Conditions: COVID-19
Keywords: Hydroxychloroquine Coronavirus Infections Novel Coronavirus Protective agents Prophylaxis Chemoprophylaxis Severe Acute Respiratory Syndrome Respiratory Distress Syndrome, Adult Acute Lung Injury Virus Diseases Lung Diseases Respiratory Tract Diseases Respiration Disorders Lung Injury Coronaviridae Infections Nidovirales Infections RNA Virus Infections Respiratory Tract Infections Antimalarials Antiprotozoal Agents Antiparasitic Agents Anti-Infective Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antirheumatic Agents Chloroquine Chloroquine diphosphate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1360
Healthy volunteers: yes

Brief summary:
This is a double blind, placebo controlled study in approximately 2,000 health care workers at risk for being exposed to COVID-19. Eligible participants will be randomly assigned (1:1) to either treatment group (HCQ) or placebo in a double-blind fashion. Course of treatment is 30 days.

Detailed description:
This is a double blind, placebo controlled study in approximately 2,000 health care workers at risk for being exposed to COVID-19. Eligible participants will be randomly assigned (1:1) to either treatment group (HCQ) or placebo in a double-blind fashion. After enrollment, baseline assessments will include nasopharyngeal swab for COVID-19 and a blood sample to detect seroconversion to COVID-19. For convenience, follow-up will be performed weekly through a direct to participant portal. A call center will provide support for any missed visits. Follow-up includes screening for any COVID-19 clinical infections, other respiratory infections, clinical events, adverse events, and Quality of Life (QoL) assessments. Course of treatment is 30 days. Participants are followed via survey weekly. At the end of treatment participants will return for repeat nasopharyngeal swab for COVID-19 and a blood sample to detect seroconversion to COVID-19. There will be one last contact at 8 weeks (2 months) from baseline.

Arms:
arm 1: Hydroxychloroquine tablet 600mg bid loading dose on day 1 followed by 400mg on days 2-30. arm 2: Matching placebo tablets

Interventions: intervention 1: Hydroxychloroquine intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: oral self administered tablet intervention 2: oral self administered tablet

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL 
HERO-HCQ Protocol [v3.0] 
 
 
1 
 
 
 
Healthcare Worker Exposure Response and Outcomes of 
Hydroxychloroquine Trial (HERO-HCQ Trial) 
 
 
 
 
Protocol Number:  
 
COVID-19-2020-001 
 
IND Number: 
 
149266 
Principal 
Investigator/IND 
Sponsor: 
Adrian Hernandez, MD 
Duke Clinical Research Institute 
300 West Morgan St. 
Durham, NC 27701 
Phone: 919-668-7515 
Email: adrian.hernandez@duke.edu 
Co-Principal 
Investigator 
Susanna Naggie, MD 
Duke Clinical Research Institute 
300 West Morgan St. 
Durham, NC 27701 
Phone: 919-684-2584 
Email: susanna.naggie@duke.edu 
Data Coordinating 
Center Investigator 
Kevin Anstrom, PhD 
Duke Clinical Research Institute 
300 West Morgan St. 
Durham, NC 27701 
Phone: 919-668-8902 
Email: kevin.anstrom@duke.edu 
Lead 
 
Funding Agency: 
 
Patient-Centered Outcomes Research Institute 
Version: 
 
3.0 
Date: 
7/07/2020 
 
 


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HERO-HCQ Protocol [v3.0] 
 
 
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Statement of Compliance 
 
This trial will be conducted in compliance with the International Council for Harmonisation 
(ICH) E6(R2) guideline for Good Clinical Practice (GCP), and the applicable regulatory 
requirements from the United States Code of Federal Regulations (CFR), including 45 CFR 46 
(Human Subjects Protection); 21 CFR 312 (Investigational New Drug); 21 CFR  50 (Informed 
Consent), and 21 CFR 56 (Institutional Review Board [IRB]). 
All individuals who are responsible for the conduct, management, or oversight of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
 
 
 


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HERO-HCQ Protocol [v3.0] 
 
 
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Site Principal Investigator Statement 
 
I have read the protocol, including all appendices, and the package insert/product label, and I 
agree that the protocol contains all necessary details for my staff and me to conduct this study as 
described. I will personally oversee the conduct of this study as outlined herein and will make a 
reasonable effort to complete the study within the time designated. I agree to make all reasonable 
efforts to adhere to the attached protocol. 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by the sponsor or the sponsor’s representative. I will discuss this 
material with study personnel to ensure that they are fully informed about the efficacy and safety 
parameters and the conduct of the study in general. I am aware that, before beginning this study, 
the Institutional Review Board (IRB), or equivalent oversite entity must approve this protocol in 
the clinical facility where it will be conducted. 
I agree to obtain informed consent from participants, as required by the IRB of record and 
according to government regulations and ICH guidelines. I further agree to report to the sponsor 
or its representative any adverse events in accordance with the terms of this protocol and the U.S. 
Code of Federal Regulations, Title 21, part 312.64, ICH GCP 4.11. I further agree to ensure the 
study is conducted in accordance with the provisions as stated and will comply with the 
prevailing local laws and customs. 
 
 
 
 
 
Site Principal Investigator Name (Print) 
 
 
 
 
 
 
 
Site Principal Investigator Signature 
 
Date 


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HERO-HCQ Protocol [v3.0] 
 
 
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Table of Contents 
1. 
Protocol Summary ........................................................................................................11 
1.1. 
Synopsis ..........................................................................................................................11 
1.2. 
Schema ............................................................................................................................13 
2. 
Introduction ...................................................................................................................14 
2.1. 
Study Rationale ...............................................................................................................14 
2.2. 
Background .....................................................................................................................14 
2.3. 
Benefit/Risk Assessment ................................................................................................15 
2.3.1. 
Risk Assessment .............................................................................................................15 
2.3.2. 
Benefit Assessment .........................................................................................................16 
3. 
Objectives and Endpoints ............................................................................................17 
4. 
Study Design ..................................................................................................................18 
4.1. 
Overall Design ................................................................................................................18 
4.2. 
End of Study Definition ..................................................................................................18 
5. 
Study Population ...........................................................................................................19 
5.1. 
Inclusion Criteria ............................................................................................................19 
5.2. 
Exclusion Criteria ...........................................................................................................19 
5.3. 
Recruitment and Engagement .........................................................................................20 
5.3.1. 
Participant Recruitment ..................................................................................................20 
5.3.2. 
Participant Engagement ..................................................................................................20 
5.3.3. 
Participant Randomization Process.................................................................................20 
5.4. 
Screen Failures ................................................................................................................21 
6. 
Study Drug(s) ................................................................................................................22 
6.1. 
Hydroxychloroquine .......................................................................................................22 
6.1.1. 
Formulation, Appearance, Packaging, and Labeling ......................................................22 
6.1.2. 
Drug Dispensing, Storage, and Stability .........................................................................22 
6.1.3. 
Dosing and Administration .............................................................................................22 
6.1.4. 
Rationale for Selection of Dose ......................................................................................22 
6.2. 
Placebo ............................................................................................................................23 
6.2.1. 
Formulation, Appearance, Packaging, and Labeling ......................................................23 
6.2.2. 
Drug Dispensing, Storage, and Stability .........................................................................23 
6.2.3. 
Dosing and Administration .............................................................................................23 
6.2.4. 
Rationale for Selection of Dose ......................................................................................23 
6.3. 
Study Drug Accountability .............................................................................................23 
6.4. 
Concomitant Therapy .....................................................................................................24 
6.5. 
Dose Modification ..........................................................................................................24 
6.6. 
Intervention After the End of the Study..........................................................................25 
7. 
Participant Withdrawal/Termination and Study Termination ................................26 
7.1. 
Participant Withdrawal/Termination ..............................................................................26 
7.2. 
Premature Termination or Suspension of the Study .......................................................26 
7.3. 
Lost to Follow-up............................................................................................................26 
8. 
Study Assessments and Procedures.............................................................................28 
8.1. 
Schedule of Events..........................................................................................................28 


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8.1.1. 
Baseline (On-site, Day 0) ................................................................................................29 
8.1.2. 
Follow-Up .......................................................................................................................29 
8.1.3. 
Final Visit (Day 60 + 5 days - Remote) ..........................................................................30 
8.2. 
Clinical Assessments ......................................................................................................30 
8.3. 
Quality of Life and COVID Questionnaires ...................................................................30 
9. 
Safety Assessments ........................................................................................................32 
9.1. 
Adverse Events and Serious Adverse Events .................................................................32 
9.1.1. 
Collection Period for AE and SAE Information .............................................................32 
9.1.2. 
Assessing Causality of a Suspected Unexpected Serious Adverse 
Reaction (SUSAR) ..........................................................................................................33 
9.1.3. 
Reporting and Monitoring of SAEs ................................................................................33 
9.1.4. 
Events of Special Interest................................................................................................33 
9.2. 
Unanticipated Problem (UP) and Terminations..............................................................34 
9.2.1. 
Definition of Unanticipated Problem ..............................................................................34 
9.2.2. 
Reporting of an Unanticipated Problem .........................................................................35 
10. 
Statistical Considerations .............................................................................................36 
10.1. 
Statistical Hypotheses .....................................................................................................36 
10.1.1. Primary Hypothesis .........................................................................................................36 
10.1.2. Secondary Hypotheses ....................................................................................................36 
10.2. 
Sample Size Determination ............................................................................................36 
10.3. 
Randomization ................................................................................................................36 
10.4. 
Blinding ..........................................................................................................................36 
10.5. 
Populations for Analyses ................................................................................................37 
10.6. 
Statistical Analyses .........................................................................................................37 
10.6.1. General Considerations ...................................................................................................37 
10.6.2. Primary Endpoint ............................................................................................................37 
10.6.3. Secondary Endpoint(s) ....................................................................................................38 
10.6.4. Exploratory Analysis ......................................................................................................38 
10.6.5. Subgroup Analyses .........................................................................................................38 
10.6.6. Adherence and Retention Analysis .................................................................................38 
10.7. 
Interim Analyses .............................................................................................................39 
10.8. 
Data Safety Monitoring Board (DSMB) .........................................................................40 
11. 
Ethical Standards ..........................................................................................................41 
11.1. 
Institutional Review Board (IRB) ...................................................................................41 
11.2. 
Informed Consent Process ..............................................................................................41 
11.3. 
Participant and Data Confidentiality...............................................................................41 
11.4. 
Intended and Future Use of Stored Biosamples and Data ..............................................42 
11.5. 
Site Management and Quality Assurance .......................................................................42 
11.6. 
Site Monitoring ...............................................................................................................43 
12. 
Data Handling and Record Keeping ...........................................................................44 
12.1. 
Data Collection and Management Responsibilities ........................................................44 
12.2. 
Study Records Retention ................................................................................................45 
12.3. 
Protocol Deviations.........................................................................................................45 
12.4. 
Publication and Data Sharing Policy ..............................................................................46 


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13. 
Study Leadership ..........................................................................................................47 
14. 
Summary of Changes....................................................................................................48 
15. 
References ......................................................................................................................52 
 


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Abbreviations 
ACE 
Angiotensin-converting Enzyme 
AE 
Adverse Event 
AGEP 
Acute Generalized Exanthematous Pustulosis 
ARB 
Angiotensin II Receptor Blockers 
ARDS 
Acute Respiratory Distress Syndrome 
ARNI 
Angiotensin Receptor Neprilysin Inhibitor 
CCC 
Clinical Coordinating Center 
CONSORT 
Consolidated Standards of Reporting Trials 
DCC 
Data Coordinating Center 
DIC 
Disseminated Intravascular Coagulation 
DSMB 
Data Safety Monitoring Board 
DUA 
Data Use Agreement 
EC50 
Half Maximal Effective Concentration 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EE 
Emotional Exhaustion 
EOSI 
Event of Special Interest 
FAQs 
Frequently Asked Questions 
FDA 
Food and Drug Administration 
HCQ 
Hydroxychloroquine 
HCW 
Healthcare Worker 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 


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HERO-HCQ Protocol [v3.0] 
 
 
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ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 
IRB 
Institutional Review Board 
MBI 
Maslach Burnout Inventory 
MOI 
Multiplicity on Infection 
MOP 
Manual of Procedures 
NIH 
National Institute of Health 
OHRP 
Office for Human Research Protections 
PHI 
Personal Health Information 
PHQ 
Patient Health Questionnaire 
PROMIS 
Patient-reported Outcomes Measurement Information System 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
UP 
Unanticipated Problems 
 
 
 
 
 
 


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Table of Figures 
Figure 1: Data Flow Diagram ....................................................................................................... 44 
Figure 2: Operational Structure Diagram ..................................................................................... 47 
 


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List of Tables 
Table 1: Schedule of Events ......................................................................................................... 28 
 
 


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1. 
Protocol Summary 
1.1. 
Synopsis 
 
Title 
Healthcare Worker Exposure Response and Outcomes of 
Hydroxychloroquine Trial (HERO-HCQ Trial) 
Clinical study phase 
III 
Rationale 
Severe acute respiratory syndrome coronavirus 2 associated disease 
or COVID-19 is caused by a novel betacoronavirus, SARS-CoV-2, 
that was first isolated in January 2020 and has since caused a global 
pandemic unseen in decades in cases and mortality. [1, 2] At the 
time of initial protocol submission in April 2020, human vaccine 
clinical trials had just begun and experts predicted that a vaccine 
would not be available until April 2021 at the earliest, therefore 
new measures remain desperately needed to prevent the spread of 
disease.[3] In vitro studies suggest a potential moderate antiviral 
effect of  hydroxychloroquine (HCQ) and its well known safety 
profile and oral formulation make it an ideal drug candidate for 
prevention.  
Primary Objective 
 
To evaluate the efficacy of HCQ to prevent COVID-19 clinical 
infection in healthcare workers (HCWs)  
Secondary 
Objectives 
 
To evaluate the efficacy of HCQ to prevent viral shedding of 
SARS-CoV-2 among HCWs  
 
Evaluate safety and tolerability of HCQ 
Exploratory 
Objectives 
 
Evaluate SARS-CoV-2 seroconversion in participants taking 
HCQ 
 
Describe COVID-19 infectious complications in participants 
taking HCQ 
 
Describe time off from work for medical reasons in 
participants taking HCQ 
 
Describe Quality of Life (QoL) 
 
Describe experience of household contacts 
Intervention 
Treatment Group: Hydroxychloroquine 600 mg BID (two times 
a day) loading dose for 1 day, followed by 400 mg QD (once a 
day) for 29 days 
Control Group: placebo 
Study Design 
Eligible participants will be randomized (1:1), stratified by site, 
in a blinded fashion to either the treatment group (HCQ) or 
placebo.  Participants will receive a 30-day supply of study drug 
or placebo, depending on randomization arm.  There will be two 
on-site visits and four remote visits over an approximately 60 
day period during which participants will complete various QoL 
questionnaires, provide serum samples, and undergo COVID-19 
testing.    
Population 
Approximately 2,000 adult HCWs   


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Study Duration 
12 months 
Study Location 
Approximately 40 US PCORnet sites  
Key Inclusion 
Criteria 
 Healthcare worker age >18 years old  
 Currently working in any environment in which there is a risk of 
exposure to patients with COVID-19 infections (“healthcare 
worker”)   
Key Exclusion 
Criteria 
 Prior diagnosis of COVID-19 infection 
 Respiratory illness with new-onset fever (Temperature > 100°F) 
or ongoing cough or dyspnea within 14 days 
 Congenital prolonged QT syndrome 
 Current or planned use of QT prolonging drugs (see Section 
5.2) and other contraindicated medications 
 End stage renal disease 
 Current or planned use of the following for treatment or 
prevention of COVID-19 infection: 
o Hydroxychloroquine (study drug) or chloroquine 
o Azithromycin 
 Ventricular arrhythmias requiring medical treatment 
 Severe coronary artery disease or heart failure/cardiomyopathy 
with ongoing symptoms 
Sample Size 
Considerations 
A sample size of approximately 2,000 randomized participants is 
expected to provide 80% power to detect a relative 50% 
reduction in the risk of clinical infection with COVID-19 
assuming a control group risk of 5%.  
Statistical Analysis 
Plan for Primary 
Objective 
The primary objective will be assessed by the risk of clinical 
infection with COVID-19 at the end of the treatment period.  For 
the clinical infection with COVID-19 endpoint, a comparison of 
treatment and control groups will be conducted using a Fisher’s 
exact test. The primary measure of treatment effect will be based on 
a difference in proportions with the associated 95% confidence 
interval. A secondary analysis will be performed using a logistic 
regression model.  
Data Safety 
Monitoring Board 
(DSMB)  
Frequent DSMB reviews will be conducted to ensure the safety of 
study participants and evaluate the accumulating endpoint data by 
treatment group. Regular DSMB meetings will monitor the 
following parameters at a minimum: 
 Recruitment progress 
 Enrollment overall and by subgroups 
 Adherence, retention, and status of data collection 
 Serious adverse events  
Interim Analysis 
Given the rapid spread of COVID-19, it is expected that reviews of 
the study data will occur approximately weekly following the 
enrollment of the first participants. Formal interim reviews for 
efficacy will be based on the accrual of primary endpoint data. 


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1.2. 
Schema 
 
 


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HERO-HCQ Protocol [v3.0] 
 
 
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2. 
Introduction 
2.1. 
Study Rationale 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel betacoronavirus first 
isolated in January 2020 and has since caused a global pandemic unseen in decades with respect 
to the number of cases and overall mortality. [1, 2] The clinical disease related to SARS-CoV-2 
is referred to as COVID-19. Human vaccine clinical trials have just begun, but experts predict 
that a vaccine will not be available for 12-18 months, and new measures are desperately needed 
to prevent the spread of disease. [3] In vitro studies suggest a potential moderate antiviral effect 
of  hydroxychloroquine (HCQ) and its well known safety profile and oral formulation make it an 
ideal drug candidate for prevention.   
2.2. 
Background 
In December 2019, numerous patients in Wuhan, China were diagnosed with pneumonia caused 
by an unknown virus. By January 7, 2020, Chinese scientists had isolated SARS-CoV-2. This is 
a novel betacoronavirus closely related to severe acute respiratory syndrome coronavirus (SARS-
CoV-1). [2]  In the subsequent months the spread of the virus led to a global pandemic. As of 
March 31, 2020, there were approximately 803,313 confirmed COVID-19 cases resulting in 
39,014 deaths worldwide. [1] 
Healthcare workers have been disproportionately affected by the current pandemic. Over 3,300 
Chinese healthcare workers have been infected. In Spain 5,400 healthcare workers have become 
infected, accounting for 14% of the country’s total infections. In Brescia, the center of Italy’s 
outbreak, 10-15% of doctors and nurses have been infected and are unable to work. [4] In 
addition to potential exposure to infected patients, a critical shortage of personal protective 
equipment and respirators put healthcare professionals at even greater risk. [5] 
The virus continues to spread despite social distancing measures and travel restrictions. Human 
vaccine clinical trials have just begun, but experts predict that a vaccine will not be available for 
12-18 months, and new measures are desperately needed to prevent the spread of disease. [3] 
As of July 2020, multiple clinical trials have completed providing early guidance to clinical 
providers on management of COVID-19, particularly in the hospital setting. Two therapies, one 
investigational (remdesivir) and one that has been FDA approved for years (dexamethasone), 
have been reported to improve clinical disease and in the case of dexamethasone, mortality. [6, 
7] Numerous medications are currently under investigation including additional studies of 
remdesivir, lopinavir/ritonavir, chloroquine, HCQ, and numerous immunomodulatory agents. No 
therapies have been approved for pre- or post-exposure prophylaxis and clinical trials are 
currently underway. [8, 9] While the large RECOVERY trial has reported results from the HCQ 
arm and report no benefit from HCQ for therapy in the hospital setting, it remains unclear if there 
is a benefit from HCQ in the setting of pre- or post-exposure prophylaxis. 
In February 2020, Wang and his colleagues demonstrated potent in vitro activity of chloroquine 
against SARS-CoV-2 at low micromolar concentrations. This was consistent with prior data 
illustrating chloroquine’s activity against SARS-CoV-1 and MERS-CoV. [10] Liu et al and Yao 
et al have similarly reported micromolar concentration EC50 for hydroxychloroquine on SARS-
CoV-2. [11, 12] 


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HERO-HCQ Protocol [v3.0] 
 
 
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Both Chloroquine and HCQ are alkalinizing lysosomatrophic drugs that accumulate in 
lysosomes and block viral infection by increasing lysosomal pH, which is required for the 
virus/cell fusion. Coronavirus infectivity is extremely sensitive to pH, and increasing the pH 
inhibits virus/cell fusion. [13] They also interfere with the glycosylation of the cellular receptors 
of coronaviruses, including SARS-CoV-2. One of the benefit of chloroquine and HCQ function 
at both entry and post-entry stages of the infection. [10]  
In addition to the potential antiviral effect, hydroxychloroquine is a well-recognized 
immunomodulatory agent, currently used as a disease-modifying agent in autoimmune diseases 
including systemic lupus erythematosus. Use may prevent the severity of COVID-19 or attenuate 
the development of immune-mediated complications such as acute respiratory distress syndrome 
(ARDS). [14] ARDS is a potentially severe complication of COVID-19 infection. In the study of 
138 patients in Wuhan, ARDS developed in 20 percent after a median of eight days, and 
mechanical ventilation was implemented in 12.3 percent. [15] In another study of 201 
hospitalized patients with COVID-19 in Wuhan, 41 percent developed ARDS. Of note, age 
greater than 65 years, diabetes mellitus, and hypertension were all associated with development 
of ARDS. [16] 
Hydroxychloroquine has similar activity to chloroquine in prior studies examining its efficacy in 
treatment of MERS and SARS. It has a better safety and tolerability profile than chloroquine. [8] 
It has already been FDA approved for malaria prophylaxis and treatment of various autoimmune 
conditions including rheumatoid arthritis and lupus. It can be dosed orally in a once daily 
formulation, which would be ideal for prophylaxis. It has a long serum half-life and, if effective, 
protection should last beyond cessation of prophylaxis.  
2.3. 
Benefit/Risk Assessment 
The risks for participation in this study include taking study drug, phlebotomy blood draws, and 
nasopharyngeal swabs. The safety of HCQ is well known and the risk of taking the drug is 
particularly low given the short course of therapy.  There may be some benefit to the participant 
if the prophylactic therapy is effective and prevents transmission of infection and/or clinical 
disease. 
2.3.1. 
Risk Assessment 
Blood draw risks: Risks associated with drawing blood include momentary discomfort and/or 
bruising. Infection, excess bleeding, clotting, or fainting are also possible, although unlikely. 
Nasopharyngeal swab risks: Risks include mild irritation, insignificant local pain, and minor 
bleeding. 
Hydroxychloroquine risks: Hydroxychloroquine has been used clinically for years as a 
prophylactic and treatment for malaria, and in the United States more broadly for autoimmune 
conditions. The primary toxicity concerns include retinopathy, QTc prolongation, nausea, rash 
and bone marrow suppression. While toxicity is more common with long-term use as done for 
autoimmune conditions, it’s prudent to consider these risks.  Risks of HCQ include: 
 Retinopathy: The recommended maximum dose to limit toxicity is 5 mg/kg actual body 
weight per day. The retinopathy risks increases once the total exposure is >1000 g. The 


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HERO-HCQ Protocol [v3.0] 
 
 
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proposed dose of 600 mg BID on day 1 followed by 400 mg QD for 29 days does not 
exceed 20 g. Due to the finite therapy and the low total exposure, the risk for retinopathy 
is low and thus does not warrant a baseline eye exam.  
 QTc prolongation: QTc prolongation is a risk for chloroquine and thus may be a risk for 
HCQ, although the risk is believed to be lower. The risk of QTc prolongation is more 
likely an issue for HCQ when dosed with other concomitant medications that prolong 
QTc. For this reason, concomitant medications with high risk for QTc prolongation will 
be excluded as will congenital QTc prolongation syndromes.  
 Allergic rash: In approximately 1-5% of patients, an allergic rash develops. This pruritic 
eruption usually occurs after 1-2 weeks of dosing. Guidance will be provided to teams for 
managing allergic rash. 
 Nausea/diarrhea: Gastrointestinal symptoms may occur with higher doses and sometimes 
with daily dosing of HCQ. Dividing daily dosing BID or TID is a commonly used 
strategy to improve tolerance. Guidance will be provided to teams for managing nausea 
and diarrhea. 
 Severe hypoglycemia including loss of consciousness that could be life threatening has 
been reported in patients treated with or without antidiabetic medications.   
 Neuropsychiatric events, including suicidal behavior have been reported. 
 Other potential toxicities including bone marrow suppression, arrhythmia, and 
hypoglycemia.  These are not likely with a finite course of therapy. Furthermore, there is 
no evidence that G6PD deficiency is a problem with HCQ. While different class of 
antimalarial causes hemolysis with G6PD deficiency, there are no reports of hemolysis 
with HCQ.  
Risk lowering measures: Study procedures to manage and minimize risks include careful 
selection of the participants and monitoring over time to check on participants’ health. 
Additional guidance to manage any risks will be provided to the study teams, as needed.  In 
addition, an independent DSMB will monitor safety of the participants throughout the study. 
2.3.2. Benefit Assessment 
Participants who randomize to the treatment group may benefit from the prophylactic study drug 
administration.  There is no direct benefit to participants randomized to the control group apart 
from participating in generating evidence that may ultimately support preventative therapy for 
SARS-CoV-2 infection. Participants will receive information about the best personal protective 
measures to prevent SARS-CoV-2 infection. In addition, they will benefit from involvement with 
the team following their health status during the study. The knowledge gained will be a benefit to 
others in the future. This is an opportunity to answer important questions for public health and 
prevention of SARS-CoV-2 infection for HCWs. Clarifying the adverse effect profile of HCQ in 
HCWs will also inform the public taking HCQ for prophylaxis of SARS-CoV-2 infection and 
potentially treatment of COVID-19. 


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HERO-HCQ Protocol [v3.0] 
 
 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
 To evaluate the efficacy of HCQ to 
prevent COVID-19 clinical infection in 
HCWs 
 Clinical infection with COVID-19: 
o Confirmed:  new-onset of fever or 
cough or dyspnea AND confirmed 
COVID-19 positive test result via 
local PCR testing, OR 
o Suspected:  new-onset fever or 
cough or dyspnea without local 
PCR testing due to local 
restrictions and/or testing policies 
Secondary 
 
 To evaluate the efficacy of HCQ to 
prevent viral shedding of SARS-CoV-2 
among HCWs  
 Evaluate safety and tolerability of HCQ 
 Viral shedding of SARS-CoV-2:  
o Central lab confirmed COVID-19 
test 
 Safety and tolerability as determined by 
weekly DSMB assessment of subject 
reported serious adverse events (SAEs) 
and HCQ-associated Events of Special 
Interest (Section 9.1.4) 
Exploratory 
 
 Evaluate SARS-CoV-2 seroconversion in 
participants taking HCQ 
 Describe COVID-19 infectious 
complications in participants taking HCQ 
 
 Describe time off from work for medical 
reasons in participants taking HCQ 
 Describe QoL 
 
 
 
 
 
 Describe experience of household 
contacts 
 Seroconversion at 1 month 
 
 COVID-19 complications: 
o hospitalization 
o ICU level care or ventilation 
 Days sick or lost work-time 
 
 Patient-Reported Outcomes Measurement 
Information System (PROMIS) Emotional 
Distress-Anxiety-Short Form, a Single 
Item Burnout Measure, Patient Health 
Questionnaire (PHQ-2) 
 
 Patient-reported clinical infections among 
household contacts and other impacts on 
household 


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4. 
Study Design 
Refer to Section 1.2 for the Study Schema. 
4.1. 
Overall Design 
Potential participations will be pre-screened from the HERO Registry.  Potentially eligible 
participants who indicate interest in trial participation in the HERO Registry and work at one of 
the 40 U.S. sites participating in this trial will be approached for participation in the HERO-HCQ 
trial.  Please refer to Section 5.3 for more details about the recruitment and informed consent 
process.  Approximately 2,000 HCWs from 40 U.S. sites will be enrolled in this trial and 
followed for ~60 days. 
 
Eligible participants will be randomly assigned (1:1), stratified by site, to either treatment group 
(HCQ) or placebo in a double-blind fashion.  After enrollment, baseline assessments will include 
nasopharyngeal swab for COVID-19 and a blood sample to assess baseline serology for SARS-
CoV-2.  For convenience, follow-up will be performed weekly through a direct to participant 
portal.  A call center will provide support for any missed visits.  Follow-up includes screening 
for COVID-19 clinical signs and/or symptoms, other respiratory infections, non-infectious 
clinical events, adverse events, and QoL assessments.  For more details regarding follow-up 
procedures, please refer to Section 8.1.2. 
 
A visit at approximately 30 days after randomization will be done on site to assess any 
subsequent clinical or safety events and adherence to study drug.  A nasopharyngeal swab for 
COVID-19 and a blood sample will be obtained to assess for seroconversion for COVID-19 or 
other related tests. 
 
An end of study visit will be conducted at approximately 60 days via the direct to participant 
portal or call center to assess for any subsequent clinical or safety events. 
4.2. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed the Final Visit at 
60 days. 
The end of the study is defined as the date of the last visit of the last participant in the study.  
Data from interim analyses or recommendations by the DSMB may result in protocol 
modifications or early termination of the study.  
 


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5. 
Study Population 
All Eligibility Criteria will be obtained per participant.   
5.1. 
Inclusion Criteria 
1. Completed Informed Consent 
2. Age ≥ 18 years old 
3. Currently working in any environment in which there is a risk of exposure to patients 
with COVID-19 infections (“healthcare worker”) including, but not limited to, the 
following example work exposures: 
a. in the Intensive Care Unit (ICU), or 
b. in the Emergency department, or 
c. in Emergency services, or 
d. in a COVID-19 hospital unit/ward, or 
e. in respiratory services, or 
f. in COVID-19 testing location, or 
g. in a clinical or research laboratory handling COVID-19 patient samples, or 
h. in inpatient hospital unit/area, or 
i. in long-term care, assisted living or skilled nursing facilities, or 
j. in outpatient care, or 
k. in dental offices, or 
l. in home health care, or 
m. in health services for incarcerated populations, or 
n. in dialysis centers. 
5.2. 
Exclusion Criteria  
1. Prior diagnosis of COVID-19 infection 
2. Participation in another COVID-19 prophylaxis trial within 30 days of consent 
3. Respiratory illness with new-onset fever (Temperature > 100°F) or ongoing cough or 
dyspnea within 14 days 
4. Known allergy to HCQ or chloroquine 
5. Congenital prolonged QT syndrome 
6. Current or planned use of QT prolonging drugs (e.g. procainamide, disopyramide, 
mexiletine, flecainide, propafenone, amiodarone, sotalol, cimetidine, dronedarone, 
dofetilide, levofloxacin, ciprofloxacin, moxifloxacin) and other contraindicated 
medications [see Manual of Procedures (MOP) for full list of contraindicated 
medications] 
7. End stage renal disease 
8. Pre-existing retinopathy 
9. Current or planned use of HCQ (study drug) for any indication 
10. Current or planned use of the following for treatment or prevention of COVID-19 
infection: 
a. Chloroquine 
b. Azithromycin 


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11. Known cirrhosis or severe liver disease 
12. History of severe skin reactions such as Steven-Johnson syndrome, toxic epidermal 
necrolysis 
13. History of psoriasis or porphyria 
14. Ventricular arrhythmias requiring medical treatment 
15. Severe coronary artery disease or heart failure/cardiomyopathy with ongoing symptoms 
16. Current or planned use of use of anti-seizure drugs 
17. History of Glucose-6-phosphate dehydrogenase deficiency 
5.3. 
Recruitment and Engagement 
5.3.1. 
Participant Recruitment 
To ensure HERO-HCQ accrues and retains the number and diversity of participants required to 
assess the primary and secondary endpoints, the HERO Registry will be used to facilliate 
participant recruitment.  Sites may also recruit directly from their communities, with onboarding 
facilitated through the HERO Registry. 
IRB-approved materials will be available on the HERO study website, including videos with 
English or Spanish subtitles, frequently asked questions (FAQs), and testimonials from 
participants. Potential participants who would like to learn more about the study will be directed 
to the study call center or the study website. 
The HERO registry will be used to pre-screen potential HCWs for this study.  Registry 
leadership will periodically review the list of registry participants to identify potential 
participants and ensure methods are used to populate the trial to achieve the objectives as well as 
diversity. Participants who appear to be eligible based on demographics (including geographic 
region), clinical characteristics, and interest in being contacted about trial participation will either 
be sent an email invitation or be contacted directly regarding the HERO-HCQ clinical trial. The 
email invitation will contain instructions for contacting the trial team to obtain more information 
and complete screening. 
5.3.2. 
Participant Engagement 
Participants will be engaged in the study through multiple channels.  This includes, but is not 
limited to, ongoing participation in the HERO Registry and Patient Reported Outcomes via the 
online pariticipant portal. Additionally, participant engagement will include:  
 creating a study-wide Healthcare Worker Advisory Group;  
 developing participant-centered approaches that recognize the needs and preferences of 
healthcare workers locally and nationally; and 
 multifaceted approaches that combine engagement tools, leverage the participant portal, 
use of social media, and representative healthcare worker associations or leaders. 
5.3.3. 
Participant Randomization Process 
Randomization will be stratified by site and occur onsite. Randomization will be monitored 
closely and the HERO registry for pre-screening will be used to ensure inclusion of key 


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subgroups and to ensure the trial results are applicable to an appropriately diverse population of 
HCWs who work in COVID-19 exposure areas. Both participants and the study team will remain 
blinded to assignment throughout the study. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study, who 
fulfill inclusion and exclusion criteria, but are not subsequently randomized. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.  
Individuals who are considered screen failures may not be re-screened. 


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6. 
Study Drug(s) 
Study drug is defined as any investigational drug(s), marketed product(s), or placebo intended to 
be administered to a study participant according to the study protocol. 
6.1. 
Hydroxychloroquine 
6.1.1. 
Formulation, Appearance, Packaging, and Labeling 
Hydroxychloroquine sulfate tablets are provided as white/off-white, film-coated, round tablets.  
Each tablet contains 200 mg of the active ingredient (HCQ sulfate).  The non-active ingredients 
in the formulation include black ink, calcium hydrogenophosphate, carnauba wax, cornstarch, 
magnesium stearate, Opadry White YS-I-7443 and polyethylene glycol 400. 
Study drug will be packaged and labeled in a masked manner and in compliance with regulatory 
requirements. 
6.1.2. 
Drug Dispensing, Storage, and Stability 
A quantity of study drug sufficient for 30-days will be provided to the participant at enrollment.  
Hydroxychloroquine should be stored at room temperature (15°C - 30°C). 
6.1.3. 
Dosing and Administration 
Participants will receive a 600 mg BID loading dose of study drug for the first day, followed by 
400 mg QD for 29 days.  All study drug doses will be oral self-administrations.  Study drug will 
be supplied as 200 mg tablets.    
6.1.4. 
Rationale for Selection of Dose 
Hydroxychloroquine is an aminoquinolone antimalarial agent that is also approved and used for 
the treatment of autoimmune diseases including rheumatoid arthritis and systemic lupus 
erythematosus.  
Studies have demonstrated in vitro activity of chloroquine against SARS-CoV. [17, 18] Both 
chloroquine and HCQ have been reported to have in vitro antiviral activity against SARS-CoV-2. 
[11, 12] In vitro testing using Vero cells vary; Yao et al demonstrated an EC50 of 23.90 and 5.47 
uL for chloroquine at 24 and 48 hours respectively, compared to 6.14 and 0.72 for HCQ. [12] 
Liu et al reported on four multiplicities of infection (MOIs) (0.01, 0.02, 0.2, and 0.8); the 50% 
maximal effective concentration (EC50) for chloroquine was (2.71, 3.81, 7.14, and 7.36 μM) and 
for HCQ was (4.51, 4.06, 17.31, and 12.96 μM). Hydroxychloroquine may exhibit higher activity 
to chloroquine in protecting Vero cells from infection (“prophylaxis”); when Vero cells were 
pre-treated with drug before SARS-CoV-2 challenge, EC50 for chloroquine was >100 and 18.01 
uL at 24 and 48 hours, respectively, compared to 6.25 and 5.85 for HCQ. [12] In animals, both 
drugs share similar tissue distribution patterns, with high concentrations in the liver, spleen, 
kidney, and lung reaching levels of 200–700 times higher than those in the plasma. [19] 
The optimal dose of HCQ for treatment or prophylaxis is unknown. Absorption after oral dosing 
is incomplete and variable (~70% [range: 25 to 100%]). [20] Metabolism is primarily hepatic 
with metabolites including bidesethylchloroquine, desethylhydroxychloroquine, and 
desethylchloroquine. [21] The drug has long half-life elimination of approximately 40 days. [20] 


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Standard dosing in other medical conditions include: systemic lupus erythematosus (200-400 mg 
daily given once or divided BID), malaria treatment (800 x1, followed by 400 mg at 6, 24 & 48 h 
after initial dose), Q fever (600 mg/day in 1 to 3 divided doses) and rheumatoid arthritis (200-
400 mg daily in 1-2 divided doses). The recommended maximum dose of HCQ is 5 mg/kg 
Actual Body Weight daily. 
The dose chosen for this study is 600 mg orally BID on day 1 as a loading dose followed by 400 
mg QD for an additional 29 days. This dose was chosen for several reasons:  
 current in vitro studies report a wide range of EC50 for SARS-CoV-2,  
 variability of absorption and of tissue distribution into the lung,  
 due to a lack of phase 1b data for this drug in SARS-CoV-2 infection, the optimal 
pharmacokinetic/pharmacodynamic target is unknown.  
Yao et al made assumptions regarding the absorption and tissue distribution that were optimistic 
and recommended as an optimal treatment dose 400 mg BID on day 1 as a loading dose followed 
by 200 mg BID daily for the remainder of the treatment course. [12] There is concern that this 
dose will not meet the necessary pharmacokinetic/pharmacodynamic targets for efficacy, in 
which case a negative study would not be due to failure of the antiviral efficacy but of 
suboptimal dosing. Yao et al also noted that the drug exposure was the same for 200 mg BID or 
400 mg QD daily dosing. We propose a higher loading dose of 600 mg BID on day 1 to ensure 
more rapid steady state tissue distribution and 400 mg QD (versus BID) dosing for ease of 
dosing and adherence. 
6.2. 
Placebo 
6.2.1. 
Formulation, Appearance, Packaging, and Labeling 
Placebo will be provided in a similar appearance as the study drug and be packaged and labeled 
in a masked manner in compliance with regulatory requirements. 
6.2.2. 
Drug Dispensing, Storage, and Stability 
A quantity of study drug sufficient for 30-days will be provided to the participant at enrollment.  
Placebo should be stored at room temperature (15°C - 30°C). 
6.2.3. 
Dosing and Administration 
All placebo doses will be oral self-administrations.  Placebo tablets will be provided in a dose 
that mimics the pill count of the study drug (HCQ).   
6.2.4. 
Rationale for Selection of Dose 
N/A 
6.3. 
Study Drug Accountability  
Use of study drug will be tracked via the participant portal, call center, or final in-person study 
visit. Adherence to study drug as provided will be assumed unless reported otherwise. 


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Participants will dispose of any unused study drug as they would normally when stopping a 
medication. 
6.4. 
Concomitant Therapy 
Select concomitant medications of interest that the participant is receiving at the time of 
enrollment or receives during the course of the study will be recorded along with dosing 
information. Select concomitant medications of interest include the following: 
 Therapeutics that are being used in other COVID clinical trials  
 Antibiotics  
 Antifungals  
 Immunosuppressants including steroids  
 Tylenol  
 Nonsteroidal anti-inflammatory drugs 
 Angiotensin-converting-enzyme (ACE)/angiotensin II receptor blockers 
(ARB)/angiotensin receptor neprilysin inhibitor (ARNI) 
 Statin 
 HIV protease inhibitors including lopinavir, ritonavir, atazanavir, darunavir 
 ribavirin  
Prohibited medications include those at high risk for QT prolongation including: 
 procainamide,  
 disopyramide,  
 mexiletine,  
 flecainide,  
 propafenone.  
 amiodarone,  
 sotalol,  
 cimetidine 
 dronedarone,  
 dofetilide 
 fluoroquinolones including ciprofloxacin, levofloxacin, moxifloxacin 
 see MOP for full list of contraindicated medications 
6.5. 
Dose Modification 
This protocol allows some alteration from the currently outlined dosing schedule.  The maximal 
daily dosing should not exceed what is specified in the protocol. 
If moderate or severe adverse event (AE) occurs, that is, in the opinion of the investigator, 
reasonably attributable to study intervention, then dose may be altered by changing from QD to 
BID dosing, may be temporarily halted, or may be reduced, in consultation with the study CCC.  
Relevant reporting and discussion with the CCC study personnel, must take place prior to dose 
modification. 


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If the same SAE occurs consistently across participants, then dose or frequency of dosing may be 
reduced by trial leadership or per any DSMB recommendations.  
6.6. 
Intervention After the End of the Study 
No additional study drug will be provided to the participant following completion of the study.   


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7. 
Participant Withdrawal/Termination and Study Termination 
7.1. 
Participant Withdrawal/Termination 
Participants will be followed until participant closeout, withdrawal of consent, or death. 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
Those who request withdrawal from the study will be asked to continue on study follow-up with 
limited participation through the Final Visit (Section 8.1.3).  Limited participation may include a 
call at 30 days and 60 days to assess safety. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
7.2. 
Premature Termination or Suspension of the Study 
The study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification will be provided documenting reason for study suspension 
or termination to the investigators, funding agency, and regulatory authorities, as appropriate. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to participants 
 Insufficient compliance to protocol requirements 
 Data that are not sufficiently complete and/or evaluable 
 Determination of futility after a sufficient time has passed for accrual of the primary and 
secondary outcomes 
 Recommendation by the DSMB 
7.3. 
Lost to Follow-up 
Participants will be asked for proxy contacts to assess vital status and/or other clinical events if a 
participant repeatedly fails to return for scheduled visits or does not participant in remote visits.  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits or does not participate in remote visits and neither the participant nor his or her 
proxy can be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic or participate in 
remote visits as required by the study: 
 
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule. 
 
The site or call center will contact the participant’s proxy to assess vital status or other 
clinical or safety events. 


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 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.  If safe, and appropriate, participants who fail to respond 
to study contact should be contacted at work by the study team since these participants 
are employees of the facility. 
 
Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up.  


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8. 
Study Assessments and Procedures 
The study site will perform the baseline visit, which includes randomization, if eligible. The site 
will confirm suitability to receive study drug. Sites will be responsible for notifying the 
coordinating center for participant withdrawals, lost to follow-up, permanent cessation of study 
drug, study drug dose modifications, or change in vital status. Data is being collected directly 
from participant and supported by medical records, as needed. 
8.1. 
Schedule of Events  
 
Table 1: Schedule of Events 
                                                 
 
 
 
1 Participant’s medical record may be reviewed to confirm SAEs and Events of Special Interest (EOSIs). 
Baseline: Onsite 
(Day 0) 
Follow-up: Remote 
(Day 7 ± 2 days) 
Follow-up: Remote  
(Day 14 ± 2 days) 
Follow-up: 
Remote (Day 
21 ± 2 days) 
Follow-up: 
Onsite (Day 
30 + 5 days) 
Final Visit: 
Remote (Day 
60 + 5 days) 
Healthcare Worker Clinical Trial 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
Eligibility criteria confirmed 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Receipt of study drug or placebo 
X 
 
 
 
 
 
Continued use study drug  
 
Continuous 
 
Clinical Assessments 
 
 
 
 
 
 
Abbreviated medical history 
X 
 
 
 
 
 
Concomitant Meds of Interest 
X 
 
X 
 
X 
X 
Temperature 
X 
 
 
 
 
 
COVID-19 Questionnaire 
 
X 
X 
X 
X 
X 
QoL Questionnaires 
X 
 
X 
 
X 
X 
SAEs and Events of Special Interest1 
 
Continuous via participant portal and at Onsite 
Visits 
Biospecimen Collection 
 
 
 
 
 
 
Nasopharyngeal swab for COVID-19 
X 
 
 
 
X 
 
Blood collection for exploratory analysis 
X 
 
 
 
X 
 


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8.1.1. 
Baseline (On-site, Day 0) 
The following events will occur at the Baseline study visit: 
 Consent: The consent process should be done in accordance with local IRB requirements.  
Phone consenting may be facilitated through the e-consent process via the online portal. 
 Demographic information will be collected including, but not limited to, age, sex, race, 
ethnicity, and occupation  
 Eligibility criteria confirmation 
 Randomization: Participants must be randomized within 3 days of consent, which can be 
done in-person or by phone.    
 Participant will receive 30-day supply of study drug or placebo 
 Abbreviated medical history including smoking status, pre-existing underlying lung 
disease, underlying immunosuppression (transplant, malignancy, HIV, autoimmune 
disease), medical conditions that may increase risk of COVID-19 infections or 
complications (diabetes, cardiovascular disease)  
 Concomitant medications of interest (Section 6.4) 
 Temperature 
 QoL questionnaires 
 Nasopharyngeal swab for COVID-19 diagnosis 
 Blood collection for exploratory analysis 
8.1.2. 
Follow-Up 
The following events will occur at the Follow-Up study visits: 
Follow-up (Day 7 ± 2 days – Remote): 
 COVID-19 Questionnaire 
 Serious Adverse Event and EOSI collection 
Follow-up (Day 14 ± 2 days – Remote): 
 Concomitant medications of interest (Section 6.4) 
 COVID-19 Questionnaire 
 QoL questionnaires 
 Serious Adverse Event and EOSI collection 
Follow-up (Day 21 ± 2 days – Remote): 
 COVID-19 Questionnaire 
 Serious Adverse Event and EOSI collection 
Follow-up (Day 30 + 5 days – Onsite): 
 Concomitant medications of interest (Section 6.4) 
 COVID-19 Questionnaire 
 QoL questionnaires 
 Serious Adverse Event and EOSI collection 
 Nasopharyngeal swab for COVID-19 diagnosis 


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 Blood collection for exploratory analysis 
8.1.3. 
Final Visit (Day 60 + 5 days - Remote) 
The following events will occur at the Final Visit: 
 Concomitant medications of interest (Section 6.4) 
 COVID-19 Questionnaire 
 QoL questionnaires 
 Serious Adverse Event and EOSI collection 
8.2. 
Clinical Assessments 
Temperature: temperature will be assessed 
Nasopharyngeal swab for COVID-19:   Nasopharyngeal swabs are commonly used for the 
detection of respiratory viruses such as respiratory syncytial virus, influenza virus and 
coronavirus.  A swab is inserted into the nostril and advanced along the floor of the nose until the 
posterior nasopharynx has been reached and gently rotated several times to collect sufficient 
specimen for testing.  
The reference lab will notify sites of positive COVID-19 test results.  Sites are expected to 
inform participants and the state health department of positive COVID-19 test results.  The 
notification process will occur per local guidance and will not be tracked or documented by the 
study team. 
8.3. 
Quality of Life and COVID Questionnaires 
COVID-19 Questionnaire 
The following QoL questionnaires will be used in this study: 
 PROMIS Emotional Distress – Anxiety – Short Form: Patient-Reported Outcomes 
Measurement Information System (PROMIS) measures were developed through a 
collaborative process funded by the National Institutes of Health (NIH). [22] Anxiety has 
been identified by the PROMIS Steering Committee as a key domain of mental health 
and was defined as “autonomic arousal and experience of threat”, [23] which may 
compound the effects of stress in healthcare providers. [24] The PROMIS Emotional 
Distress – Anxiety-Short Form [25] has previously been shown to reliably assess anxiety 
in a variety of clinical populations. [26-28] The Anxiety short form consists of eight 
items each rated from 1-5 points (1=never and 5=always), with higher scores indicating 
greater anxiety.   
 Single-item burnout measure: Prior work has demonstrated that burnout among medical 
professionals may adversely affect patient care. The current standard for burnout 
assessment is the Maslach Burnout Inventory (MBI), however, the full MBI consists of 
22 items and may be burdensome to complete. Across previous studies, one emotional 
exhaustion (EE) question (“I feel burned out from my work”, rated on a 7-point Likert 
scale ranging from “Never” to “Daily”, with higher scores indicating more burnout) has 
exhibited high factor loading within its respective domain (MBI-EE). [29-32] A non-


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proprietary adaptation of this item [33] has shown good performance relative to the full 
MBI in prior studies of medical students and physicians. [34, 35]     
 Patient Health Questionnaire (PHQ-2): The Patient Health Questionnaire (PHQ-9) is a 9-
item tool commonly used to assess depression severity. Given the need for a briefer 
measure to screen for depression in busy settings, a 2-item version of the depression 
module has been developed and validated. [36] The abbreviated scale, known as the 
PHQ-2, consists of questions about two domains: frequency of depressed mood and 
anhedonia, each scored from zero (not at all) to three (every day), with higher scores 
indicating greater depression severity. The measure has demonstrated good performance 
in diverse clinical [37-40] and healthcare provider populations. [41-44]  


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9. 
Safety Assessments 
9.1. 
Adverse Events and Serious Adverse Events 
An AE is any untoward medical occurrence in humans, whether or not considered drug-related, 
which occurs during the conduct of a clinical trial. An AE can therefore be any change in clinical 
status, ECGs, routine labs, x-rays, physical examinations, etc., that is considered clinically 
significant by the study investigator.  
A SAE or serious suspected adverse reaction or serious adverse reaction as determined by the 
investigator or the sponsor is an adverse event that results in any of the following serious 
outcomes:  
 Death  
 Life-threatening AE (“life-threatening” means that the study participant was, in the 
opinion of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention)  
 Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
 Inpatient hospitalization or prolongation of existing hospitalization  
 Congenital abnormality or birth defect  
 Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline does not meet the definition of an SAE. Hospitalization is defined as a stay in the 
hospital exceeding 24 hours.  
An unexpected adverse event is defined as any adverse event, the specificity or severity of which 
is not consistent with the package insert. 
9.1.1. 
Collection Period for AE and SAE Information 
Study participants (and their designated emergency proxies) will be instructed to report Events of 
Special Interest (EOSI) and SAEs through their access to the study’s participant portal.  Events 
of special interest and SAEs will also be elicited during each remote follow-up visit and during 
the Baseline and Day 30 onsite visits. Participants will have access to AE reporting via the 
electronic portal from the signing of the informed consent form (ICF) until the Final Visit (Day 
60).  
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will not be considered an AE. 
Non-serious AEs will not be collected unless the event meets the criteria of an EOSI.  
Events of Special Interest will be collected from the start of study drug until Final Visit or until 
30 days after the last dose if participant early terminates the study. 
Serious adverse events will be collected from the start of study drug until Final Visit or until 30 
days after the last dose if participant early terminates the study. 


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9.1.2. 
Assessing Causality of a Suspected Unexpected Serious Adverse Reaction 
(SUSAR) 
If a SUSAR occurs, the investigator/delegate will assess the relationship to study drug by using 
the following criteria: 
 Related: The event has a relationship to study drug. 
 Not related: The event has no temporal relationship to study drug or the AE has a much 
more likely alternate etiology or due to an underlying or concurrent illness or effect of 
another drug. 
9.1.3. 
Reporting and Monitoring of SAEs 
Although HCQ is approved for marketing in the United States, its investigational use for 
prevention of COVID-19 infection is not an approved indication, but will be under an IND and 
subject to IND regulations in 21 CFR 312. Listings of all SAEs, Events of Special Interest, and 
Unanticipated Problems that are reported will be compiled for frequent DSMB review. There 
will be no expedited reporting of individual SAEs as safety reports per 21 CFR 
312.32(c)(1)(i)(A) or 21 CFR 312.32(c)(1)(i)(B). The DSMB chair will review SAEs weekly, 
and the convened DSMB will perform aggregate reviews of SAEs every two weeks. The 
convened DSMB will be responsible for determining if the safety reporting criteria are met per 
21 CFR 312.32(c)(1)(i)(C) and 21 CFR 312.32(c)(1)(iv) so that the IND sponsor and study team 
remain blinded. The DSMB will prepare an aggregate report for submission to the FDA if the 
DSMB determines that an SAE occurs markedly more frequently in the drug treatment group 
than in the control group. An aggregate safety report will be submitted to FDA as soon as 
possible, but in no case later than 15 calendar days after the DSMB determination. If the DSMB 
determines that an unexpected fatal or life-threatening suspected adverse reaction occurs 
markedly more frequently in the drug treatment group than in the control group, an aggregate 
safety report will be submitted to the FDA as soon as possible, but in no case later than 7 
calendar days after the DSMB determination.  Information on individual SAEs will be available 
upon request from the Agency following the submission of any aggregate reports. 
Individual SUSARs will be reported by the DSMB as expedited events to the FDA; 7-day reports 
for unexpected fatal or life-threatening adverse reactions and 15-day reports for serious and 
unexpected adverse reactions. If the DSMB or FDA note a clinically important increase in the 
rate of a SUSAR, the DSMB will notify investigators no later than 15 calendar days after 
determining that the information qualifies for reporting. 
9.1.4. Events of Special Interest  
The following are considered Events of Special Interest and should be recorded even if they do 
not meet the criteria above as Serious Adverse Events. 
The following are EOSI that are possibly related to the use of HCQ: 
 Arrhythmias (ventricular) 
 Hepatic Failure 
 Bone marrow failure 
 Aplastic anemia 


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 Prolonged QT interval 
 Angioedema 
 Dermatitis exfoliative  
 Acute generalized exanthematous pustulosis (AGEP) 
 Psychosis 
 Suicidal Ideation 
 Seizure 
 Methemoglobinemia 
 
The following are also considered Events of Interest to the study:  
 Fevers 
 Sepsis 
 Acute renal failure 
 Disseminated Intravascular Coagulation (DIC) 
 Secondary bacterial infection 
The following are treatments or interventions associated with an event that will be collected:  
 Supplemental oxygen use 
 Non-invasive ventilation including BiPAP/CPAP 
 Pressors 
 Mechanical ventilation/intubation 
 Intensive Care Unit (ICU) admission 
 Extracorporeal Membrane Oxygenation (ECMO) 
9.2. 
Unanticipated Problem (UP) and Terminations 
9.2.1. Definition of Unanticipated Problem  
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
 Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied. 
 Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research). 
 Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 


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9.2.2. Reporting of an Unanticipated Problem  
The site investigator will report UPs for their participants to the Data Coordinating Center 
(DCC). The site may also be required to inform their reviewing IRB about an UP occurring at the 
local institution. The UP report to the DCC will include the following: 
 A detailed description of the event, incident, experience, or outcome  
 An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP  
 A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP 
 The Coordinating Center will document and review all UPs.  Details of the UP reporting 
process will be located in the MOP. 


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10. 
Statistical Considerations 
10.1. 
Statistical Hypotheses 
10.1.1. 
Primary Hypothesis 
 Allocation to HCQ results in prevention of COVID-19 infection among HCWs at risk for 
COVID-19 infection. 
10.1.2. 
Secondary Hypotheses 
 Allocation to HCQ results in prevention of viral shedding of SARS-CoV-2 among HCWs 
at risk for COVID-19 infection. 
 Hydroxychloroquine administration will be safe and well tolerated. 
10.2. 
Sample Size Determination 
The sample size of approximately 2,000 randomized participants was selected to yield reasonable 
power for testing the primary outcome of clinical infection with COVID-19.  Several design 
factors and research objectives have been considered in developing an appropriate sample size 
for the HERO-HCQ study.  
Based on several recent randomized clinical trials studying HCQ for inpatient COVID-19 disease 
conditions, a reduction in the clinical infection risk by a relative 50% is considered a clinically 
important treatment effect.  For the primary outcome of clinical infection of COVID-19, the  
sample size will provide 80% power to detect a 50% relative decrease in the risk for the 
intervention group compared to usual care assuming that the placebo group risk is 5%.  
Similarly, the proposed sample size will provide 80% power to detect a difference of 6.5% 
(active) vs. 10% (placebo). These calculations assume a two-sided Type I error rate of 0.05 with 
1:1 randomization and are based on a two-group continuity corrected chi-square test. 
10.3. 
Randomization 
HERO-HCQ is a multi-center, double blind, randomized, parallel group, superiority study. 
Randomization will occur at the level of the individual participant. Eligible participants will be 
randomized via the study website in a 1:1 ratio to either HCQ or matching placebo. 
Randomization will be stratified by clinical site using a permuted block design with random 
block sizes. [45]   
10.4. 
Blinding 
The HERO-HCQ Steering Committee along with site investigators, PCORI Program Staff, and 
study participants will remain blinded until database lock.  Limited staff will be unblinded to 
handle randomization codes, deliver the interventions to sites, and prepare DSMB reports. The 
statistical staff responsible for preparing DSMB reports will not directly interact with the clinical 
team that delivers care to the study participants. 
The Interactive Voice Response System/Interactive Web Response System will be programmed 
with blind-breaking instructions. Participant safety must always be the first consideration in 
making an unblinding determination. If the investigator decides that unblinding is warranted, the 


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investigator should contact the Coordinating Center for unblinding a participant’s intervention 
assignment.  
10.5. 
Populations for Analyses 
The primary analyses will include all randomized participants with a baseline negative RT-PCR 
test.  
Analyses of safety and clinical events will be based on the population of all randomized 
participants. 
10.6. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to database lock and it will include a more 
technical and detailed description of the statistical analyses outlined in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
10.6.1. General Considerations 
Statistical comparisons will be performed using two-sided significance tests. Baseline 
demographic and clinical variables will be summarized for each randomized arm of the study. 
Descriptive summaries of the distribution of continuous variables will be presented in terms of 
percentiles (e.g., median, 25th and 75th percentiles) along with means and standard deviations.  
Categorical variables will be summarized in terms of frequencies and percentages. 
The primary endpoint is clinical infection with COVID-19.  Individual participants are expected 
to receive study drug for 30 days and will be followed for another 30 days for clinical events and 
patient-reported outcomes. Data collected during the 60-day follow-up will be included in the 
primary analyses. 
Participants that develop symptoms of COVID-19 will follow local clinical and/or employee 
health protocols for testing and management.  If testing is done per protocol, the results will be 
used for confirmation of the primary outcome.  However, in some regions, testing may not be 
done for individuals with suspected COVID-19 symptoms and low risk factors for severe 
disease.  Instead, these individuals may be told to self-isolate and monitor symptoms in lieu of 
testing.  To reflect the different approaches expected for testing and management of healthcare 
workers who develop symptoms of COVID-19, the primary outcome includes both confirmed 
and suspected clinical COVID-19 infections.   
The primary endpoint will be tested at the two-sided 0.05 level.  All secondary endpoints will be 
tested at the 0.05 level.   
10.6.2. 
Primary Endpoint 
The primary analysis of the primary endpoint will be based on the Fisher’s exact test.  The 
difference in proportions and the associated 95% confidence interval will be the primary measure 
used to summarize the treatment effect.   
A secondary analysis of the primary outcome of clinical infection with COVID-19 will be based 
on a logistic regression model with an indicator variable for the treatment group. The estimated 


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odds ratio and associated 95% confidence interval will be used to summarize the results from 
these analyses.   
A sensitivity analysis will use the time-to-clinical infection with COVID-19 outcome.  For that 
analysis, the treatment groups will be compared using a Cox proportional hazards regression 
model with the baseline hazard function stratiﬁed by site. [46, 47] The estimated hazard ratio and 
associated 95% confidence interval will be used to summarize the treatment effect.   
10.6.3. 
 Secondary Endpoint(s) 
For the viral shedding of SARS-CoV-2 endpoint, a linear regression model with an indicator 
variable for the treatment group and additional pre-specified covariates will be applied. Analytic 
details about other secondary endpoints will be included in the Statistical Analysis Plan. 
The statistical comparisons of the randomized arms with respect to the SAEs and EOSI interest 
will use chi-square or other appropriate 2-sample methods. Analysis of all-cause mortality will 
be conducted using a log-rank test with event curves presented as Kaplan-Meier estimates. A 
Cox proportional hazards will be used to estimate the hazard ratio associated with the HCQ 
intervention.  Analyses of all-cause and cause-specific hospitalizations will use similar strategies.  
10.6.4. 
Exploratory Analysis 
Details of the exploratory analyses will be described in the Statistical Analysis Plan. 
10.6.5. 
Subgroup Analyses 
In addition to analyses of secondary outcomes in Section 10.6.3, a set of analyses will be 
reported to explore whether intervention effects on the primary and secondary outcomes are 
consistent across subgroups of interest defined according to baseline characteristics.  These 
subgroups will be specified in the Statistical Analysis Plan.  The planned sub-groups will include 
age, sex, race/ethnicity, occupation, and COVID-19 risk factors. 
For each subgroup analysis, a logistic regression model (or linear model) will be used that is 
similar to the one described above, but with additional terms identifying subgroup membership 
and the intervention by subgroup interaction.   
10.6.6. 
Adherence and Retention Analysis 
Treatment dropouts and consent withdrawals will be tracked by verifiable means at each follow-
up assessment.  Participants will be asked about their use of study drug during telephone follow-
up.  Those reporting discontinuation or switching will be asked about the reasons for 
discontinuation/switching.   
Because study participants are HCWs, it is expected that this study will have excellent retention.  
Measures of study retention to inform follow-up time will be based on a number of measures, 
weekly web-based check-ins for symptoms and exposure history or in-person visit. 


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10.7. 
Interim Analyses  
Regular DSMB reviews will be conducted to ensure the safety of study participants and evaluate 
the accumulating endpoint data by treatment group.  Regular DSMB meetings will monitor the 
following parameters at a minimum: 
 Recruitment progress 
 Enrollment overall and by subgroups 
 Adherence, retention, and status of data collection 
 Events of special interest 
 Unanticipated problems 
 Serious adverse events (SAEs) 
Interim examination of clinical endpoints will be based on the accrual of primary endpoint data.  
It is expected that reviews of the data will occur approximately weekly following the enrollment 
of the first participants.  
For ethical reasons, interim examinations of key safety and process data will be performed at 
regular intervals during the course of the trial.  The DCC will create reports to track participant 
enrollment, rates of adherence with the assigned treatment strategy, and frequency of protocol 
violations.  Prior to each meeting, the DCC will conduct any requested statistical analyses and 
prepare a summary report along with the following information: participant enrollment reports, 
rates of adherence with the assigned treatment, and description of SAEs.  
Safety reports will be prepared for the DSMB approximately weekly once enrollment begins.  
For futility monitoring, HERO-HCQ will employ a flexible approach based on the prediction 
interval methods of Evans, Li, and Wei. [48]  These flexible methods allow for the assessment of 
treatment differences as well as the precision related to those estimates.  The futility reviews may 
include predicted interval plots as a tool to summarize the information.  To implement these 
methods, we will predict the confidence intervals at the end of the study conditional on a range 
of reasonable assumptions including the null hypothesis, the alternative hypothesis, and the 
observed trend.  The upper and lower limits of these prediction intervals will be compared with 
‘acceptable’ treatment group differences that allow for the incorporation of other information 
including the safety profile of the intervention.  It is expected that the first futility assessment 
will occur once the first 1000 randomized participants have completed their 30-day visit.  
Additionally, conditional power calculations will be used to assess the futility of continuation in 
the presence of a small or negative treatment effect.  
The method of Haybittle and Peto will be proposed as the primary guide for interpreting interim 
efficacy analyses. [49, 50]  The four interim efficacy analyses are expected to occur after the first 
1000, 1250, 1500, and 1750 participants have completed their 30-day visits.  The proposed 
efficacy monitoring guideline uses large critical values (p≤0.001) for the treatment group 
comparison of the outcome of clinical infection with COVID-19 at each assessment until the 
planned final analysis.  A two-sided stopping boundary for all-cause mortality with p<0.001 will 
be recommended for all reviews. 
Monitoring boundaries are intended to guide the interpretation of interim analyses and are not a 
strict rule for early termination.  It is expected that both internal and external factors will 


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influence the decisions of the DSMB.  The Statistical Analysis Plan will describe the planned 
interim analyses and futility monitoring in greater detail. 
10.8. 
Data Safety Monitoring Board (DSMB) 
The DSMB will monitor participant safety and study performance.  A DSMB charter that 
outlines the operating guidelines for the committee and the procedures for the interim 
evaluations of study data will be developed by the DCC and agreed upon by the DSMB.  Reports 
will be prepared by the DCC in accordance with the plan outlined in the charter, or as requested 
by the DSMB chair, and will include interim analyses of primary and secondary endpoints, 
additional safety events, and other information as requested by the committee.  After each 
scheduled closed meeting, the DSMB will send a recommendation to the IND sponsor to 
continue, modify, or terminate the study.  After approval, the recommendations will be 
forwarded by the CCC to investigators for submission to their local, regional and national 
IRB/Ethic Committees, as applicable. DSMB reports will be the primary mechanism for 
reporting safety concerns to FDA, as needed.  The DSMB will establish links with the FDA and 
other appropriate DSMBs as possible to ensure rapid communication of important safety findings 
as needed.  Please refer to the DSMB Charter for further details. 


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11. 
Ethical Standards 
11.1. 
Institutional Review Board (IRB) 
The protocol, ICF(s), recruitment materials, and all participant materials will be submitted to the 
IRB(s) of record for review and approval. This approval must be obtained before any participant 
is enrolled. Any amendment to the protocol will require review and approval by the IRB(s) 
before being implemented in the study. All changes to the consent form will also be IRB-
approved and a determination will be made regarding whether previously consented participants 
need to be re-consented. 
11.2. 
Informed Consent Process 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and documentation of informed consent is required prior to starting study procedures. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants. Consent forms 
will be IRB-approved and the participant will be asked to read and review the document. The 
investigator (or their delegate) will explain the research study to the participant and answer any 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants.  Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study and think about it prior to 
agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any 
time throughout the course of the study. A copy of the informed consent document will be given 
to the participants for their records. The rights and welfare of the participants will be protected 
by emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 
The study team will distinguish between the desire to discontinue study drug and the desire to 
withdraw consent for study follow-up. In the event that a participant withdraws consent, the 
investigator or his designee will clarify with the participant and document whether the 
withdrawal is a temporary or permanent, and if a full or partial withdrawal. 
11.3. 
Participant and Data Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical and private information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. The study participant’s contact 
information will be securely stored in the clinical study database. 
 


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Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at Duke Clinical Research Institute. The study data 
entry and study management systems used by clinical sites and by research staff will be secured 
and password protected. At the end of the study, all study databases will be de-identified and 
archived. 
11.4. 
Intended and Future Use of Stored Biosamples and Data 
Samples and data will be available for use to understand COVID-19 exposure or related 
conditions. De-identified biological samples will be stored at the central lab. The central lab will 
be provided with a code-link that will allow linking the biological specimens with the phenotypic 
data from each participant, maintaining the masking of the identity of the participant. Access to 
stored samples will be reviewed using a biospecimen ancillary proposal application and review 
process. Data collected for this study will be stored at the DCRI. Data generated from the use of 
the biospecimens will be tracked and saved in password-protected computers. 
After the study is completed, the de-identified, archived biospecimens and biospecimen data will 
be sent to the Coordinating Center. These samples could be used for research into COVID-19 or 
other health outcomes in this population. During the conduct of the study, an individual 
participant can choose to withdraw consent to have biological specimens stored for future 
research. Study participants who request destruction of samples will be notified of compliance 
with such request and all supporting details will be maintained for tracking. However, 
withdrawal of consent with regard to biosample storage will not be possible after the study is 
completed; however, samples already distributed to investigators will not be recalled and data 
generated from those samples will be retained. 
11.5. 
Site Management and Quality Assurance 
The study team will work in tandem to ensure that the data collected in this study are as complete 
and correct as possible. We will implement a four-step, multi-functional approach to quality 
control: 
 Training: Prior to the start of enrollment, the clinician investigators and study coordinators 
at each site will be trained with the clinical protocol and data collection procedures, 
including how to use the Electronic Data Capture (EDC) system. Follow-up training and 
training for new study personnel will be conducted as needed. 
 Monitoring: The CCC, along with the DCC, will ensure that data collection is handled 
properly, will provide in-service training, and will address questions from site investigators 
and coordinators. Review of data quality and completeness will occur on a regular and 
ongoing basis.  Any issues will be addressed.  There will be no on-site monitoring or 
source document verification. 
 Managing data: After the data have been transferred for statistical summarization, data 
description, and data analysis, further crosschecking of the data will be performed with 
discrepant observations being flagged and appropriately resolved through a data query 
system. 
 Reviewing data: Events of interest will be reviewed to ensure an appropriate standardized 
classification of the component events comprising the primary composite endpoint. 


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11.6. 
Site Monitoring 
This study will employ a centralized risk-based approach to monitoring with routine and periodic 
review of participant-submitted data to validate informed consent process, identify and follow-up 
on missing data, inconsistent data, data outliers, etc. and ensure completion of administrative and 
regulatory processes.  The study team will facilitate regular communication through training 
sessions, teleconferences, videoconferencing, email, etc.  Using quality-by-design principles, 
steps will be taken at the study design stage to foresee and limit problems that might occur 
during the study conduct. Participant selection facilitated by the HERO registry should lead to 
efficient identification and enrollment of those who satisfy study eligibility and enrichment 
criteria. Follow-up from the portal and call center is expected to keep participants engaged and 
help them maintain their assigned treatment by regularly asking them about the treatment they 
take. Minimal levels of intervention and a focus on observing rather than influencing the study 
participants greatly increases the likelihood that Good Clinical Practices will be followed.  
Central statistical monitoring is particularly useful for identifying unusual patterns in data. We 
will deploy an integrated approach to quality surveillance, which will be detailed in the 
appropriate study management plans. 


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12. 
Data Handling and Record Keeping 
12.1. 
Data Collection and Management Responsibilities 
The data management platform for this study is primarily focused on a single web-based portal 
that will support all data collection and interactions with participants and study sites.  Related 
operational systems supporting the Coordinating Center activities and services provided partners 
(e.g. lab, drug supply) will be embedded within each of those organizations and interfaced via a 
routine set of data transfers or application interfaces.  The figure below (Figure 1) illustrates the 
systems and interactions required to enable a well-coordinated study delivery plan.  Study 
participants accessing the system directly and the emphasis on self-reported data does require 
primary identifiers to be maintained within a limited number of systems.  These data will be 
secured such that it is only maintained in the minimum required systems and accessible to the 
minimum number of people to perform the study procedures described in this protocol.  The 
primary method of identifying a participant will be with a unique participant identification 
number.  
 
Figure 1: Data Flow Diagram 
Participants will use a study portal developed by Verily for the consent, data reporting and 
scheduling activities in this study.  The Verily system leverages the Google infrastructure, 
including hosting, security, user account management and the study-specific data system.  
Leveraging this infrastructure ensures very high levels of system security and support are 
embedded in the portal.  Although leveraging Google infrastructure this is a stand-alone portal 
Almac
Clinical 
Supply 
Packaging & 
Distribution
Integrated Study Data 
Repository
[automated receipt, integration, reconciliation, 
transactional exchanges, QC]
(Informatica, Oracle)
Trial 
Payment 
System
Consent, Self-report  & trial data
Trial System
Analysis and Dataset Creation, 
Reporting
[Transfomation, Registry/Trial dataset generation, 
visual analytics & reporting, aggregate quality 
reviews, protocol compliance checks, etc]
(SAS, SAS VA, R, etc.)
Registry 
System
CTMS
(Siebel)
DCRI System
Study Data Platform
Vendor / Sub
Site
Participant
Central Lab
Call Center 
Comms 
Center Db
(Model Db)
DSMB 
Meetings
Green = for required for 
registry
Verily
Baseline Platform 
PHI
PHI
PHI
Blinding data
Coding
(IBM CD)


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and no data is shared from other sources with the study, and no study data will be shared with 
any other Google systems.   
The study systems at the DCRI DCC support the orchestration of work across partners/vendors, 
integration of study data for operational reporting and statistical analysis, and business processes 
like tracking regulatory documents and processing site payments. All systems are 21CFR11 
compliant and adhere to the Duke Information Security Office policies. All external data 
transfers are exchanged via SSH File Transfer Protocol (SFTP) or encrypted application 
programming interface (API) directly between systems.  
The call center staff will contact study participants directly, as described in the study consent 
form, to obtain precious follow-up information should a participant not respond directly within 
the portal.  The participant contact information will be transferred from the portal into the 
communications system used by the call center for these contacts.  This system manages call 
queues, scheduling, and call processing information.  The study data obtained by the call center 
will be entered directly into the study portal.   
The study data is managed using a set of tools including Oracle (relational database management 
system), Informatica (data exchange/extract-transform-load procedures), Cognos (operational 
reporting), SAS, and SAS Visual Analytics (statistics).   
Data quality is managed at each stage of its lifecycle. Data collected in the portal conforms at 
inception to highly structured data elements and protocol-specific rules, subsequent data transfers 
are checked to conform to format and semantic specifications and all data is assessed for 
referential integrity across sources through a set of reconciliation practices upon integration then 
followed by a variety of logical checks within a participant and in aggregate.  
12.2. 
Study Records Retention 
Study documents should be retained for a minimum of six years after the study has ended. 
However, if required by local regulations, these documents should be retained for a longer 
period. No records will be destroyed without the written consent of the sponsor, if applicable. It 
is the responsibility of the sponsor to inform the investigator when these documents no longer 
need to be retained. 
12.3. 
Protocol Deviations 
A protocol deviation is defined as non-compliance with the clinical study protocol, GCP, or 
MOP requirements. The non-compliance may be on the part of the participant, site investigator, 
or the site staff.  
A major protocol deviation is a significant divergence from the protocol that may have 
significant effect on the subject’s safety, rights, or welfare and/or on the integrity of the study 
data.  Major protocol deviations must be sent to the study IRB and local IRB per their guidelines, 
recorded in source documents, and reported to the coordinating center. Major protocol deviations 
will be tracked. 


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12.4. 
Publication and Data Sharing Policy 
This study will comply with the PCORI Public Access Policy, which ensures that the public has 
access to the results of PCORI-funded research. Methods of data sharing for HERO-HCQ will 
include 1) archiving de-identified data in a data repository and 2) sharing of limited datasets 
under a Data Use Agreement (DUA) and IRB approval. Data will be made available to qualified 
investigators by archiving a fully de-identified dataset in a platform to be determined at the end 
of the trial. Both repositories allow users to search, view study information, and then submit an 
application to receive data. Prior to archiving study data, the DCC will produce a final dataset 
that will be stripped of all personal health information (PHI), including full date elements, in 
compliance with the Health Insurance Portability and Accountability Act (HIPAA) privacy rule. 
The relative timing of an event will be retained in the dataset converting to study days instead of 
dates.  
The study result will be returned, including some participant specific results, to enhance value from 
participation.  Study results will be disseminated to the public and the medical community through 
presentations at scientific meetings and publishing manuscripts in high impact peer-reviewed 
journals. The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical studies registration policy as a condition for publication. The ICMJE defines a 
clinical study as any research project that prospectively assigns human participants to 
intervention or concurrent comparison or control groups to study the cause-and-effect 
relationship between a medical intervention and a health outcome. The ICMJE policy, and the 
Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all 
clinical studies be registered in a public registry such as ClinicalTrials.gov, which is sponsored 
by the National Library of Medicine. For interventional clinical trials performed under NIH IC 
grants and cooperative agreements, it is the grantee’s responsibility to register the study in an 
acceptable registry, so the research results may be considered for publication in ICMJE member 
journals.  
 


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13. 
Study Leadership 
The Steering Committee is a multi-stakeholder committee that oversees the study and includes 
representatives from clinical sites, the trial coordinating center, the PCORnet Coordinating 
center, HCWs and chaired by a member selected by the funding agency, PCORI.  
The HCW Committee is composed of HCWs who represent potential participants of the trial to 
provide perspective of those who will ultimately benefit the most from the learnings or results of 
the trial. The HCW Committee will have input into the design, conduct, interpretation and 
dissemination of the trial.    
The Executive Committee is a subset of the Steering Committee and consists of the Principal 
Investigators of the Clinical Coordinating Center (CCC), the DCC, and the Steering Committee 
Co-Chair. The Executive Committee is charged with overseeing the day-to-day operations of the 
trial as an extension of the Steering Committee, to ensure efficient and high-quality performance.  
The Coordinating Center is composed of a CCC and a DCC, each overseen by principal 
investigator(s).  The CCC is responsible for study coordination, site management, 
communication, and financial administration.  The DCC is responsible for treatment allocations, 
receipt and processing of data, quality control programs, and statistical analysis and reporting.   
An independent DSMB will oversee the safety and welfare of trial participants as well as provide 
recommendations for continuation, discontinuation or revision of the trial. 
 
 
 
Figure 2: Operational Structure Diagram 


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14. 
Summary of Changes 
Protocol Version (version #, date) 
Summary of Changes 
Version 0.2, 4/07/2020 
Changed all study dates from weeks to days; 
updated Key Exclusion Criteria in the 
synopsis to be consistent with the Exclusion 
Criteria in the eligibility section (Section 5.2); 
updated schema to correct events that will 
occur in HERO Registry vs. HERO-HCQ 
Clinical trial (Section 1.2); clarified that all 
Eligibility Criteria will be obtained per 
participant (Section 5); modified inclusion 
criteria to allow HCWs in “related healthcare 
services” and those who work in a COVID-19 
testing location or inpatient hospital unit/area 
with potential COVID-19 cases (Section 5.1); 
added cirrhosis as an Exclusion Criteria 
(Section 5.2); clarified that participant 
recruitment will be exclusively from the 
HERO Registry (Section 5.3.1); clarified that 
participants may be called at 30 and 60 days 
for follow-up after early withdrawal (Section 
7.1); added that participants may be contacted 
at work for follow-up (Section 7.3); added 
windows to Study Visits (Section 8.1); added 
“Serious” to the AE collection line and a 
footnote to details medical record review at 
Final Visit for SAEs and Events of Special 
Interest (Table 1); added language that 
positive COVID-19 test results be 
communicated to sites and they are expected 
to report to the participant and state health 
department per local regulations (Section 
8.2); provided more details about safety 
reporting to FDA (Section 9.1.3); removed 
specified document requirements for 
unblinding (Section 10.4); participants with 
suspected COVID-19 will be included in the 
primary outcome (Section 10.6.1); updated 
Interim Analysis Plan (Section 10.7); 
specified that the DSMB will send study 
recommendations to the IND sponsor only 
(Section 10.8); clarified that blood samples 
will be sent to a central lab (Section 11.4); 
updated the Data Flow Diagram to reflect 


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changes in data flow (Figure 1); clarified that 
PCORI is the funding agency (Section 13); 
removed PCORI from the Operational 
Structure Diagram (Figure 2). 
Version 1.0, 4/10/2020 
Changed Randomization Section under Study 
Population to Participation Randomization 
Process sub-heading (Section 5.3.3) to avoid 
confusion with Randomization section in the 
Statistical Section (Section 10.3); corrected 
HCQ table shape from peanut-shaped to 
round (Section 6.1.1); added the following 
exclusion criteria per FDA recommendation 
(Section 5.2): history of severe skin reactions, 
history of psoriasis or porphyria, ventricular 
arrhythmias requiring medical treatment, 
severe coronary artery disease or heart 
failure/cardiomyopathy with ongoing 
symptoms, known cirrhosis or severe liver 
disease, current or planned use of anti-seizure 
drugs, history of Glucose-6-phosphate 
dehydrogenase deficiency; adding 
hypoglycemia and neuropsychiatric events as 
risks of taking HCQ (Section 2.3.1); updated 
the primary analysis population to include 
only randomized participants with a baseline 
negative RT-PCR test per FDA 
recommendation (Section 10.5); removed ITT 
population analysis (Sections 10.5 and 
10.6.1); added all-cause mortality analysis 
(Section 10.6.3); changed proportional 
hazards to logistic regression (Section 10.6.5). 
Version 2.0, 5/01/2020 
Updated Key Inclusion and Exclusion Criteria 
in the Synopsis (Section 1); numbered 
eligibility criteria (Sections 5.1 and 5.2); 
added the following to Inclusion Criteria: 
broadened definition of HCW and removed 
“able to speak and read English or Spanish” 
(Section 5.1); added the following Exclusion 
Criteria: current or planned use of HCQ 
(study drug) for any indication and removed 
HCQ from the subsequent bullet due to 
redundancy with the added criteria (Section 
5.2); updated participant recruitment and 
engagement strategies (Sections 5.3.1 and 


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5.3.2); COVID-19 questionnaire and AE 
collection removed at baseline (Table 1 and 
Section 8.1.1); clarified that data may be 
collected from participant’s medical record 
(Section 8 and Table 1); sites should notify 
CC of HCW dose modifications (Section 8); 
added that randomization should occur within 
3 days of consent and may be done in-person 
or by phone (Section 8.1.1); AE collection 
changed to SAE and EOSI collection as only 
SAEs and EOSIs will be collection (Sections 
8.1.1, 8.1.2, and 8.1.3); added SUSAR 
causality and expedited reporting of SUSARs 
to FDA (Section 9); corrected Quality 
Insurance to Quality Assurance (Section 
11.5); other administrative changes. 
Version 3.0, 7/07/2020 
Updated Study Rationale and Background 
(Sections 1.2, 2.1, 2.2).  Changed the 
definition of confirmed and suspected clinical 
infection with COVID-19 for the primary 
endpoints (Section 3).  The rationale for this 
update is as follows: Initial reports of COVID 
like illness identified fever as the most 
common symptom, reported as occurring in 
>80% of cases; thus, in an attempt to increase 
the specificity of the definition for suspected 
clinical infection, the originally primary 
endpoint required 2 symptoms of fever plus 
either cough or dyspnea. Data from a recent 
publication [51] resulted in calculations that 
showed only 40% of lab confirmed cases 
reported fever, 30% reported fever plus cough 
and only 10% reported fever plus shortness of 
breath. Similarly, only 38% of probably cases 
reported fever,  25% reported fever plus 
cough and only 8% reported fever plus 
shortness of breath. This data indicates that 
the more stringent definition of suspected 
COVID infection would underestimate actual 
case rate. Thus the endpoint is being amended 
to redefine suspected clinical COVID 
infection as only one of three new-onset 
symptoms (fever or cough or dyspnea).  


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Updated sample size (Sections 1.1, 1.2, 4.1 
and 10.2), updated the statistical analysis plan 
for the primary objective and the interim 
analysis (Sections 1.1, 10.6.1, 10.6.2, 10.7), 
updated inclusion to broaden definition of 
HCW (Sections 1.1 and 5.1), clarified End of 
Study Visit as completing the Final Visit at 60 
days (Section 4.2), and other minor 
administrative changes. 


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15. 
References 
1. 
COVID-19 Map FAQ. 2020  [cited 2020; Available from: 
https://coronavirus.jhu.edu/map-faq.html. 
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McIntosh, K. Coronavirus disease 2019. 2020  [cited 2020 March 24]. 
3. 
Burton, T.a.L., P, Human Testing Begins Earlier Than Expected For U.S. Coronavirus 
Vaccine. The Wall Street Journal, 2020. 
4. 
Minder, R.a.P., E, Virus Knocks Thousands of Health Workers Out of Action in Europe. 
The New York Times, 2020. 
5. 
Wang, X., X. Zhang, and J. He, Challenges to the system of reserve medical supplies for 
public health emergencies: reflections on the outbreak of the severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) epidemic in China. Biosci Trends, 2020. 14(1): p. 
3-8. 
6. 
Grein, J., et al., Compassionate Use of Remdesivir for Patients with Severe Covid-19. 
New England Journal of Medicine, 2020. 382(24): p. 2327-2336. 
7. 
Beigel, J.H., et al., Remdesivir for the Treatment of Covid-19 — Preliminary Report. New 
England Journal of Medicine, 2020. 
8. 
McCreary, E.K., J.M. Pogue, and o.b.o.t.S.o.I.D. Pharmacists, COVID-19 Treatment: A 
Review of Early and Emerging Options. Open Forum Infectious Diseases, 2020. 
9. 
Kalil, A.C., Treating COVID-19—Off-Label Drug Use, Compassionate Use, and 
Randomized Clinical Trials During Pandemics. JAMA, 2020. 
10. 
Wang, M., et al., Remdesivir and chloroquine effectively inhibit the recently emerged 
novel coronavirus (2019-nCoV) in vitro. Cell Research, 2020. 30(3): p. 269-271. 
11. 
Liu, J., et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in 
inhibiting SARS-CoV-2 infection in vitro. Cell Discovery, 2020. 6(1): p. 16. 
12. 
Yao, X., et al., In Vitro Antiviral Activity and Projection of Optimized Dosing Design of 
Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2). Clin Infect Dis, 2020. 
13. 
Sturman, L.S., C.S. Ricard, and K.V. Holmes, Conformational change of the coronavirus 
peplomer glycoprotein at pH 8.0 and 37 degrees C correlates with virus aggregation and 
virus-induced cell fusion. J Virol, 1990. 64(6): p. 3042-50. 
14. 
Zhou, D., S.-M. Dai, and Q. Tong, COVID-19: a recommendation to examine the effect 
of hydroxychloroquine in preventing infection and progression. Journal of Antimicrobial 
Chemotherapy, 2020. 
15. 
Wang, D., et al., Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel 
Coronavirus–Infected Pneumonia in Wuhan, China. JAMA, 2020. 323(11): p. 1061-
1069. 
16. 
Wu, C., et al., Risk Factors Associated With Acute Respiratory Distress Syndrome and 
Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA 
Internal Medicine, 2020. 


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17. 
Keyaerts, E., et al., In vitro inhibition of severe acute respiratory syndrome coronavirus 
by chloroquine. Biochem Biophys Res Commun, 2004. 323(1): p. 264-8. 
18. 
Vincent, M.J., et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and 
spread. Virol J, 2005. 2: p. 69. 
19. 
Fox, R.I., Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin 
Arthritis Rheum, 1993. 23(2 Suppl 1): p. 82-91. 
20. 
Tett, S.E., Clinical pharmacokinetics of slow-acting antirheumatic drugs. Clin 
Pharmacokinet, 1993. 25(5): p. 392-407. 
21. 
McChesney, E.W., et al., Studies of the metabolism of some compounds of the 4-amino-7-
chloroquinoline series. J Pharmacol Exp Ther, 1966. 151(3): p. 482-93. 
22. 
Cella, D., et al., The Patient-Reported Outcomes Measurement Information System 
(PROMIS): progress of an NIH Roadmap cooperative group during its first two years. 
Med Care, 2007. 45(5 Suppl 1): p. S3-S11. 
23. 
The Patient Reported Outcomes Measurement Information System (PROMIS): A Walk 
Through the First Four Years, (2009). 
24. 
Dyrbye, L.N., et al., Association of Clinical Specialty With Symptoms of Burnout and 
Career Choice Regret Among US Resident Physicians. JAMA, 2018. 320(11): p. 1114-
1130. 
25. 
Pilkonis, P.A., et al., Item banks for measuring emotional distress from the Patient-
Reported Outcomes Measurement Information System (PROMIS(R)): depression, 
anxiety, and anger. Assessment, 2011. 18(3): p. 263-83. 
26. 
Batterham, P.J., et al., Psychometric Properties of 7- and 30-Day Versions of the 
PROMIS Emotional Distress Item Banks in an Australian Adult Sample. Assessment, 
2019. 26(2): p. 249-259. 
27. 
Teresi, J.A., et al., Measurement Equivalence of the Patient Reported Outcomes 
Measurement Information System((R)) (PROMIS((R))) Pain Interference Short Form 
Items: Application to Ethnically Diverse Cancer and Palliative Care Populations. 
Psychol Test Assess Model, 2016. 58(2): p. 309-352. 
28. 
Schalet, B.D., et al., Clinical validity of PROMIS Depression, Anxiety, and Anger across 
diverse clinical samples. J Clin Epidemiol, 2016. 73: p. 119-27. 
29. 
Maslach C, Jackson SE. The measurement of experienced burnout. J Occ Behav. 
1981;2:99–113. 
30. 
Gil-Monte, P.R., Factorial validity of the Maslach Burnout Inventory (MBI-HSS) among 
Spanish professionals. Rev Saude Publica, 2005. 39(1): p. 1-8. 
31. 
Kanste, O., J. Miettunen, and H. Kyngas, Factor structure of the Maslach Burnout 
Inventory among Finnish nursing staff. Nurs Health Sci, 2006. 8(4): p. 201-7. 
32. 
West, C.P., et al., Single item measures of emotional exhaustion and depersonalization 
are useful for assessing burnout in medical professionals. J Gen Intern Med, 2009. 
24(12): p. 1318-21. 


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33. 
Rohland BM, Kruse GR, Rohrer JE. Validation of a single-item measure of burnout 
against the Maslach Burnout Inventory among physicians. Stress and Health. 
2004;20(2):75–9. doi: 10.1002/smi.1002. 
34. 
McMurray, J.E., et al., The work lives of women physicians results from the physician 
work life study. The SGIM Career Satisfaction Study Group. J Gen Intern Med, 2000. 
15(6): p. 372-80. 
35. 
Dolan, E.D., et al., Using a single item to measure burnout in primary care staff: a 
psychometric evaluation. J Gen Intern Med, 2015. 30(5): p. 582-7. 
36. 
Kroenke, K., R.L. Spitzer, and J.B. Williams, The Patient Health Questionnaire-2: 
validity of a two-item depression screener. Med Care, 2003. 41(11): p. 1284-92. 
37. 
Arroll, B., et al., Validation of PHQ-2 and PHQ-9 to screen for major depression in the 
primary care population. Ann Fam Med, 2010. 8(4): p. 348-53. 
38. 
Chagas, M.H., et al., Validity of the PHQ-2 for the screening of major depression in 
Parkinson's disease: two questions and one important answer. Aging Ment Health, 2011. 
15(7): p. 838-43. 
39. 
Richardson, L.P., et al., Evaluation of the PHQ-2 as a brief screen for detecting major 
depression among adolescents. Pediatrics, 2010. 125(5): p. e1097-103. 
40. 
Corson, K., M.S. Gerrity, and S.K. Dobscha, Screening for depression and suicidality in 
a VA primary care setting: 2 items are better than 1 item. Am J Manag Care, 2004. 10(11 
Pt 2): p. 839-45. 
41. 
Unrath, M., et al., The mental health of primary care physicians in Rhineland-Palatinate, 
Germany: the prevalence of problems and identification of possible risk factors. Dtsch 
Arztebl Int, 2012. 109(11): p. 201-7. 
42. 
Brennan, J., McGrady, A., Whearty, K. et al. Emotional Status of Third Year Medical 
Students and Their Responses to a Brief Intervention. ANN BEHAV SCI MED EDUC 18, 
10–14 (2012). https://doi.org/10.1007/BF03355199. 
43. 
Sen, S., et al., A prospective cohort study investigating factors associated with depression 
during medical internship. Arch Gen Psychiatry, 2010. 67(6): p. 557-65. 
44. 
Earle, L. and L. Kelly, Coping strategies, depression, and anxiety among Ontario family 
medicine residents. Can Fam Physician, 2005. 51: p. 242-3. 
45. 
Broglio, K., Randomization in Clinical Trials: Permuted Blocks and Stratification. Jama, 
2018. 319(21): p. 2223-2224. 
46. 
Cox, D.R., Regression Models and Life-Tables. Journal of the Royal Statistical Society. 
Series B (Methodological), 1972. 34(2): p. 187-220. 
47. 
Glidden, D.V. and E. Vittinghoff, Modelling clustered survival data from multicentre 
clinical trials. Stat Med, 2004. 23(3): p. 369-88. 
48. 
Evans, S.R., L. Li, and L. Wei, Data Monitoring in Clinical Trials Using Prediction. 
Drug Information Journal, 2007. 41(6): p. 733-742. 


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49. 
Haybittle, J.L., Repeated assessment of results in clinical trials of cancer treatment. Br J 
Radiol, 1971. 44(526): p. 793-7. 
50. 
Peto, R., et al., Design and analysis of randomized clinical trials requiring prolonged 
observation of each patient. I. Introduction and design. Br J Cancer, 1976. 34(6): p. 585-
612. 
51. 
Boulware, D.R., et al., A Randomized Trial of Hydroxychloroquine as Postexposure 
Prophylaxis for Covid-19. New England Journal of Medicine, 2020. 
 

SAP_001.pdf: 
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Statistical Analysis Plan (HERO-HCQ) 
 
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Version 1.0  
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Statistical Analysis Plan 
 
HERO-HCQ  
  
 
 
Healthcare Worker Exposure Response and Outcomes of 
Hydroxychloroquine Trial (HERO-HCQ Trial) 
  
Version: 1.0 
Effective: 04 September 2020 
 
 
Protocol Date: 7/07/2020 
Version: 3.0 
Funded By: PCORI 
 
 
 
 
 
 
 
 
 
 
Prepared by: 
Jyotsna Garg, Steven NcNulty, Hillary Mulder 
Biostatistician(s) 
Duke Clinical Research Institute 
 
Reviewed by: 
Kevin Anstrom, PhD 
Professor of Biostatistics and Bioinformatics 
Duke Clinical Research Institute 
 
 


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SAP approved by: 
 
 
 
 
 
 
Adrian Hernandez, MD, MHS 
Date 
Duke Clinical Research Institute 
 
 
 
 
 
Susanna Naggie, MD 
Date 
Duke Clinical Research Institute 
 
 
 
 
 
Kevin Anstrom, PhD 
Date 
Duke Clinical Research Institute 
 
 
 
 
 
 
 
 
 


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Version 1.0  
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Summary of Changes 
Date 
Description 
8/25/2020 
 
DRAFT 
9/4/2020 
 
Final, ready for signature 
 
 


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Table of Contents 
1. 
Introduction ...............................................................................................................................5 
1.1 Objectives of Study ...............................................................................................................5 
1.1.1 
Primary ........................................................................................................................ 5 
1.1.2 
Secondary .................................................................................................................... 5 
1.1.3 
Exploratory ................................................................................................................. 5 
1.2 Study Population and Stratification ......................................................................................5 
1.3 Sample Size Determination...................................................................................................5 
1.4 Blinding.................................................................................................................................5 
1.4.1 
Blinding Method ......................................................................................................... 5 
1.4.2 
Interim Analyses ......................................................................................................... 5 
2. 
General Analysis Considerations ..............................................................................................6 
2.1 Analysis Populations .............................................................................................................6 
2.1.1 
Intention-to-treat (ITT) analysis set ............................................................................ 6 
2.1.2 
Modified Intention-to-treat (mITT) analysis set ......................................................... 6 
2.2 Study Day Derivation ...........................................................................................................6 
2.3 Handling of Dropouts and Missing data ...............................................................................6 
2.4 Type 1 Error Rate..................................................................................................................6 
3. 
Enrollment and Study Conduct .................................................................................................7 
4. 
Efficacy Evaluations .................................................................................................................7 
4.1 Primary Endpoint ..................................................................................................................7 
4.1.1 
Primary Efficacy Analysis .......................................................................................... 7 
4.2 Secondary Endpoint ..............................................................................................................7 
4.2.1 
Viral Shedding of SARS-CoV-2 ................................................................................. 7 
4.3 Other Secondary Endpoints ..................................................................................................8 
4.3.1 
All-Cause Mortality .................................................................................................... 8 
4.3.2 
All-Cause Hospitalization ........................................................................................... 8 
4.3.3 
Cause specific Hospitalization .................................................................................... 8 
4.4 Exploratory Endpoint ............................................................................................................8 
4.5 Sensitivity Analysis ..............................................................................................................8 
4.5.1 
Cox proportional hazard model stratified by site ........................................................ 8 
5. 
Subgroup Analysis ....................................................................................................................9 
6. 
Safety Evaluations ....................................................................................................................9 
6.1 Safety and Tolerability of HCQ ............................................................................................9 
6.2 Adverse Events .....................................................................................................................9 
7. 
Database Sources ....................................................................................................................10 
8. 
References ...............................................................................................................................10 
 
 
 


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1. Introduction  
  
The HERO-HCQ is a phase 3, randomized, double-blind, placebo controlled study of the 
efficacy and safety of Hydroxychloroquine to prevent COVID-19 clinical infection in healthcare 
workers (HCWs). Screening and randomization will be followed by a total of 30 days of blinded, 
placebo-controlled treatment and 30 more days of follow-up. This document describes data 
analysis methods and data summaries for the primary manuscript.  Analysis approaches detailed 
within supersede the protocol with respect to the analyses and summaries. 
1.1 Objectives of Study 
1.1.1 Primary 
To evaluate the efficacy of HCQ to prevent COVID-19 clinical infection in healthcare 
workers (HCWs) 
1.1.2 Secondary 
 
To evaluate the efficacy of HCQ to prevent viral shedding of SARS-CoV-2 among HCWs  
 Evaluate safety and tolerability of HCQ  
1.1.3 Exploratory 
 
Evaluate SARS-CoV-2 seroconversion in participants taking HCQ 
 
1.2 Study Population and Stratification 
Randomization will be stratified by site and occur onsite. Both participants and the study team 
will remain blinded to assignment throughout the study. 
1.3 Sample Size Determination 
The sample size of approximately 2,000 randomized participants was selected to yield high 
power for testing the primary outcome of clinical infection with COVID-19.  Please reference 
section 10.2 of the clinical study protocol for further details about the sample size calculations. 
1.4 Blinding  
1.4.1 Blinding Method 
The statistical team working on the final analyses as governed by this SAP will be blinded to 
treatment through data base lock.  
1.4.2 Interim Analyses  
Regular DSMB reviews will be conducted to ensure the safety of study participants and evaluate 
the accumulating endpoint data by treatment group.  


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It is expected that both internal and external factors will influence the decisions of the DSMB.  
The Statistical Analysis Plan for the DSMB will describe the planned interim analyses and 
futility monitoring in greater detail. 
2. General Analysis Considerations 
This report will utilize participant data through their most recent mortality status or last visit date 
in the 60 day follow-up period unless specified otherwise.     
Any reference to new-onset of symptom in context of this trial is defined as reporting of a 
symptom at a visit. Any negative or unknown result COVID-19 test with missing or unknown 
date will not be used while defining clinically confirmed or suspected COVID-19. Data from all 
sites will be pooled for analyses.  
Analyses will be performed using SAS software version 9.4 or higher (SAS Institute, Inc., Cary, 
NC). 
2.1 Analysis Populations  
2.1.1 Intention-to-treat (ITT) analysis set 
The ITT population (ITT) is defined as all randomized participants. The ITT population will be 
used for all secondary and exploratory efficacy analysis and for safety analyses. Participants will 
be analyzed according to their assigned randomized treatment. 
2.1.2 Modified Intention-to-treat (mITT) analysis set 
The mITT population includes participants in the ITT with baseline negative RT-PCR test.  
Subjects will be analyzed according to their assigned randomized treatment. The modified ITT 
population (mITT) will be used for analysis of the primary efficacy endpoint 
2.2 Study Day Derivation 
The day of the study is the day relative to randomization date, (study date – randomization 
date)+1.  
2.3 Handling of Dropouts and Missing data 
Missing data will not be imputed for the primary efficacy analysis of clinical infection with 
COVID-19.  
2.4 Type 1 Error Rate 
All the Type 1 error will be used for the primary analysis. Hence, the statistical significance of 
the secondary analyses is dependent on first achieving statistically significant results in the 
primary efficacy analysis.  


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3. Enrollment and Study Conduct 
Descriptive summaries of enrollment, baseline characteristics, medical history, participant status, 
retention, adherence to randomized treatment, and concomitant medication will be presented in 
table and graphical format as applicable.  
4. Efficacy Evaluations 
4.1 Primary Endpoint  
The primary endpoint for the study is clinical infection with COVID-19 through day 30 visit. It 
is defined as  a binary composite outcome of : 
(1) clinically confirmed COVID-19 identified as new-onset of fever, or cough, or dyspnea along  
with  a positive COVID-19 test result via local or central laboratory test results, or  
(2) a suspected COVID-19 identified as new-onset of fever, or cough or dyspnea in the absence  
of negative COVID-19 test result within 7 days following any reported symptoms, via local 
or central laboratory test results.  
 
The possible values of the endpoint are : 
Yes : confirmed or suspected COVID-19 
No : neither confirmed nor suspected COVID-19 
4.1.1 Primary Efficacy Analysis 
The primary efficacy analysis conducted in mITT will test for treatment effect presented as 
difference in the proportion of participants with COVID-19 clinical infection between the 
treatment groups. The 95% CI for this difference will be constructed using Miettinen-Nurminen 
method and Chang-Zhang exact method.  
Additionally, we will use a logistic regression model with an indicator for the treatment group as 
supportive analysis. The estimated odds ratio and associated 95% confidence interval as well as 
the P value testing the null hypothesis will be reported.   
The primary hypothesis is: 
H0 (null hypothesis): Allocation to HCQ results in no change in COVID-19 infection 
among HCWs at risk for COVID-19 infection 
Ha (alternative hypothesis) Allocation to HCQ results in prevention of COVID-19 
infection among HCWs at risk for COVID-19 infection. 
The primary hypothesis will be formally tested (two-tailed) at the alpha level of 0.05.  
 
4.2  Secondary Endpoint 
4.2.1  Viral Shedding of SARS-CoV-2   
Viral shedding of SARS-CoV-2 data at 30 days received as a binary response from the 
central lab and collected via nasal swabs will be analyzed in ITT to assess the efficacy of 


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HCQ to prevent viral shedding of SARS-CoV-2 among HCWs. This viral shedding 
endpoint is independent of reported symptoms. 
 
Analyses of the viral shedding secondary efficacy endpoint will be conducted using a 
logistic  regression model with an indicator for the treatment group or the Fisher’s exact 
test dependent on distribution of data. Adjustment covariates such as age,sex, race may 
be used in the logistic regression model if the data allow.  
4.3 Other Secondary Endpoints 
Additional secondary endpoints, not adjusted for alpha are:  
4.3.1 All-Cause Mortality  
Analysis of the binary response for all-cause mortality at day 30 in ITT will be conducted 
using logistic  regression model with an indicator for the treatment group or the Fisher’s 
exact test dependent on distribution of data.  
4.3.2 All-Cause Hospitalization 
Analyses of all-cause hospitalization at day 30 in ITT defined as a hospitalization 
indicated on the COVID-19 questionnaire or within the SAE/EOSI form will use similar 
strategy as All-cause mortality 
4.3.3 Cause specific Hospitalization 
Covid specific hospitalizations in participants defined as those reported on the COVID-
19 questionnaire will also be analyzed in ITT using similar strategy as all-cause 
mortality.  
4.4 Exploratory Endpoint 
Serology results received as a binary response at baseline and day 30 will be used to 
define the exploratory endpoint of seroconversion at day 30, measured as change to 
positive serology at day 30 with negative serology at baseline. The response will be 
analysed in the ITT population with negative baseline serology using logistic regression 
model with an indicator for the treatment group or the Fisher’s exact test dependent on 
distribution of data. 
4.5 Sensitivity Analysis 
Below methods will be used to assess sensitivity of various analyses completed. 
4.5.1 Cox proportional hazard model stratified by site  
A sensitivity analysis will use the time-to-clinical infection (confirmed or suspected) with 
COVID-19 outcome in mITT. For this analysis, the treatment groups will be compared 
using a Cox proportional hazards regression model with the baseline hazard function 
stratified by site. The estimated hazard ratio and associated 95% confidence interval will 
be used to summarize the treatment effect. The model will account for clustering of 
participants within site by using the robust sandwich covariance estimate. 


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Time-to-clinically confirmed Covid-19 and time-to-clinically suspected Covid-19 will be 
analyzed similar to the composite of time-to-clinical infection. 
            Finally, a Kaplan-Meier curve for time to clinical infection with  
            COVID-19 will be included.   
 
5. Subgroup Analysis 
Subgroup analyses will be conducted for the following pre-specified sub-groups for the   primary 
endpoint:  
o Age (<35, 35-50, >=50) 
o Sex (M, F) 
o Race (White, Others) 
o Ethnicity (Hispanic/Latino, non-Hispanic/Latino) 
For each subgroup analysis, a logistic regression model similar to the one described above for the 
primary analyses will be used, but with additional terms identifying subgroup membership and the 
intervention by subgroup interaction. 
6. Safety Evaluations 
6.1 Safety and Tolerability of HCQ  
Safety assessments will be based on ITT population and if needed by treated population. 
Descriptive summaries of SAE, Events of special interest (EOSI), and unanticipated 
problems will be generated for each randomized treatment group. The statistical 
comparisons of the randomized arms with respect to the SAEs and EOSI will use Fisher's 
exact test.  
1. Safety and tolerability of HCQ via serious adverse events (SAE) 
2. Safety and tolerability of HCQ via events of special interest (EOSI)  
 
Supplementary analyses will only be performed where these summaries suggest that there may be 
clinically significant differences.  
For continuous safety parameters, at least one post-randomization measurement is required for 
inclusion in the analysis. To assess change from baseline, a baseline measurement is also required. 
6.2 Adverse Events  
Events of special interest (EOSI) and serious adverse event (SAE) data will be collected on the 
“Adverse Events” eCRF and coded using the MedDRA dictionary.  
 
A participant level summary table of adverse events by treatment through 60 days will be 
presented.  This table will include: 
 
• Participants who experienced at least one SAE/EOSI 
• Serious TEAE 


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• SAE with fatal outcome 
• SAE resulting in permanent treatment discontinuation  
• SAE related to study drug 
• Severe TEAE 
   
The incidence of each SAE will also be summarized by system organ class, preferred term and 
treatment assignment. Multiple AEs mapped to the same preferred term will be counted once per 
participant though the number of events per preferred term may also be presented.   
7. Database Sources 
The data used for analysis will come from 4 main sources:  
 the Interactive Web/Voice Response System (Almac),  
 the HERO-HCQ e-CRF includes participant self reported data, call center information 
and site reported data (Verily),  
 limited baseline information from HERO Registry e-CRF (Verily),  
 the central laboratory which provides results of nasopharyngeal swab (Covance). 
 And the serology data from Duke laboratory.  
Data from the IXRS will be used to determine treatment assignment. The e-CRF will be the 
source for site-level geographic information, all baseline and follow-up data entered by the sites, 
participants or the call center. The HERO-HCQ clinical database will be housed in EDC 
(Electronic Data Capture) hosted by Verily Health Sciences.  The central laboratory from 
Covance and the serology data from Duke laboratory will be transferred to the Duke Clinical 
Research Center (DCRI). DCRI will obtain unblinded randomization data collected in the 
Interactive Voice/Web Response System (IXRS) from Almac after the 60 day follow-up data are 
locked for analysis.  
 
8. References 
1. Will, G., Constructing Confidence Intervals for the Differences of Binomial Proportions in 
SAS® 
2. Broglio, K., Randomization in Clinical Trials: Permuted Blocks and Stratification. Jama, 
2018. 319(21): p. 2223-2224.  
3. Cox, D.R., Regression Models and Life-Tables. Journal of the Royal Statistical Society. 
Series B (Methodological), 1972. 34(2): p. 187-220. 
4. Glidden, D.V. and E. Vittinghoff, Modelling clustered survival data from multicentre 
clinical trials. Stat Med, 2004. 23(3): p. 369-88