
Safety Parameters 
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determinations completes all safety assessments. Safety 
parameters include vital sign measurements, adverse events and serious adverse events.  
11.2. 
Adverse and Serious Adverse Events 
11.2.1. 
Definition of Adverse Events 
11.2.1.1. Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject regardless of 
its causal relationship to study drug.  An AE can be any unfavorable and unintended sign 
(including any clinically significant abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study drug, whether or not it is considered to be 
study-drug related.  Included in this definition are any newly-occurring events or previous 
condition that has increased in severity or frequency since the administration of study drug. 
All AEs that are observed or reported by the subject during the study (from time of 
administration of the first dose at the Day 1 visit until the final visit indicated in Table 3 must be 
reported, regardless of their relationship to study drug or their clinical significance. 
11.2.1.2. Serious Adverse Event 
A serious adverse event (SAE) is any AE occurring at any dose and regardless of causality that: 
 Results in death; 
 Is life-threatening; 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 Is a congenital anomaly or birth defect in an offspring of a subject taking study drug; 
 Is an important medical event.  
The term "life-threatening" refers to an event in which the subject was at immediate risk of death 
at the time of the event.  It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during the study (from the time of the first dose of study drug until the final visit 


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indicated in Table 3, as appropriate).  Certain pregnancy outcomes will require submission as an 
SAE (See Section 9.6). 
The investigator is responsible for reporting to BSWRI or designee all AEs and SAEs that are 
observed or reported by the subject during the study (from the time of administration of the first 
dose of study drug until the final visit indicated in Table 3, as appropriate), regardless of their 
relationship to study drug or their clinical significance.   
The Sponsor, or the Contract Research Organization (CRO) on the behalf of the Sponsor, must 
be notified immediately regarding the occurrence of any SAE that occurs after the subject is 
enrolled and throughout the study, regardless of study drug administration, including SAEs 
resulting from protocol-associated procedures, as defined in relevant legislation.  The procedures 
for reporting all SAEs, regardless of causal relationship, are as follows: 
 Record the SAE on the AE eCRF and complete the “Serious Adverse Event Report” 
form within the electronic database. 
 In the event the electronic database is not functional, a paper SAE form will be 
available for the reporting of SAEs. 
The Sponsor may request additional information from the investigator to ensure the timely 
completion of accurate safety reports. 
All SAEs reported or observed during the study must be followed to resolution or until the 
investigator deems the event to be chronic or the subject to be stable.  BSWRI or designee may 
contact the investigator to obtain additional information on any SAE which has not resolved at 
the time the subject completes the study. 
11.3. 
Eliciting Adverse Event Information  
At every study visit, subjects must be asked a standard, non-directed question, such as, “How 
have you been feeling since your last visit?” to elicit any medically related changes in their 
well-being.  They may also be asked if they have been hospitalized, had any accidents, used any 
new medications, or changed concomitant medication regimens (including prescription drugs, 
over-the-counter medications, vitamins, herbal products, and minerals).  Responses must be 
documented in the source documents. 
In addition to subject observations, AEs must be documented for any clinically significant 
diagnosis resulting from abnormal laboratory test values, physical examination findings, or ECG 
abnormalities, or from other documents that are relevant to subject safety. 
11.4. 
Assessment of Causality  
The investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
Not Related: This relationship suggests that there is no association between the study drug and 
the reported event. 
Unlikely Related: This relationship suggests that the temporal sequence of the event with study 
drug administration makes a causal relationship improbable and/or other factors also provide 
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Possibly Related: This relationship suggests that treatment with the study drug caused or 
contributed to the AE.  That is, the event follows a reasonable temporal sequence from the time 
of study drug administration, and/or, follows a known response pattern to the study drug, but 
could have been produced by other factors. 
Probably Related: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with study drug 
administration seems likely. 
Definitely Related: This relationship suggests that a definite causal relationship exists between 
the drug administration and the AE, and other conditions (e.g., concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
11.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
Mild: Symptoms causing no or minimal interference with usual social and functional activities 
Moderate: Symptoms causing greater than minimal interference with usual social and functional 
activities 
Severe: Symptoms causing inability to perform usual social and functional activities  
11.6. 
Recording Adverse Events 
All conditions present prior to the administration of the first dose of study drug (Day 1) should 
be documented as medical history.  After the first dose, documentation of adverse events (AEs) 
shall continue until 49 days following administration of the final dose of study medication, 
regardless of the relationship of the AE to study drug.  Information to be collected includes type 
of event, date of onset, date of resolution, investigator-specified assessment of severity and 
relationship to study drug, seriousness, as well as any action taken.  
While an AE is ongoing, changes in the severity (e.g., worsening and improving) should be 
noted in the source documents, but when documenting the AE, only the total duration and 
greatest severity should be recorded in the eCRF.  AEs characterized as intermittent require 
documentation of onset and duration. 
All drug-related (possibly, probably, or definitely related, see Section 11.4) AEs and abnormal 
laboratory test results reported or observed during the study must be followed to resolution 
(either return to baseline or within normal limits).  All other AEs will be followed through the 
final visit indicated in Table 3, as appropriate. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported.  Preexisting conditions 
(present before the start of the AE collection period) are considered concurrent medical 
conditions and should NOT be recorded as AEs.  However, if the subject experiences a 


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worsening or complication of such a concurrent condition, the worsening or complication should 
be recorded as an AE.  Investigators should ensure that the AE term recorded captures the 
change in the condition (e.g., “worsening of…”).  Any improvement in condition should be 
documented per Section Error! Reference source not found.. 
Each AE should be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as 
additional AEs.  If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an 
AE(s).  Changes in laboratory test values are only considered AEs if they are judged to be 
clinically significant (i.e., if some action or intervention is required or if the investigator judges 
the change to be beyond the range of normal physiological fluctuation).  If abnormal laboratory 
test values are the result of pathology for which there is an overall diagnosis (e.g., increased 
creatinine levels in renal failure), only the diagnosis should be reported as an AE. 
Elective procedures (surgeries or therapies) that were scheduled prior to the start of AE 
collection are not considered AEs.  These elective procedures should not be recorded as AEs, but 
should be documented in the subject’s source documents as elective (e.g., elective periodontal 
surgery).  However, if a pre-planned procedure is performed early (e.g., as an emergency) 
because of a worsening of the preexisting condition, the worsening of the condition should be 
captured as an AE. 
11.7. 
Reporting Serious Adverse Events 
Any AE the investigator considers serious according to the previously described criteria must be 
reported within 24 hours from the time the site personnel first learn about the event.  The eCRF 
system within the clinical database is the preferred method of reporting an SAE.  
To report the SAE, the investigator will complete the SAE form in the clinical database and 
submit to BSWRI Safety (Refer to Table 5) within 24 hours of awareness.  If the clinical 
database is down for any reason, the manual SAE forms should be used; however, sites are 
responsible for ensuring the information on the manual SAE forms is entered into the clinical 
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Table 5: 
SAE Reporting Contact Information 
BSWRI Safety Hotline North America 
Safety Hotline:  
Safety Fax:  
E-mail: 
  
For questions regarding SAE reporting, contact your study manager, monitor, or BSWRI 
Safety. 
Follow-Up Reports 
The investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies. 
Within 24 hours of receipt of new information, the SAE form should be updated within the 
clinical database and submitted along with any supporting documentation (e.g., subject discharge 
summary or autopsy reports) to BSWRI Safety NA (refer to Table 5).  If the clinical database is 
down for any reason, the manual SAE forms should be used; however, sites are responsible for 
ensuring the updated information on the manual SAE forms is entered into the clinical database 
once available.  
The Sponsor or designee will notify regulatory agencies of any fatal or life-threatening 
unexpected events associated with the use of the study drug as soon as possible but no later than 
7 calendar days after the initial receipt of the information.  Initial notification will be followed by 
a written report within the timeframe established by the appropriate regulatory agency.  For other 
SAEs that do not meet the fatal or life-threatening unexpected criteria, but are reported to be 
associated with the use of the study drug, BSWRI or designee will notify the appropriate 
regulatory agencies in writing within the timeframe established by those regulatory agencies.  
BSWRI or designee will provide copies of any reports to regulatory agencies regarding serious 
and unexpected SAEs to the investigators for review and submission to their institutional review 
board (IRB) or Ethics Committee (EC), as appropriate.  
Principal investigators are responsible for informing their IRB/EC of any SAEs at their site.  
SAE correspondence with regulatory authorities or IRBs/ECs must be submitted to the Sponsor 
or designee for recording in the study file. 
These events will be reviewed on a regular basis in aggregate and will be reported in an 
expedited manner if a safety signal is detected.  Regular safety study updates will be reported to 
regulatory authorities according to local guidelines. 


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12. 
STATISTICS 
12.1. 
Sample Size 
A total sample of 360 individuals (180 in each arm) would provide at least 80% power to detect a 
relative risk reduction of 40% in the rate of positive NP samples when the anticipated rate of 
positive conversion among those taking hydroxychloroquine is approximately 30%.  
The power calculation, which was based on Pearson Chi Square test, assumes the following: 
• 
One-sided Type I error rate of 0.05 
• 
Anticipated positive NP samples rate of 30% in the clinical arm 
• 
A 40% lower risk of a positive NP sample comparing the hydroxychloroquine group vs the 
controls 
• 
Loss to follow-up rate of 15% 
12.1.1. 
Efficacy Variables 
Result of COVID-19 weekly nasopharyngeal (NP) test . 
12.1.2. 
Safety Variables 
The safety variables include results of vital sign measurements, adverse events, and serious 
adverse events. 
12.2. 
Statistical Analyses 
A statistical analysis plan (SAP) detailing the analyses will be developed prior to the database 
lock.  All statistical analyses and data summaries will be performed using SAS® (Version 9.1 or 
higher) or other validated software.  The SAP will serve as the final arbiter of all statistical 
analyses.  Data will be summarized overall using descriptive statistics.  Continuous data will be 
summarized with number of subjects (n), mean, median, minimum, maximum, relevant quartiles, 
standard deviation, coefficient of variation, and geometric mean (where applicable).  Categorical 
data will be summarized using frequency counts and percentages. Chi Square or Fisher exact test 
will be used for comparing binary outcomes between treatment and control groups. Continuous 
variables will be compared between the study groups by means of two sample T test or 
Wilcoxon-rank-sum test. 
12.2.1. 
Primary Analysis of Efficacy 
All subjects who received at least one dose of study medication, will be used as the primary 
population for assessment of efficacy. The proportion of people whose NP sample becomes 
positive at least once during the trial will be compared between the study groups using Chi 
square or Fisher exact test. Survival analysis will be utilized to estimate the potential effects of 
hydroxychloroquine on COVID-19 free survival times. We will apply generalized linear mixed 
models to compare the positive conversion rate of COVID-19 between the study arms while 
controlling for other confounding factors. AIC and BIC criteria will be used to choose an 
appropriate covariance structure between the measurements collected at consecutive visits. An 


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interaction effect between time and study group will be added to the model to evaluate whether 
the relative risk of a positive conversion changes from visit to visit.  


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB/EC review, and regulatory inspections, by providing direct access to 
all study records.  In the event of an audit, the principal investigator agrees to allow the Sponsor, 
representatives of the Sponsor, the US Food and Drug Administration (FDA), and other relevant 
regulatory authorities access to all study records. 
The principal investigator should promptly notify the Sponsor or designee of any audits 
scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to the Sponsor or designee. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1. 
Quality Assurance 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
BSWRI may conduct a quality assurance audit of the investigator’s clinical site, including 
CTM/IMP storage facilities.   
14.2. 
Financial Disclosure  
Principal investigators and sub-investigators are required to provide financial disclosure 
information prior to starting the study.  In addition, the principal investigator and sub-
investigators must provide the Sponsor or designee with updated information, if any relevant 
changes occur during the course of the investigation and for one year following the completion 
of the study. 
No potential investigator who has a vested financial interest in the success of this study may 
participate in this study. 
14.3. 
Sponsor Obligations  
The Sponsor or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the Screening process.  In addition, in the absence 
of specific arrangements, the Sponsor or designee is not financially responsible for treatment of 
the subject’s underlying disease. 
14.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R1) 
8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents 
to the Sponsor or designee, which include but are not limited to the following: 
 An original investigator-signed investigator agreement page of the protocol;  
 The IRB/EC approval of the protocol; 
 The IRB- or EC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study that 
is to be provided to the subject or legal guardians; 
 A Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572; 
 Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
are accurate and current; 
 Completed financial disclosure forms (Section 14.2) to allow the Sponsor or designee 
to submit complete and accurate certification or disclosure statements required under 
US Title 21 CFR 54.  In addition, the investigators must provide to the Sponsor or 


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designee a commitment to update this information promptly if any relevant changes 
occur during the course of the investigation and for 1 year following the completion 
of the study; 
 Laboratory certifications and normal ranges for any laboratories used by the site for 
the conduct of this study. 
14.5. 
Clinical Study Insurance 
In accordance with the respective national drug laws, the Sponsor has taken out subject liability 
insurance for all subjects who give their consent and enroll in this study.  This insurance covers 
potential fatalities, physical injuries, or damage to health that may occur during the clinical 
study. 
14.6. 
Use of Information  
All information regarding hydroxychloroquine supplied by the Sponsor to the investigator is 
privileged and confidential.  The investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from the Sponsor.  Furthermore, the 
investigator is obligated to provide the Sponsor with complete data obtained during the study.  
The information obtained from the clinical study will be used towards the development of 
hydroxychloroquine/azithromycin and may be disclosed to regulatory authorities, other 
investigators, corporate partners, or consultants as required. 


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15. 
ETHICS 
15.1. 
Institutional Review Board (IRB) or Ethics Committee Review 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB/EC before study start.  Each investigator must provide the Sponsor or 
its designee a signed and dated statement that the protocol and informed consent have been 
approved by the IRB/EC for that site before consenting subjects.  Prior to study initiation, the 
investigator is required to sign a protocol signature page confirming agreement to conduct the 
study in accordance with this protocol and to give access to all relevant data and records to the 
Sponsor, its designee, and regulatory authorities as required. 
The IRB/EC chairperson or designee must sign all IRB/EC approvals and must identify the 
IRB/EC by name and address, the clinical protocol, and the date approval and/or favorable 
opinion was granted. 
The principal investigator is responsible for obtaining reviews of the clinical research at intervals 
specified by the IRB/EC, but not exceeding 1 year.  The principal investigator must supply the 
Sponsor or designee with written documentation of reviews of the clinical research. 
15.2. 
Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (e.g., US Code of Federal Regulations Title 21, European Directive 2001/20/EC), 
and with the ethical principles laid down in the Declaration of Helsinki.  
The principal investigator agrees to conduct the study in accordance with the International 
Conference on Harmonization (ICH) for Guidance for Industry on Good Clinical Practice (GCP) 
ICH E6(R1) 
[http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_
Guideline.pdf] and the principles of the Declaration of Helsinki 
[http://www.wma.net/en/30publications/10policies/b3/].  The principal investigator must conduct 
all aspects of this study in accordance with all national, state, and local laws or regulations. 
15.3. 
Written Informed Consent 
Because the study will be conducted under a United States Investigational New Drug 
Application, a signed informed consent form, in compliance with Title 21 of the United States 
Code of Federal Regulations (CFR) Part 50, will be obtained from each subject before the 
subject enters the study.  For sites outside of the United States, the signed consent will be 
obtained in accord with local regulations, ICH E6 (R1), and principles of the Declaration of 
Helsinki.  An informed consent template may be provided by the Sponsor or designee to the 
investigators.  The consent must be reviewed by the Sponsor or designee before IRB/EC 
submission.  Once reviewed, the consent will be submitted by the principal investigator to his or 
her IRB/EC for review and approval before the start of the study.  If the informed consent form 
is revised during the course of the study, all participants affected by the revision must sign the 
revised IRB/EC-approved consent form. 


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Before enrollment, each prospective subject will be given a full explanation of the study and be 
allowed to read the approved informed consent form.  Once the principal investigator or designee 
is assured that the subject understands the implications of participating in the study, the subject 
will be asked to give consent to participate in the study by signing the informed consent form.  
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent.  Informed consent must be 
obtained before conducting any study-specific procedures (i.e., all of the procedures described in 
the protocol).  The process of obtaining informed consent must be documented in the subject 
source documents. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/EC, and a copy of the approved version and the notice 
of approval must be provided to the Sponsor’s designated monitor after IRB/EC approval. 
The principal investigator or designee will provide a copy of the informed consent form (signed 
copy to be provided per applicable law) to the subject and/or legal guardian.  The original form 
will be maintained in the subject’s medical records at the site. 
15.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality.  All records will be kept in a secure 
storage area with limited access.  Clinical information will not be released without the written 
permission of the subject (or the subject’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the 
IRB/EC. 
The principal investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to them for the purpose of the study.  Prior 
written agreement from the Sponsor or designee must be obtained for the disclosure of any said 
confidential information to other parties. 
15.5. 
Modification of the Protocol 
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments.  The FDA or other applicable regulatory agencies must be notified of protocol 
amendments.  The changes will become effective only after approval of the Sponsor, the 
investigator, the IRB/EC, and where necessary, the applicable regulatory agency.  In cases when 
the protocol is modified to enhance subject safety, changes may be implemented and the 
amendment must be immediately submitted to the IRB/EC. 
The investigator is responsible for informing the IRB/EC of all problems involving risks to 
subjects according to national legislation.  In case of urgent safety measures, the Sponsor will 
immediately notify the investigators and relevant regulatory agencies, including FDA in accord 
with 21 CFR 312.32. 


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15.6. 
Protocol Deviations 
The principal investigator or designee must document any protocol deviation.  The IRB/EC must 
be notified of all protocol deviations in a timely manner by the principal investigator or designee 
as appropriate.  Protocol deviations will be documented by the responsible monitor during 
monitoring visits, and those observations will be communicated to the investigator. 
If there is an immediate hazard to a subject the principal investigator may deviate from the 
protocol without prior Sponsor and IRB/EC approval.  The Sponsor and IRB/EC must be 
notified of the deviation. 


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Retention of Records 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).  Records will be retained for at least 2 years after the last marketing application 
submission or 2 years after formal discontinuation of the clinical development of the 
investigational product.  If the investigator withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person willing to accept the responsibility.  The 
Sponsor must be notified in writing if a custodial change occurs.  
16.2. 
Case Report Forms 
All case report form data will be entered in paper or electronic forms at the investigational site.  
A 21 CFR Part 11 compliant Electronic Data Capture system (EDC) will be used to capture data 
electronically for all subjects. 


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17. 
PUBLICATION POLICY 
The Sponsor supports communication and publication of study results whatever the findings of 
the study.   
The Sponsor reserves the right to review all planned communications and manuscripts based on 
the results of this study.  This reservation of the right is not intended to restrict or hinder 
publication or any other dissemination of study results, but to allow the Sponsor to confirm the 
accuracy of the data, to protect proprietary information, and to provide comments based on 
information that may not yet be available to the study investigators.  The Sponsor also 
encourages disclosure of any conflict of interest from all authors or investigators when 
manuscripts are submitted for publication.  Those individuals, who have contributed greatly to 
this study, including lead external advisors and select principal investigators, may serve on any 
potential publications committee for the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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18 
APPENDICES 
18.1 
Appendix I: Registry for Screened and Not Randomized 
For healthcare workers who have been screened and who would have qualified as eligible 
subjects but decline participation because of personal choice or logistical reasons, a registry will 
be offered with the same baseline data collection, schedule of NP sampling, and capture of 
outcomes. This will serve as a form of community surveillance for the medical center and will 
have a sample size that will not be pre-specified and limited only by the availability of NP 
COVID-19 sampling.  For those who develop a positive NP test, the current guidance from the 
medical center administration and in concert with guidance from the U.S Federal Government, 
State and Local Authorities, Centers for Disease Control, and State and Local Health 
Departments, will all be applied in terms of next steps in monitoring and control of COVID-19 
viral spread. 
 
 
 
 
 
 
 
 


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18.2 
Appendix II: Cough Visual Analog Scale 
 
 


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18.3 
 
Appendix III: Exposure Assessment Questionnaire 
 
 
Exposure Questions                                                                   Visit:                                                                           Date 
# 
Question 
Details 
Comments 
1 
Number of shifts worked in the last 7d 
(in ICU/ED, +other COVID-19 unit) 
 
Number of hours 
worked in last 7 d? 
(in ICU/ED,  +COVID 
unit) 
 
 
2 
Were you present in the room for a 
procedure likely to generate higher 
concentrations of respiratory secretions 
or aerosols1? 
□ no 
 
□ 
yes 
If yes: 
List details 
(procedures, 
frequency, 
duration, 
etc.) 
 
3 
Did you have extensive body contact 
with a +COVID-19 pt (e.g. rolling the 
patient, assisting in ADLs)? 
□ no 
 
□ 
yes 
If yes: 
List details 
(activity, 
frequency, 
duration, 
etc.) 
 
4 
Did you have prolonged close contact 
with a suspected/confirmed +COVID-19 
pt (within 6 feet for > 15 min 
cumulatively in 1 or more shifts)? 
□ no 
 
□ 
yes 
If yes: 
Were you in 
contact with 
secretions 
and/or 
excretions? 
□ no 
 
□ 
yes 
If Yes, did 
secretions 
contact 
unprotected: 
 Mouth 
 Eyes 
 Nose 
 hands 
 
1 Examples:  CPR, manual respiration, intubation, extubation, bronchoscopy, nebulizer therapy, or sputum induction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Staff initials:____________ 


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Exposure Questions -continued                                                                  Visit:                                                                           Date 
# Question 
Details Comments 
 
 
5 
Do you feel your PPE has been 
adequate? 
□ no 
 
□ yes 
If no: 
Please 
describe: 
 
6 
Did you have unprotected exposures 
not described above (eg incomplete 
PPE for any duration with COVID19 
patient): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         Staff initials:___________


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19 
REFERENCES 
1 Bedford J, Enria D, Giesecke J, Heymann DL, Ihekweazu C, Kobinger G, Lane 
HC, Memish Z, Oh MD, Sall AA, Schuchat A, Ungchusak K, Wieler LH; 
WHO Strategic and Technical Advisory Group for Infectious Hazards. 
COVID-19: towards controlling of a pandemic. Lancet. 2020 Mar 17. pii: 
S0140-6736(20)30673-5. doi:10.1016/S0140-6736(20)30673-5. [Epub ahead 
of print] PubMed PMID: 32197103 
2 https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-
they-happen 
3 Tran DH, Sugamata R, Hirose T, Suzuki S, Noguchi Y, Sugawara A, Ito F, 
Yamamoto T, Kawachi S, Akagawa KS, Ōmura S, Sunazuka T, Ito N, 
Mimaki M, Suzuki K. Azithromycin, a 15-membered macrolide antibiotic, 
inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus 
internalization process. J Antibiot (Tokyo). 2019 Oct;72(10):759-768. doi: 
10.1038/s41429-019-0204-x. Epub 2019 Jul 12. PubMed PMID: 31300721. 
4 Zeng S, Meng X, Huang Q, Lei N, Zeng L, Jiang X, Guo X. Spiramycin and 
azithromycin, safe for administration to children, exert antiviral activity 
against enterovirus A71 in vitro and in vivo. Int J Antimicrob Agents. 2019 
Apr;53(4):362-369. doi: 10.1016/j.ijantimicag.2018.12.009. Epub 2018 Dec 
30.  PubMed PMID: 30599241. 
5 Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, 
Mancia Leon WR, Krencik R, Ullian EM, Spatazza J, Pollen AA, Mandel-
Brehm C, Nowakowski TJ, Kriegstein AR, DeRisi JL. Zika virus cell 
tropism in the developing human brain and inhibition by azithromycin. Proc 
Natl Acad Sci U S A.  2016 Dec 13;113(50):14408-14413. Epub 2016 Nov 
29. PubMed PMID: 27911847; PubMed Central PMCID: PMC5167169. 
6 Porter JD, Watson J, Roberts LR, Gill SK, Groves H, Dhariwal J, Almond MH, 
Wong E, Walton RP, Jones LH, Tregoning J, Kilty I, Johnston SL, Edwards 
MR. Identification of novel macrolides with antibacterial, anti-inflammatory 
and type I and III IFN-augmenting activity in airway epithelium. J 
Antimicrob Chemother. 2016 Oct;71(10):2767-81. doi: 10.1093/jac/dkw222. 
Epub 2016 Jul 25. PubMed PMID: 27494903; PubMed Central PMCID: 
PMC5031920. 
7 Guo Y, Guo R, Zhou Q, Sun C, Zhang X, Liu Y, Liu Q. Chlamydiaphage 
φCPG1 Capsid Protein Vp1 Inhibits Chlamydia trachomatis Growth via the 
Mitogen-Activated Protein Kinase Pathway. Viruses. 2016 Apr 14;8(4):99. 
                                                 


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doi: 10.3390/v8040099. PubMed PMID: 27089359; PubMed Central 
PMCID: PMC4848593. 
8 Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses 
in bronchial epithelial cells. Eur Respir J. 2010 Sep;36(3):646-54. doi: 
10.1183/09031936.00095809. Epub 2010 Feb 11. PubMed PMID: 20150207. 
9 Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect 
of hydroxychloroquine in preventing infection and progression. J Antimicrob 
Chemother. 2020 Mar 20. pii: dkaa114. doi: 10.1093/jac/dkaa114. [Epub 
ahead of print] PubMed PMID: 32196083. 
10 Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines Against 
Coronavirus Disease 2019 (COVID-19): Chloroquine or 
Hydroxychloroquine. Int J Antimicrob Agents. 2020 Mar 16:105945. doi: 
10.1016/j.ijantimicag.2020.105945. [Epub ahead of print] PubMed PMID: 
32194152. 
11 Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral 
effects of chloroquine against coronavirus: what to expect for COVID-19? 
Int J Antimicrob Agents. 2020 Mar 11:105938. doi: 
10.1016/j.ijantimicag.2020.105938. [Epub ahead of print] PubMed PMID: 
32171740. 
12 Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song 
C, Zhan S, Lu R, Li H, Tan W, Liu D. 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 Infect Dis. 2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237. 
[Epub ahead of print] PubMed PMID:32150618. 
13 Biot C, Daher W, Chavain N, Fandeur T, Khalife J, Dive D, De Clercq E. 
Design and synthesis of hydroxyferroquine derivatives with antimalarial and 
antiviral activities. J Med Chem. 2006 May 4;49(9):2845-9. PubMed PMID: 
16640347. 
14 Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of 
COVID‐19: results of an open‐label non‐randomized clinical trial. 
International Journal of Antimicrobial Agents – In Press 17 March 2020 – 
DOI : 10.1016/j.ijantimicag.2020.105949 

SAP_001.pdf: 
 
A Prospective Clinical Study of Hydroxychloroquine in the 
Prevention of SARS-COV-2 (COVID-19) Infection in Health 
Care Workers after High-Risk Exposures 
 
Protocol Version 1.4 – 28-MAY-2020 
 
Statistical Analysis Plan 
 
NCT04333225 
 
ClinicalTrials.gov Submission Date 02-AUG-2021 


1 
 
 
Table of Contents 
1. 
Introduction ............................................................................................................................. 2 
2. 
Study design ............................................................................................................................ 3 
2.1. 
Sample size calculation .................................................................................................... 3 
3. 
Aims and objectives................................................................................................................. 4 
3.1. 
Objectives ......................................................................................................................... 4 
3.2. 
Primary Objective ............................................................................................................ 4 
3.3. 
Secondary Objective ........................................................................................................ 4 
4. 
Endpoints ................................................................................................................................. 4 
4.1. 
Primary Efficacy Endpoint ............................................................................................... 4 
4.2. 
Secondary Efficacy Endpoints ......................................................................................... 4 
4.3. 
Exploratory Efficacy Endpoints ....................................................................................... 4 
4.4. 
Safety Endpoints .............................................................................................................. 5 
5. 
Populations to be analyzed ...................................................................................................... 5 
5.1. 
Intention-to-treat (ITT) ..................................................................................................... 5 
5.2. 
Per Protocol (PP) .............................................................................................................. 5 
6. 
Analyses................................................................................................................................... 5 
6.1. 
Primary Analysis of Efficacy ........................................................................................... 5 
7. 
Missing data ............................................................................................................................. 6 
8. 
References ............................................................................................................................... 6 
 
 
 
 
 
 
 
 
 


2 
 
1. Introduction 
New major epidemic foci of coronavirus disease 2019 (COVID-19), have been identified and are 
rapidly expanding in Europe, North America, Asia, and the Middle East, with the first confirmed 
cases being identified in African and Latin American countries.1 By March 16, 2020, the number 
of cases of COVID-19 outside China had increased drastically and the number of affected 
countries, states, or territories reporting infections to WHO was 143.1 On the basis of”alarming 
levels of spread and severity, and by the alarming levels of inaction”, on March 11, 2020, the 
Director-General of WHO characterized the COVID-19 situation as a pandemic. 
To respond to COVID-19, many countries are using a combination of containment and 
mitigation activities with the intention of delaying major surges of patients and levelling the 
demand for hospital beds, while protecting the most vulnerable from infection, including elderly 
people and those with comorbidities.  
SARS-CoV-2, like other emerging high-threat pathogens, has infected health-care workers in 
China and several other countries. Epidemiological records in China suggest that up to 85% of 
human-to-human transmission has occurred in family clusters and that 2055 health-care workers 
have become infected, demonstrating that patient to healthcare worker is tractable. 
From studies of viral shedding in patients with mild and more severe infections, shedding seems 
to be greatest during the early phase of disease. The role, if any, of asymptomatic carriers in 
transmitting infection is not yet completely understood.  Pre-symptomatic infectiousness is a 
concern among healthcare workers and many countries are now using 1–2 days of symptom 
onset as the start day for contact identification. 
Hydroxychloroquine and chloroquine are antimalarial agents that have been used for decades for 
both active treatment and prophylaxis.  Several sources of data and rationale have been 
developed to support the notion that hydroxychloroquine may have activity against COVID-19.2 
3 4 5 6 
A prospective open-label trial from France evaluated the efficacy of hydroxychloroquine alone 
and in combination with azithromycin in symptomatic, hospitalized patients with positive 
COVID-19. The study composed of 36 patients, out of which 20 received 600 mg of 
hydroxychloroquine daily for 10 days. The remaining 16 patients who either refused the 
treatment or were not eligible to receive it because they were at other centers in France were 
considered as the control group.  The primary endpoint was virological clearance of NP sampling 
at six days.  Six patients who received hydroxychloroquine contributed incomplete NP sampling 
to the analysis because three worsened and were transferred to the intensive care unit, one patient 
died, one patient left the hospital, and one patient could not tolerate the study medication due to 
nausea.  At day 6, 70% of hydroxychloroquine-treated patients were virologically cured 
comparing with 12.5% in the control group (p= 0.001). The investigators found the rate of 
recovery in patients taking hydroxychloroquine to be approximately 5 times more than that of 
patients in the control group.   
Finally, research gaps about COVID-19 should be addressed in prospective, clinical trials as 
proposed in this study.  The present study will leverage information concerning the infectious 
curve associated with COVID-19 exposure as illustrated in the figure. 
 


3 
 
 
 
 
2. Study design 
This prospective open label trial will study the safety, tolerability, and efficacy of 
hydroxychloroquine in qualified health care workers. Qualified individuals will be administered 
hydroxychloroquine twice a day on day 1 (two 200 mg twice a day) and once a week (two 200 
mg) afterwards for a total of 7 weeks. Dose de-escalation is permitted during the study if 
indicated clinically. All study individuals will follow the same visit and assessment schedule.  
Following study enrollment, participants will be scheduled to be assessed in person at Days 7, 
14, 21, 28, 35, 42 and 49. 
2.1. Sample size calculation 
A total sample of 360 individuals (180 in each arm) would provide at least 80% power to detect a 
relative risk reduction of 40% in the rate of positive NP samples when the anticipated rate of 
positive conversion among those taking hydroxychloroquine is approximately 30%.  
The power calculation, which was based on Pearson Chi Square test, assumes the following: 
 One-sided Type I error rate of 0.05 
 Anticipated positive NP samples rate of 30% in the clinical arm 
 A 40% lower risk of a positive NP sample comparing the hydroxychloroquine group vs 
the controls 
 Loss to follow-up rate of 15% 


4 
 
3. Aims and objectives 
3.1. Objectives 
For healthcare workers with 
 One day or more of exposure to suspected and/or positive COVID-19 patients, including 
but not limited to those working in the Emergency Department or Intensive Care Unit. 
OR 
 Unprotected exposure to a known positive COVID-19 patient within 72 hours of 
screening. 
 
3.2. Primary Objective 
To assess the efficacy of hydroxychloroquine 400 mg twice a day (two 200 mg tablets twice a 
day) on day 1 followed by two 200 mg tablets once a week for a total of 7 weeks in the 
prevention of COVID-19 infection  
 
3.3. Secondary Objective 
To compare the rate of COVID-19 positive conversion among emergency department workers 
versus intensive care unit workers 
 
4. Endpoints 
4.1. Primary Efficacy Endpoint 
Rate of COVID-19 positive conversion on weekly nasopharyngeal (NP) sampling 
4.2. Secondary Efficacy Endpoints 
Time-to-first clinical event consisting of a persistent change for any of the following: 
 One positive NP sample 
 Common clinical symptoms of COVID-19 infection including fever, cough, and 
shortness of breath 
 Less common signs and symptoms of COVID-19 infection including headache, muscle 
pain, abdominal pain, sputum production, and sore throat 
 
4.3. Exploratory Efficacy Endpoints 
Time-to-first clinical worsening event consisting of any of the following: 
 Hospitalization for COVID-19 infection 
 Intensive care unit admission for COVID-19 infection 
 All cause death 


5 
 
4.4. Safety Endpoints 
Frequency, intensity, and relationship to study drug of adverse events and serious adverse events, 
change from baseline in body temperature. 
 
5. Populations to be analyzed 
5.1. Intention-to-treat (ITT) 
 All subjects who received the study drug 
 All subjects who participated in at least one post-baseline assessment 
 
5.2. Per Protocol (PP) 
All randomised study subjects completing the whole study period (complete cases) 
 
6. Analyses 
All statistical analyses and data summaries will be performed using SAS® (Version 9.1 or 
higher) or other validated software.  The SAP will serve as the final arbiter of all statistical 
analyses.  Data will be summarized overall using descriptive statistics.  Continuous data will be 
summarized with number of subjects (n), mean, median, minimum, maximum, relevant quartiles, 
standard deviation, coefficient of variation, and geometric mean (where applicable).  Categorical 
data will be summarized using frequency counts and percentages. Chi Square or Fisher exact test 
will be used for comparing binary outcomes between treatment and control groups. Continuous 
variables will be compared between the study groups by means of two sample T test or 
Wilcoxon-rank-sum test. 
 
6.1. Primary Analysis of Efficacy 
All subjects who received at least one dose of study medication, will be used as the primary 
population for assessment of efficacy. The proportion of people whose NP sample becomes 
positive at least once during the trial will be compared between the study groups using Chi 
square or Fisher exact test. Survival analysis will be utilized to estimate the potential effects of 
hydroxychloroquine on COVID-19 free survival times. We will apply generalized linear mixed 
models to compare the positive conversion rate of COVID-19 between the study arms while 
controlling for other confounding factors. AIC and BIC criteria will be used to choose an 
appropriate covariance structure between the measurements collected at consecutive visits. An 
interaction effect between time and study group will be added to the model to evaluate whether 
the relative risk of a positive conversion changes from visit to visit. 
 


6 
 
7. Missing data 
If the proportions of missing data are above 5%, multiple imputation methods will be used to 
construct complete data sets under different missing patterns. Otherwise, linear mixed models 
will be used that allow for presence of missing values in the data. 
 
8. References 
1 Bedford J, Enria D, Giesecke J, Heymann DL, Ihekweazu C, Kobinger G, Lane HC, 
Memish Z, Oh MD, Sall AA, Schuchat A, Ungchusak K, Wieler LH; WHO 
Strategic and Technical Advisory Group for Infectious Hazards. COVID-19: 
towards controlling of a pandemic. Lancet. 2020 Mar 17. pii: S0140-
6736(20)30673-5. doi:10.1016/S0140-6736(20)30673-5. [Epub ahead of print] 
PubMed PMID: 32197103 
2 Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of 
hydroxychloroquine in preventing infection and progression. J Antimicrob 
Chemother. 2020 Mar 20. pii: dkaa114. doi: 10.1093/jac/dkaa114. [Epub ahead of 
print] PubMed PMID: 32196083. 
3 Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines Against Coronavirus 
Disease 2019 (COVID-19): Chloroquine or Hydroxychloroquine. Int J Antimicrob 
Agents. 2020 Mar 16:105945. doi: 10.1016/j.ijantimicag.2020.105945. [Epub ahead 
of print] PubMed PMID: 32194152. 
4 Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of 
chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob 
Agents. 2020 Mar 11:105938. doi: 10.1016/j.ijantimicag.2020.105938. [Epub ahead 
of print] PubMed PMID: 32171740. 
5 Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan 
S, Lu R, Li H, Tan W, Liu D. 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 Infect Dis. 2020 
Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237. [Epub ahead of print] PubMed 
PMID:32150618. 
6 Biot C, Daher W, Chavain N, Fandeur T, Khalife J, Dive D, De Clercq E. Design and 
synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. 
J Med Chem. 2006 May 4;49(9):2845-9. PubMed PMID: 16640347.