Conditions: COVID-19 Coronavirus Coronavirus Infections SARS-CoV 2
Keywords: COVID-19 Coronavirus Healthcare Workers SARS-CoV 2 First Responders Emergency Medical Technicians Paramedics Firefighters Police Officers Detroit Michigan Henry Ford Hospital
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 624
Healthy volunteers: yes

Brief summary:
This is a prospective, multi-site study designed to evaluate whether the use of hydroxychloroquine in healthcare workers (HCW), Nursing Home Workers (NHW), first responders (FR), and Detroit Department of Transportation bus drivers (DDOT) in SE, Michigan, can prevent the acquisition, symptoms and clinical COVID-19 infection

The primary objective of this study is to determine whether the use of daily or weekly oral hydroxychloroquine (HCQ) therapy will prevent SARS-CoV-2 infection and COVID-19 viremia and clinical COVID-19 infection healthcare workers (HCW) and first responders (FR) (EMS, Fire, Police, bus drivers) in Southeast Michigan.

Preventing COVID-19 transmission to HCW, FR, and Detroit Department of Transportation (DDOT) bus drivers is a critical step in preserving the health care and first responder force, the prevention of COVID-19 transmission in health care facilities, with the potential to preserve thousands of lives in addition to sustaining health care systems and civil services both nationally and globally. If efficacious, further studies on the use of hydroxychloroquine to prevent COVID-19 in the general population could be undertaken, with a potential impact on hundreds of thousands of lives.

Detailed description:
The study will randomize a total of 3,000 HCW, NHW, FR and DDOT bus drivers within Henry Ford Hospital System, the Detroit COVID Consortium in Southeast, Michigan. The participants will be randomized in a 1:1:1 blinded comparison of daily HCQ, weekly HCQ, or placebo. A fourth non-randomized comparator group of HCW, NHW, DDOT bus drivers, and FR who are currently on standard HCQ therapy will be recruited to assess the impact of weightbased daily dosing of HCQ as compared to the randomized arms.

Eligible participants who are asymptomatic for pre-specified signs and symptoms suggestive of COVID-19 infection will have a whole blood specimen obtained at study entry.

Participants will be provided with weekly dosing of hydroxychloroquine (HCQ) 400mg po q weekly, daily dosing of HCQ 200mg po q daily following a loading dose of 400mg day 1, or placebo. Participants will receive monitoring at each study week visit to assess for the development of COVID-19 related symptoms, COVID-19 clinical disease, and medication side effects. At week 8 or if diagnosed positive, participants will provide additional samples of whole blood and complete the final study questionnaire.

Data including demographic, clinical results, work duties, location of main work area and possible exposures in the community will be collected through questionnaires and EMR review. Disease-specific, immunologic, and other serologic marker data will be obtained from stored samples.

Arms:
arm 1: The daily hydroxychloroquine treatment arm will receive a 200 mg oral dose daily following day 1 dose of 400 mg orally once. This dose represents approximately half the standard weight-based dosing recommended for management of autoimmune diseases and therefore less likely to produce side effects than standard of care. arm 2: The once weekly randomized treatment arm will receive the proposed dose of hydroxychloroquine for prophylaxis of malaria is 6.5 mg/kg per dose (maximum of 400mg per dose) administered orally weekly on the same day of each week. This is based on the recommended dose for prophylaxis of malaria. arm 3: All treatment groups will receive placebo pills to have the patients take 2 pills a day. The randomized placebo arm will receive placebo pills made to resemble the daily dosing of HCQ. Similarly, the once a week treatment arm will receive placebo pills for the days not on HCQ medication. arm 4: A non-randomized comparator group will be enrolled in the study comprising of healthcare workers and first responders who are chronically on oral hydroxychloroquine as part of their standard of care for their autoimmune disease(s). This will be an open enrollment group and will provide information of chronic weight-based daily therapy of HCQ effectiveness as a prophylactic/preventive strategy.

Interventions: intervention 1: Hydroxychloroquine - Daily Dosing intervention 2: Hydroxychloroquine - Weekly Dosing intervention 3: Placebo oral tablet intervention 4: Monitoring Visit - Baseline intervention 5: Monitoring Visit - Week 4 intervention 6: Monitoring Visit - Week 8 intervention 7: Weekly Assessment
Intervention descriptions: intervention 1: The daily hydroxychloroquine treatment arm will receive a 200 mg oral dose daily following day 1 dose of 400 mg orally once. This dose represents approximately half the standard weight-based dosing recommended for management of autoimmune diseases and therefore less likely to produce side effects than standard of care.

All treatment groups will receive placebo pills to have the patients take 2 pills a day. intervention 2: The once weekly randomized treatment arm will receive the proposed dose of hydroxychloroquine for prophylaxis of malaria is 6.5 mg/kg per dose (maximum of 400 mg per dose) administered orally weekly on the same day of each week. This is based on the recommended dose for prophylaxis of malaria

All treatment groups will receive placebo pills to have the patients take 2 pills a day. intervention 3: Participants randomized to this arm will be provided with daily dosing of oral placebo to have the patients take 2 pills a day..

Participants will receive a monitoring phone call at 4 weeks post study entry to monitor for COVID-19 symptoms and medication side effects. At week 8, participants will provide additional samples of whole blood.

Additional studies will include serology, inflammatory and other disease associated markers. Clinical data and location of main work area will be collected. intervention 4: Face-to-face monitoring visit to obtain monitoring questionnaires to assess for COVID-19 symptoms/diagnosis, adherence and medication side effects, and collect study blood samples. Three (3) blood specimens will be collected from each Participant using the sterile procedure as routine standard of care. A total of five (5) 10 mL tubes of whole blood will be collected at each timepoint. intervention 5: Face-to-face monitoring visit to obtain monitoring questionnaires to assess for COVID-19 symptoms/diagnosis, adherence and medication side effects, and collect study blood samples. Three (3) blood specimens will be collected from each Participant using the sterile procedure as routine standard of care. A total of five (5) 10 mL tubes of whole blood will be collected at each timepoint. intervention 6: Face-to-face monitoring visit to obtain monitoring questionnaires to assess for COVID-19 symptoms/diagnosis, adherence and medication side effects, and collect study blood samples. Three (3) blood specimens will be collected from each Participant using the sterile procedure as routine standard of care. A total of five (5) 10 mL tubes of whole blood will be collected at each timepoint. intervention 7: Participants will be asked to contact the study team if COVID-19 infection is established at any time during the study. For study weeks 1,2,3,5,6 \&7, Participants will receive a monitoring questionnaire to assess for COVID-19 symptoms/diagnosis, adherence and medication side effects. These monitoring visits will be done by telephone and/or electronic encounters (virtual visits, email), whichever method the patient prefers to encourage adherence to the monitoring.

Protocol document:
SAP_002.pdf: 
1 
 
 
 
 
 
 
 
 
Data Safety Monitoring Plan  
with inclusion of Statistical Analysis Plan (SAP) in Section 6  
for 
WHIP COVID-19 Study 
 
 
 
 
Revision Date   
June 15, 2020 
 
The second revision date  
November 16, 2020 with revised text as italic  
 
 
 
 
 
 


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Table of Contents 
1. 
Summary of the protocol ................................................................................................................... 4 
1.1 Overview ........................................................................................................................................... 4 
1.2 Primary and Secondary Aims ........................................................................................................ 4 
1.3 Inclusion/Exclusion Criteria ............................................................................................................ 5 
1.4 Target Population, Sample Size and Study Duration................................................................. 7 
1.5 Participating Enrolling Clinics & Data Coordinating Center ...................................................... 7 
2. Study Data Collection & Quality Management .................................................................................. 8 
2.1 Case report forms (CRFs) .............................................................................................................. 8 
2.2 Database management system for study data collection .......................................................... 8 
2.3 EDC CRF data monitoring and quality management ................................................................. 9 
3. Site Training and Management ......................................................................................................... 10 
4. Safety data collection and reporting.................................................................................................. 11 
4.1 Adverse event definitions ............................................................................................................. 11 
4.2 Safety reporting .............................................................................................................................. 12 
5.  Reports for Study Progress and Quality Control ............................................................................ 13 
5.1 Study progress Reports ................................................................................................................ 13 
5.2 Subject accrual / randomization Reports ................................................................................... 13 
5.3 Data collection and management Reports ................................................................................ 13 
5.4 DSMB Reports ............................................................................................................................... 13 
6.  Statistical Analysis Plan (SAP) ......................................................................................................... 14 
6.1 Study Design .................................................................................................................................. 14 
6.2 Locking Data for Analysis/Transfer ............................................................................................. 14 
6.3 Study Aims, Hypothesis and Proposed Analysis ...................................................................... 15 
6.4 Sample size/power calculation .................................................................................................... 21 
6.4.1 Sample size reassessment ................................................................................................... 23 
6.5 Interim analysis schedule ............................................................................................................. 24 


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6.6 Preparing the data for analyses .................................................................................................. 24 
6.7 Stopping rule .................................................................................................................................. 24 
7. Data Safety Monitoring Board ............................................................................................................ 24 
8. Confidentiality ....................................................................................................................................... 25 
8.1 Protection of Subject Privacy ....................................................................................................... 25 
8.2 Database Protection ...................................................................................................................... 25 
8.3 Confidentiality during AE Reporting ............................................................................................ 26 
References ................................................................................................................................................ 27 
 
 
 
 


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1. Summary of the protocol 
1.1 Overview 
This is a prospective, multi-site study designed to evaluate whether the use of 
hydroxychloroquine in healthcare workers including healthcare providers and employees of 
hospitals or hospital systems (HCW), nursing home workers (NHW), employees of hospitals or 
hospital systems, first responders and correctional/law officers (FR), medical students (MS), 
public transit drivers, and family members of healthcare workers residing in the same dwelling, 
in the States of Michigan and Ohio can prevent the acquisition, symptoms and clinical COVID-
19 infection.  
The study will randomize a total of 3,000 participants who meet inclusion/exclusion criteria. 
The Study Participants will be randomized in a 1:1:1 blinded comparison of daily HCQ, 
weekly HCQ, or placebo. A fourth comparator group of HCW, NHW, MS, FR, public transit 
drivers, and family members of healthcare workers residing in the same dwelling who are 
already currently on standard HCQ therapy will be recruited to assess the impact of weight-
based daily dosing of HCQ as compared to the randomized arms. Details are provided in the 
study protocol. 
1.2 Primary and Secondary Aims 
Primary Aim 
1. To determine if the use of hydroxychloroquine as preventive therapy decreases the 
rate of acquisition of SARS-CoV 2 infections with clinical COVID-19 disease in Study 
Participants for each randomized treatment arm as compared to placebo. 
Secondary Aims 
1. Compare the rates of SARS-CoV 2 infections between the randomized treatment 
arms and the control arms to determine the effect of HCQ dose in the prevention of 
COVID-19 viremia and disease. 
2. Compare the rates of SARS-CoV 2 infections in the non-randomized comparator arm 
to the randomized groups to assess the impact of chronic weight-based dosing of 
HCQ for COVID-19 prevention. 
3. To compare the rate of SARS-CoV 2 infections as measured by SARS-CoV 2 serum 


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IgM/IgG in study participants receiving HCQ versus placebo. 
4. To compare the seroprevalence of SARS-CoV 2 IgM/IgG positive samples at study 
entry and study conclusion in all participants receiving HCQ compared to those 
receiving placebo. 
5. To compare the development of clinical symptoms or COVID-19 diagnosis in 
participants presenting asymptomatically at study entry but identified as seropositive 
by serology at entry between the randomized treatment arms and comparator arm. 
6. To compare the clinical COVID-19 disease need for participants in each treatment 
arm to require emergency room visit, hospitalization, or ability to stay home without 
hospitalization.  
7. To determine the safety and tolerability of HCQ dosing for preventive strategy 
against COVID-19. 
8. To examine other clinical determinants contributing to the risk of SARS-CoV 2 
infection including demographics, work type and location, positive COVID-19 
partners, possible exposures and clinical symptoms. 
9. Examine the association between HCQ drug levels and development of COVID-19 
symptoms or positive test results. 
10. To identify immunologic, serological and inflammatory markers associated with 
acquisition and response to COVID-19 in both HCQ and placebo Participants 
developing laboratory or clinical confirmed disease. 
 
1.3 Inclusion/Exclusion Criteria 
Inclusion Criteria 
1. 
Participant is willing and able to provide informed consent. 
2. 
Participant is 18-75 years of age. 
3. 
Participant does not have symptoms of respiratory infection, including 
cough, fever (temperature >38.0 C), difficulty breathing, shortness of 
breath, chest pains, malaise, myalgia, headaches, nausea or 


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vomiting, or other symptoms associated with COVID-19. 
4. 
Participant is willing and able to comply with study instructions, blood 
collection, other study procedures, and agrees to be contacted for required 
visits. 
5. 
The participant has no known allergies or contraindications (as stated in the 
consent form) to the use of hydroxychloroquine (HCQ) as noted in the exclusion 
criteria and Pharmacy sections.  
6. 
Participant is a HCW, FR, MS, NHW, public transit driver, or family member of a 
healthcare worker residing in the same dwelling, in the States of Michigan or 
Ohio at risk of exposure or exposed to COVID-19. 
Exclusion Criteria 
1. Does not meet inclusion criteria. 
2. Participant has any of the symptoms attributable to or has currently tested 
positive for COVID-19 infection through RT-PCR nasal or oral-pharyngeal swab, 
a laboratory defined serology test, or an FDA approved assay.  
3. Participant is currently taking select QT prolonging agents such as Lexapro, 
Celexa, or any prohibited medications per protocol. (See contraindicated 
medication list in Pharmacy Section)  
4. Participant has a known co-morbidity including history of gastric bypass, 
epilepsy, cardiovascular disease, renal disease, or other organ failure that 
precludes the use of HCQ (see pharmacy section).  
5. Participant has known renal failure with a creatinine clearance of <10 ml/min, 
pre-dialysis or requiring dialysis.  
6. Participant is currently enrolled in another study to evaluate an investigational 
drug. 
7. The participant is currently on diuretic therapy using loop-diuretics. 
8. The participant was diagnosed with retinal disease or has history retinal 
surgery prior to study entry. 
9. The participant has a diagnosis of porphyria prior to study entry. 


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10. The participant has a family history of Sudden Cardiac Death. 
11. The participant has a history of known Prolonged QT Syndrome. 
12. The participant has a history of ongoing liver failure. 
13. A history of or ongoing serious illness or medical, physical, or psychiatric 
conditions(s), or any other factor that, in the Investigator’s opinion, may interfer 
with the subject’s ability to follow study procedures and complete the study. 
14. Investigator site staff members directly involved in the conduct of the study. 
Note that the inclusion/exclusion criteria may change during trial recruitment, after 
obtaining FDA and IRB approval.      
1.4 Target Population, Sample Size and Study Duration   
Approximately 3000 participants from the States of Michigan and Ohio who meet the study entry 
criteria will be prospectively enrolled and randomized at Henry Ford Health System (a member of 
the Detroit COVID Consortium).  Future protocol amendments may expand the geographic areas 
from which patients are drawn and add additional enrolling sites.  The fourth non-randomized 
comparator arm will include participants that are already on chronic HCQ maintenance therapy 
with weight-based, twice a day dosing for their autoimmune disease, which will be continued 
throughout the study. Enrollment in this group will be open as it will be a non-randomized 
treatment arm; the total number of participants enrolled in this group is expected to be lower than 
in the randomized groups. Total study duration is expected to be up to 2 years, with participant 
enrollment starting in April 2020. 
1.5 Participating Enrolling Clinics & Data Coordinating Center 
Clinical sites:  
HFHS Center for Structural Heart Disease. This clinical site will be led by William W. O’Neill  MD. 
and Dr. John E. McKinnon MD as the trial principle investigators (co-PIs), and coinvestigators 
(Co-Is)  Dee Dee Wang, MD and Marcus Zervos, MD. The clinical site will be responsible for 
subject enrollment and follow-up.  Other clinical sites may be added as needed for study 
recruitment.  
Data Coordinating Center (DCC):  


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The HFHS Department of Public Health Science (PHS) will serve as the DCC. The DCC will 
provide statistical, database management, and site management expertise and support for the 
clinical trial—from study design, data collection and management, data analysis and reporting, 
to publication and dissemination. The DCC is also responsible for site staff training in data 
collection and management and will conduct site audits for data quality and study integrity and 
compliance with FDA regulations. Led by Dr. Mei Lu, director of the PHS DCC and a 
Biostatistician, the DCC staff include biostatisticians Jia Li PhD and Yueren Zhou MS, a project 
manager, Christina Melkonian MS,  a project coordinator, Lora Rupp MS, and the database 
programmer, Yasmeen Hafeez.    
A PHS operations committee, led by Dr. Christine C Johnson, Chair of HFHS PHS, and assisted 
by members Lonni Schultz PhD, biostatistician and head of Design and Biostatistics services, 
and Mr. Dan McLaren, Manager - Clinical Research Informatics Services of PHS, will oversee 
the trial conduct, including subject enrollment and data collection and management.    
2. Study Data Collection & Quality Management 
2.1 Case report forms (CRFs) 
Case report forms (CRFs) that use Participants’ study identifiers are designed and developed 
for the trial according to CDISC foundational standards as required for FDA-regulated trials. 
CRFs will be approved by the Trial PI. The DCC will work closely with the Trial PI and 
Biorepository Core to identify pre-analytic and analytic data elements to ensure data and 
specimen reproducibility and quality.    
Due to the urgency for trial recruitment during the COVID pandemic period, paper CRFs were 
prepared and used in the beginning of study when the CRF database was not ready for the trial 
data entry. Trial recruitment began on April 10th using the paper CRFs.   
2.2 Database management system for study data collection   
The DCC has implemented a centralized, integrated electronic data capture (EDC) system—
comprised of RedCAP, SQL, and Forte EDC data management systems—for trial data and 
sample collection and management: (1) RedCap is used to collect pre-screening data for 
possible eligible participants; (2) SQL is used for registering and tracking study samples; and (3) 
Forte EDC, an FDA 21 CFR Part 11-compliant data management system, is used for trial CRF 
data collection.  


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The DCC has prepared a data dictionary and all CRF fields will have consistent variable names 
to ensure accurate coding.  A detailed Data Collection manual of procedures (MOP) has been 
prepared by the DCC as part of the training material for the clinical sites. The DCC will be 
responsible for training study staff in EDC as well as how to apply the MOP for CRF completion. 
The DCC will also provide a CRF data-quality and data-monitoring plan as part of the study 
documentation.  
In general practice, a DCC CRF database should be ready prior to study enrollment. However, 
given the urgency for trial recruitment during the COVID pandemic period, paper CRFs were 
prepared and used before the Forte EDC database was built, validated and released on 
4/17/2020.  In addition, RedCap was used as an interim system to assist clinical sites for 
participant recruitment and study enrollment, and for the AE and SAE tracking log, until the 
Forte EDC database was up and running and clinical site staff were trained for CRF data entry. 
The RedCap AE and SAE tracking log was discontinued on 5/14/2020 when the Forte EDC AE 
and SAE tracking system was fully implemented.  To be able to enroll subjects elsewhere 
beside HFHS and to incorporate the study protocol revision to include pregnant women, a Forte 
EDC V2 database was implemented and went live on 7/26/2020 for new patient enrollment.  
The  V1 database is referred to as the original database, which retained all patients enrolled 
prior to 7/26/2020 including their follow-up data collection. The V2 database has a revised CRF 
data cluster structure which is about 70% similar to the original Forte database (named V1 CRF 
data cluster, see Table in Appendix A). As a result, data quality checks are conducted separately 
for each version of the Forte database.  The data will be integrated for analysis using SAS.   
2.3 EDC CRF data monitoring and quality management  
A backlog of paper CRFs began to be entered into Forte EDC database on 4/20/2020 by PHS 
staff who had been trained for EDC data entry. That responsibility was transferred back to 
clinical study staff by the end of April.     
Data can be entered directly into Forte EDC as they are collected at clinical sites to ensure a 
smooth and systematic flow of activities and to avoid backlogs and uneven workloads. 
Automated validation rules in Forte EDC will catch inconsistent data collection within or across 
CRFs as the data are entered. Forte EDC offers a user-friendly feature with color coding to 
reflect data status (data error versus error-free). A data discrepancy alert will also appear when 
a data element is improperly entered. For example, data element checks will be displayed as 


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soon as the data are entered into Forte EDC.  Similar data validation processes can be 
implemented using SAS.  For this study, both processes will be used.     
A specimen ID will be issued once a specimen is collected and documented in both the CRF 
and specimen tracking databases. Specimen quality will be documented in the specimen 
tracking database after the specimen is registered in the SQL database at the DCC. Data will be 
seamlessly and automatically integrated daily to ensure timely data checks and data reports.  
CRF Data quality reports will be generated daily and will include: (a) CRF status (missing but 
expected, incomplete but expected, complete as expected); and (b) data element status 
(missing, illogical, or invalid values; inconsistencies across CRFs in Forte EDC or using SAS).            
The Clinical Site Coordinator will work closely with the DCC Data Coordinator to resolve data 
discrepancies by directly entering the missing-but-expected CRF or correcting data errors 
through Forte EDC. Data quality alerts will be generated continuously until resolved. 
Prescreening data will be reported daily. The number of subject enrollments will be reported 
daily when data are available in the DCC central database.  
Due to the volume of recruitment, a serious adverse event (SAE) report will be generated and 
reported to PIs and the DSMB weekly. The DCC has implemented an MOP for central SAE 
review and reporting process (detailed in a later section).    
The DCC will work closely with the Trial PIs, laboratory core, and each site regarding non-
compliant specimens, and action will be taken to remedy the issue if possible; the DCC will 
perform a descriptive analysis to compare specimen quality before and after the problem 
resolution.  
3.  Site Training and Management  
Site staff training:   
The DCC will assist the Trial PIs in the preparation of training materials and will conduct a series 
of role-specific training sessions for site personnel including the Trial PI, regulatory staff, and 
clinical coordinators on topics including the study protocol, Forte EDC training for patient 
scheduling, informed consent, and CRF data collection.  
Training in Forte EDC will be performed at two levels: general Forte EDC data-entry training, 
and study-specific training.  This training can be completed through webinars.   


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On- and Off-Site Visits:   
DCC staff will discuss site visit results with the Trial PIs and clinical coordinators at the end of a 
site visit. An audit report will be written for each visit, listing all findings and requesting 
resolution. A follow-up meeting or conference call may be needed for clarification. Audit results 
will be documented by the DCC as part of the Trial Master Files (TMFs). The DCC will maintain 
close communication with the Trial PIs and Leadership Committee regarding auditing results. If 
a serious protocol violation occurs, action may be taken, as decided by the PI and DSMB. 
4. Safety data collection and reporting 
4.1 Adverse event definitions 
For this study, the following standard AE definitions are used: 
Adverse event: An Adverse Event (AE) is any untoward medical occurrence in a Participant 
administered an investigational product or undergoing a procedure, which does not necessarily 
have a causal relationship with the treatment. An AE can be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of an investigational product, 
whether or not it is related to the investigational product. 
Serious Adverse Event: A Serious Adverse Event (SAE) is any AE that results in any of the 
following outcomes: 
 
Results in death 
 
Is life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect. 
AEs are graded according to the following scale: 
Mild:  An experience that is transient and requires no special treatment or intervention. The 
experience does not generally interfere with usual daily activities. This includes transient 
laboratory test alterations. 
Moderate:  An experience that is alleviated with simple therapeutic treatments. The experience 
impacts usual daily activities. Includes laboratory test alterations indicating injury, but without 
long-term risk. 


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Severe:  An experience that requires therapeutic intervention.  The experience interrupts usual 
daily activities. If hospitalization (or prolongation of hospitalization) is required for treatment it 
becomes an SAE. 
The study uses the following AE attribution scale: 
Not related: The AE is clearly not related to the study drug (i.e., another cause of the 
event is most plausible, and/or a clinically plausible temporal sequence is inconsistent with the 
onset of the event). 
Possibly related: An event that follows a reasonable temporal sequence from the initiation of 
study procedures, but that could readily have been produced by a number of other factors. 
Related: The AE is clearly related to the study drug. 
Each SAE will be reviewed by an independent medical monitor, Dr. Bojana Jovanovic MD, a 
rheumatology specialist at HFHS, who is not be involved in the proposed study. The detailed 
review process is detailed in MOP. 
4.2 Safety reporting 
All problems having to do with subject safety will be reported by the Principal Investigator (PI) to 
the IRB within ten working days. Specifically, the following will be reported, in writing: 1) all 
serious adverse events potentially associated with the study drug, and/or 2) any incidents or 
problems involving the conduct of the study or patient participation, including problems with the 
recruitment and/or consent processes. The PI will provide a discussion of any side effects or 
problems noticed in the course of the study to the IRB.  
The DCC will produce safety reports that list serious adverse events, deaths, and disease or 
treatment specific events, in aggregate, for DSMB weekly meetings or at a scheduled meeting. 
The DSMB will review safety reports by blinded treatment group. If there are a significant 
number of adverse events, the DSMB may request that the treatment groups be unblinded to 
ensure there are not problematic side effects.  


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5.  Reports for Study Progress and Quality Control   
5.1 Study progress Reports 
The DCC will produce administrative reports that describe study progress. These reports will be 
reviewed internally by the DCC and PI for ongoing quality control and will be presented to the 
Data Safety Monitoring Board (DSMB) at scheduled meetings. 
5.2 Subject accrual / randomization Reports 
The DCC will produce daily accrual / randomization reports, which will include: 
1) The number of prospective Participants who completed a Volunteer Survey, and their 
eligibility, demographics and occupations.  
2) The number of Participants currently enrolled. 
A weekly report to DSMB will include a cumulative report of enrollment and enrollment 
projection.  
5.3 Data collection and management Reports      
Data quality will be assessed using measures listed below: 
 
CRF status by form (overall and by clinical site): the number of CRFs received the 
number of expected CRFs, and percentage of missing expected CRFs.  
 
The number of data queries generated and the number/percent of queries resolved 
(overall and by clinical site). 
 
Protocol deviations including: 1) number of subjects who were ineligible but randomized 
into the trial; 2) numbers of subjects who were enrolled but not according to 
randomization sequence.  
5.4 DSMB Reports 
A weekly report to DSMB will include 1) Cumulative report of enrollment and projection; 2) AE 
and SAE report.  
Reports for a scheduled DSMB meeting will include the cumulative daily and weekly reports; 
safety report; and the efficacy results at the interim analysis session.    


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6.  Statistical Analysis Plan (SAP)  
A formal SAP will be developed before study completion or database lock for an interim 
analysis. Statistical issues not addressed in the study protocol will be addressed in the formal 
SAP. 
6.1 Study Design  
Participants who meet study entry criteria and are not on HCQ prior to study enrollment will be 
randomized in a 1:1:1 blinded comparison of daily or weekly hydroxychloroquine versus placebo 
for 8 weeks. The randomization will be stratified by enrolling site and high- vs. low- risk category, 
where the high-risk category will consist of HCWs who work in COVID-19 care areas.  
A fourth non-randomized comparator group comprised of study participants who are already 
currently on standard HCQ therapy for an autoimmune disease(s) will be used to assess the 
impact of weight-based daily dosing of HCQ as compared to the randomized arms.  
The trial will use a pragmatic, adaptive enrichment design, in which the primary efficacy 
analysis will be based on all randomized patients with a negative screen for COVID-19 at 
baseline, whereas the safety analysis will be based on all randomized patients, including 
those who are later determined to have been positive for COVID-19 at baseline (given that 
there may be a time lag to get initial screening COVID-19 test results back after study 
enrollment).  
The trial is designed to have one interim look— when 50% of subjects have completed the 
study and primary endpoint assessment—for an early treatment efficacy assessment, and 
possible reassessment of study sample-size if the estimation of placebo infection rate is 
inadequate.  
6.2 Locking Data for Analysis/Transfer 
Data will be locked (frozen) for each planned data transfer/ formal data analysis. After the last 
patient’s data/ specimens are collected and all data discrepancies are resolved or closed, data 
can be locked. The final data analysis/ transfer will be completed within 30 days after the last 
patient’s data/ specimen collection. The data transfer process includes documentation of the 
database structure, data dictionary with details regarding data element names, labels, formats, 
and distribution, as well as documentation regarding data collection details, as needed.  


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6.3 Study Aims, Hypothesis and Proposed Analysis  
6.3.1 Primary Aim and Hypothesis 
As noted below, the primary aim has been changed to: (based on Study Protocol dated 
05/26/2020) 
To determine if the use of hydroxychloroquine as preventive therapy decreases the rate of 
acquisition of SARS-CoV 2 infections with clinical COVID-19 disease in Study Participants for 
each randomized treatment arm as compared to placebo. 
From: (based on original Study Protocol, dated at and after 04/06/2020) 
To determine if the use of hydroxychloroquine as preventive therapy decreases the rate of 
acquisition of SARS-CoV 2 infections in Study Participants as compared to placebo.  
 
Primary Hypothesis (P1):  Hydroxychloroquine administered daily decreases the rate of 
acquisition of SARS-CoV 2 infections with clinical COVID-19 disease, compared to placebo; and 
hydroxychloroquine administered weekly decreases the rate of acquisition of SARS-CoV 2 
infections with clinical COVID-19 disease, compared to placebo.    
The primary outcome will be defined as clinical COVID-19 disease with laboratory 
confirmation of infection.  
Presentation with COVID-19 symptoms during study follow-up (defined as fever ≥38◦ C, 
or two or more non-fever symptoms that are new since the baseline) will refer 
participants to obtain SARS-CoV 2 testing through employee health or participants’ 
primary care physician, with test results documented in their medical record. 
Laboratory confirmation of SARS-CoV 2 infection (SARS-CoV 2 test positive) will be 
defined as at least one positive RT PCR, or both IgM and IgG positive serology. The lab 
test results can be obtained from (a) study blood samples (IgM and IgG serology), and 
(b) RT PCR test results ordered by a participant’s primary care physician or through 
employee health.  
All participants who test SARS-CoV 2 positive will be followed for at least 30 days after the 
first positive test for presentation of symptoms.  
6.3.2 Full Analysis Set (FAS) 


16 
 
All randomized subjects who do not have a SARS-CoV 2 positive test at the baseline, have 
taken at least one dose of study medication and provide at least one post-baseline follow-up 
during the 8-week treatment period. Participants will be analyzed according to the treatment 
group to which they were assigned according to Intention to treat (ITT).   
 
6.3.3 Safety Analysis Set:   
The safety analysis set will consist of all subjects randomized who receive at least one dose of 
study medication.  
 
6.3.4. Proposed Analysis  
6.3.4.1 General Statistical Consideration:  
The statistical software package SAS® Version 9.4 or higher (SAS Institute, Cary, NC, USA) 
will be used to perform all analyses and to summarize data. 
 
The analyses described in this statistical analysis plan (SAP) are considered a priori, in that they 
have been defined prior to database lock. Any analyses not described herein performed 
subsequent to database lock will be considered post hoc and exploratory. 
 
6.3.4.2. Handling of missing data:  
For summary statistics, results will be reported based upon observed data. The study will make 
all possible efforts to obtain patient’s follow-up data and laboratory confirmation of infection for 
COVID 19 disease determination.  The efficacy analysis will be performed based on all 
observed data assuming missing as random (MAR), two selected imputation approaches are 
specified for the sensitivity analysis.      
6.3.4.3 Primary Efficacy Analysis.  
The FAS is considered. Chi-square test will be used to compare the rate of COVID-19 disease 
in each randomized treatment group to that of the placebo group using Dunnett’s step-up 
method to adjust for multiple comparisons and controlling for type I error1,2. Specifically, 
Dunnett’s step-up method uses a closed gatekeeping strategy, in which the largest p value will 
be evaluated first at critical value of 0.05; if that fails, the second p value will be evaluated at 
criterial value of 0.0262 (details in the sample size /power calculation section).  A treatment 
efficacy is detected if the largest p value <0.05 or the second p value<0.0262. The results of 


17 
 
efficacy analysis will be validated through two specified imputation approaches described in 
below    
Sensitivity Analysis #1: A Tipping Point Analysis (TPA) with delta-adjusting imputation  
 
The primary analyses for COVID 19 disease is based on the observed data and the results are 
valid if the missing data are missing at random (MAR), meaning that the probability of a value 
being missing, conditional on the observed data and factors in the statistical model, is random 
and not dependent on the unknown value of the missing data point.   
 
To address this, we will conduct Tipping Point Analysis (TPA) under the condition of missing not 
at random (MNAR) to assess the robustness of the primary analysis.  Specifically, the TPA first 
step (STEP 1) is to conduct m (e.g., m=5 or 10) multiple imputation (MI) based on baseline 
covariates, and the prior to 8-week and post-baseline covariates to estimate the missing primary 
binary endpoint (D) with the underlying assumption of MAR. We will use the Markov Chain 
Monte Carlo (MCMC) algorithm based on the assumption of multivariate normality (Schafer 
1997, Allison 2001) for estimating the mean of D (Allison 2017) stratified by treatment group 
without rounding to binary values. However, this approach is still under the MAR assumption 
and hence the result will be further examined by shifting the imputed mean of D in a range of 
negative to positive values, which can be done by inflecting or suppressing the mean of D 
among those who had missing D in treated group. A tipping point is identified if it reverses the 
study conclusion. Those results will be further evaluated on whether the imputed value 
associated with the tipping point is plausible.  SAS Procedures PROC MI and PROC 
MIANALYZE and SAS  %midata macro can be used for TAP analysis.   
 
Sensitivity Analysis #2: A control-based MI 
For the most conservative approach, MI can be restricted using data only from the placebo 
group for the missing endpoint D in both the treated and placebo groups using a similar 
approach described above for the sensitivity analysis #1 with the shift=0 (the first step).     
6.3.4.4 Secondary Aims, Hypotheses and Analyses   
S1: To compare the rates of SARS-CoV 2 infection status between the randomized 
treatment arms and the control arms to determine the effect of HCQ dose in the 
prevention of COVID-19 viremia and disease. 


18 
 
Secondary Hypothesis (S1): There is a hydroxychloroquine dose effect on acquisition of 
SARS-CoV 2 infection status, compared to placebo.   
The endpoint will be SARS-CoV 2 infection status, defined as 1) no SARS-CoV 2 test  
positive during study follow up; 2) SARS-CoV 2 test positive (i.e., at least one positive RT 
PCR, or both IgM and IgG positive serology) without clinical symptoms (“asymptomatic 
SARS-CoV 2 test positive”) 3) SARS-CoV 2 test positive with clinical symptoms  
(“symptomatic SARS-CoV 2 test positive”).    
The analysis will be conducted using FAS. Ordinal logistic regression will be used and 
analysis will start testing the overall daily and weekly dose effect, followed by 
pairwise/subgroup comparisons if an overall dose effect is detected at 0.05 level.    
S2: To compare the rates of SARS-CoV 2 infection status in the non-randomized 
comparator arm to the randomized groups to assess the impact of chronic weight-based 
dosing of HCQ for COVID-19 prevention. 
Secondary Hypothesis (S2): There is weekly /daily HCQ dose effect on acquisition of SARS-
CoV 2 infection, compared to patients who were already on HCQ.    
The endpoint will be the same as described for S1. The analysis will include all randomized 
in FAS and non-randomized study participants with at least one post-baseline follow-up. 
We will first test for treatment selection bias using the data collected at the baseline. Inverse 
probability treatment weighting (IPTW)/propensity score, or matched sub-cohort will be 
considered to adjust for imbalanced participant characteristics. A similar analysis to that of 
S1 will be used for testing hypothesis S2.  
S3: To compare the rate of SARS-CoV 2 infections as measured by serum IgM/IgG in 
participants receiving HCQ versus placebo. 
Secondary Hypothesis (S3): There is weekly /daily dose effect on status of SARS-CoV 2 
infection as measured by serum IgM/IgG, compared to placebo.    
The endpoint will be serum IgG/IgM status at each participant’s study conclusion, classified 
as:  
1. Negative (consistently negative for both serologies) 
2. Indeterminate (IgM positive, with IgG consistently negative) 
3. Positive (IgM and IgG positive, or IgG positive) 


19 
 
The analysis will be conducted using FAS. Ordinal logistic regression will be used to study 
the status distribution differences among three Arms. Similar to the analysis for S1, the 
analysis will start testing the overall dose effect, followed by the pairwise comparison 
between each treated arm and placebo.    
S4: To compare the seroprevalence of SARS-CoV 2 IgM/IgG positive samples at study 
entry and study conclusion in all participants receiving HCQ compared to those 
receiving placebo. 
Secondary Hypothesis (S4): There is weekly /daily dose effect on change in SARS-CoV 2 
seroprevalence at study conclusion from the baseline, compared to placebo.    
Serum IgM/IgG status at baseline and at study conclusion will be classified into the three 
categories described for S3. The endpoint will be a change in serum IgM/IgG status (from 
negative at baseline to indeterminate or positive at study conclusion, or indeterminate at 
baseline to positive at study conclusion).   
The analysis approach described for S1 will be used to study the dose effect on change in 
serum IgM/IgG status based on all randomized subjects. 
S5: To compare the development of clinical symptoms or COVID-19 diagnosis in 
participants presenting asymptomatically at study entry but identified as seropositive by 
serology at entry between the randomized treatment arms and comparator arm. 
Secondary Hypothesis (S5): There is dose effect on development of clinical symptoms or 
COVID-19 diagnosis.  
The endpoint will be the same as that defined for P1. This analysis will include all 
randomized study participants who, at baseline, have positive serology (IgM or IgG) but are 
clinically asymptomatic.  The analysis approach described for S1 will be used for this 
analysis.  
S6: To compare the clinical COVID-19 disease need for participants in each treatment 
arm to require emergency room visit, hospitalization, or ability to stay home without 
hospitalization.  
Hypothesis (S6): There is dose effect on incidence of ED visit/hospitalization, compared to 
placebo. 


20 
 
The endpoint will be rate of COVID-related ED visits or hospitalizations (by end of the 
planned 8-week follow-up period, or within 30 days after SARS-CoV 2 test positive if the 
positive test occurs <30 days before the end of the planned 8-week follow-up period).    
FAS will be considered. The analysis approach described for S1 will be used for this 
analysis. 
S7: To determine the safety and tolerability of HCQ dosing for preventive strategy 
against COVID-19. 
Secondary Hypothesis (S7): There is an HCQ dose effect on AEs and SAEs, compared to 
placebo.  
The endpoint will be any AE and any SAE observed during the 8 weeks of follow-up after 
enrollment.  
Safety Analysis Set is considered by including all randomized subjects.  
A descriptive analysis will report AE frequency and grade distribution among the three 
arms, and include a detailed list of serious adverse events (SAEs).  
S8: To examine other clinical determinants contributing to the risk of SARS-CoV 2 
infection including demographics, work type and location, positive COVID-19 partners, 
possible exposures and clinical symptoms. 
Secondary Hypothesis (S8): Risk for SARS-CoV 2 infection varies by subject 
demographics, work type and location, and clinical conditions. 
The possible covariates will include subject demographics, work type and location, and 
clinical conditions at the baseline prior to study enrollment, as well as the study treatment 
status. The endpoint will be clinical COVID-19 disease confirmed by laboratory test (same 
endpoint as P1). 
FAS is considered. Logit univariate and multivariate modeling will be conducted with 
consideration of possible treatment-by-baseline covariate interaction. Variables will be 
retained in the final model if there is significant individual effect or variable-by-treatment 
interaction at p-value 0.05. Area under the receiver operating characteristic curve (AUROC) 
will be used to assess the predictive ability.     


21 
 
S9: To examine the association between HCQ drug levels and development of COVID-19 
symptoms or positive test results. 
Secondary Hypothesis (S9): There is an association between HCQ drug levels and 
development of COVID-19 symptoms or positive test results. 
The endpoint will be the same, as described for S1 using FAS.  
A similar analysis as that described for S1 will be used. The analysis will include 
concentration of HCQ in blood at baseline, week 4 and week 8 as covariates.     
S10: To identify immunologic, serological and inflammatory markers associated with 
acquisition and response to COVID-19 in both HCQ and placebo Participants developing 
laboratory or clinical confirmed disease. 
Secondary Hypothesis (S10): There are immunologic, serological and inflammatory 
markers for COVID-19 positive.  
Two separate endpoints, SARS-CoV 2 test positive, and COVID19 disease with SARS-CoV 
2 test positive laboratory confirmation (P1), will be considered.   
FAS is considered. The immunologic, serological and inflammatory markers will be 
collected using the baseline blood samples. The same analysis approach as described for 
S8 will be used for S10. The baseline variables identified from S8 will be included for S10 
analysis.  
6.4 Sample size/power calculation  
Power Calculation for original Primary Aim: (based on original Study Protocol, dated 
04/06/2020)  
To determine if the use of hydroxychloroquine as preventive therapy decreases the rate of 
acquisition of SARS-CoV 2 infections in Study Participants as compared to placebo.  
The sample size and power calculation for the original aim are based on a SARS-CoV 2 
infection rate of 10% in the placebo-treated group, and an average of 6.8% in the randomized 
weekly- and daily- HCQ groups, with a relative reduction of 32%. Based on an alpha=0.05 two-
sided test, with 900 subjects per group that are COVID negative at the baseline, and one interim 
analysis when 50% of participants (450 per group) have completed the study and primary 


22 
 
endpoint data assessment, we will have more than 80% power (82% to be exact using nQuery) 
to detect a significant HCQ effect if the observed test statistic is ±2.9626 or p-value<0.003 in the 
interim analysis, or ±1.9685 or p-value<0.0497 in the final analysis, using an O’Brien-Fleming 
alpha spending method to ensure an overall type 1 error of 0.05 and assuming that overall 
COVID positive rate in the weekly- and daily- dose HCQ groups is 6.8% with n=1800 in the 
HCQ treated group and 900 in the placebo treated group. A reduction of 36% can be detected 
between either one of the HCQ treatment groups and placebo, using the same assumptions. 
Assuming 5-10% of patients will have SARS-CoV 2 positive at the baseline, we need 1000 per 
group, with a total of 3000 participants to complete the trial. 
Power Calculation for revised Primary Aim: (based on revised Study Protocol dated 
04/16/2020 or after)  
To determine if the use of hydroxychloroquine as preventive therapy decreases the rate of 
acquisition of SARS-CoV 2 infections with clinical COVID-19 disease in Study Participants 
for each randomized treatment arm as compared to placebo. 
The revised sample size and power calculation are based on a 10% rate of clinical COVID-
19 disease (with laboratory confirmation) in the placebo-treated group, and an average 6.8% 
rate in the two randomized HCQ-treated groups (weekly and daily dosing groups), with a 
relative reduction of 32%.  We propose two looks; one look (interim analysis) when 50% of the 
participants have completed the study and primary endpoint assessment (for P1), and a final 
look when 100% of participants have completed the study.  
Based on an alpha=0.05 two-sided test, chi-square test/logistic regression with odds ratio 
estimates, and Haybittle-Peto alpha spending method to ensure an overall type I error, the 
critical value for the interim analysis will be 0.001 and the critical value for the final analysis will 
be 0.05.  For data illustration, we have also included an O’Brien-Fleming spending function 
approach for controlling type I error with a critical value of 0.0054 for the interim analysis and 
0.0492 for the final analysis.   
Power calculations are based on n=900 or 935 participants per study arm, using a simulation 
approach (n=10,000 simulations) in three correction methods: #1 comparing the weekly and 
daily HCQ dose arms to the placebo group separately using the Dunnett’s step-up approach; #2 
comparing the weekly and daily HCQ dose arms to placebo separately using a conservative 
Bonferroni approach with critical value of 0.025 for each test at the final look; #3 comparing the 
combined weekly and daily HCQ dose arms to the placebo using a single test.   


23 
 
With Haybittle-Peto boundary and alpha=0.05 at the final look, the Dunnett’s step-up correction 
uses a closed gatekeeping strategy for testing the daily dose arm vs placebo and the weekly 
dose arm vs placebo separately: the largest p value tested first will be at 0.05; if that fails, the 
second test will be at p value 0.026, delivered from the last row of Table 2 of Dunnett and 
Tamhane (1992), and validated based on simulation using R DunnettTests package. Likewise, 
at the interim look, the largest p value tested first will be at 0.001; if that fails, the second test will 
be at 0.0005.  
 
Table 1. Power for different scenarios using varying methods.  Sample size was determined using the 
Dunnett’s Step up method with the Haybittle-Peto boundary. 
  Haybittle-Peto approach  
p0=0.1, p1=0.073, p2=0.063 
p0=0.1, p1=p2=0.068 
Method 
n=900 
n=935 
n=900 
n=935 
#1 Dunnett’s Step up 
0.800 
0.811 
0.770 
0.800 
#2  Bonferroni 
0.784 
0.800 
0.745 
0.760 
#3 Daily+weekly arms vs placebo 
0.812 
0.83 
0.819 
0.835 
p0 is the rate for the placebo treated group and p1 and p2 are the rates for the two treated groups.  
 
O’Brien-Fleming  approach 
p0=0.1, p1=0.073, p2=0.063 
p0=0.1, p1=p2=0.068 
 
Method 
n=910 
n=935 
n=900 
n=935 
n=970 
#1 Dunnett’s Step up 
0.8 
0.814 
0.76 
0.776 
0.801 
#2  Bonferroni 
0.787 
0.8 
0.741 
0.761 
0.784 
#3 Daily+weekly arms vs placebo 
0.815 
0.83 
0.815 
0.83 
0.846 
p0 is the rate for the placebo treated group and p1 and p2 are the rates for the two treated groups. 
For the primary Aim / hypothesis, we will use Dunnett’s Step up approach to test each dose 
effect vs. placebo, and a sample size of 935 per arm will insure at least 80% power. The power 
will be higher for some of the secondary Aims (S1-S4 if use the compressed binary endpoint of 
infection presence or absence), since a single test will be used to study overall dose effect first, 
followed by subgroup analysis (Correction Method #3)  
Assuming 5-10% of patients will be excluded from FAS, we need 1000 subjects per group, with 
a total of 3000 participants to complete the trial. The power and sample size calculation 
remained unchanged.   
6.4.1 Sample size reassessment 
The adaptive design will allow the study to reassess the rate of SARS-CoV 2 infection with 
clinical COVID-19 disease observed in the placebo-treated group at the interim look.  


24 
 
6.5 Interim analysis schedule 
One interim analysis will be conducted when 50% of subjects have completed the study and 
primary endpoint assessment.   
6.6 Preparing the data for analyses 
The interim analysis database will be locked 1 week after the cutoff date. The data are received 
continually throughout the trial and checked for consistency. Queries will be issued on an 
ongoing basis. The project statistician will forward statistical programs and data to the DSMB 
statistician before the scheduled DSMB meeting. The DSMB statistician will replace the dummy 
random treatment code with the actual treatment code and execute the programs. The DSMB 
statistician will summarize the findings in a report addressed to the other members of the 
DSMB. 
6.7 Stopping rule 
 
For the interim analyses of the primary efficacy analysis, Haybittle-Peto boundary 
stopping rule will be used. Treatment efficacy will be determined, compared to placebo, 
if the largest p-value is less than 0.001, or if that fails, the second p-value is less than 
0.0005.  
 
DSMB will consider stopping the trial if there is a safety concern to study participants. 
7. Data Safety Monitoring Board 
Board Membership: The DSMB will be appointed locally for this investigator-initiated study. 
Members will include: 
DSMB Chair/Director: Sid Goldstein, MD HFHS Cardiovascular Medicine 
Tel: 313-916-2720 Email: SGOLDST1@hfhs.org  
 
Jerry Yee, MD HFHS Division Head-Nephrology 
Tel: (313)916-9405 Email: jyee1@hfhs.org 
 
Erica Herc, MD HFHS Infectious Disease 
Tel:(313)-850-8694 Email: eherc1@hfhs.org 
 
Amita Bishnoi, MD, HFHS Department of Internal Medicine Rheumatology 
Tel: 313-433-6244 (cell phone) Email: ABISHNO1@hfhs.org  
 


25 
 
George Divine, PhD HFHS Department of Public Health Sciences  (Biostatistician) 
Tel: 313-799-1494 (cell phone) Email: gdivine1@hfhs.org 
 
The members of the DSMB must be experts in the field, not be involved in the study, and have 
no conflicts of interest with the study/research.     
Safety oversight will be under the purview of the DSMB. The DSMB will meet to assess safety on 
each arm of the study, to protect the interests of research patients and ensure that they are not 
exposed to undue risk. The DSMB will evaluate the progress of the trial with regard to data quality, 
recruitment, accrual and retention, and risk vs. benefit to participants. 
The DSMB chair will be provided with a weekly site AE and SAE report to monitor safety.  An 
interim analysis will be done when a half of patients have completed the 8 weeks assessments 
for an early treatment efficacy or a possible reassessment of study sample-size if the estimation 
of placebo rate is inadequate.  Depending on response to the study intervention, the DSMB may 
decide it is necessary to stop/continue the trial if 1) there are safety concerns at any point in the 
trial or 2) there is evidence of treatment efficacy at the interim analysis; or recommendation for 
trial modification as it may be suggested, or 3) to continue the trial as designed. The DSMB will 
only stop the clinical trial for safety reasons. 
8. Confidentiality  
8.1 Protection of Subject Privacy  
During this study, a limited physical examination will be performed, and questionnaires will be 
administered. Data will be kept in strict confidence. No information will be given to anyone 
outside of the study without permission from the subject. This statement guarantees 
confidentiality. Confidentiality is assured by use of identification codes. All data, whether 
generated in the laboratory or at the bedside, will be identified with a randomly generated 
identification code unique to the subject in accordance with Health Information Portability and 
Accountability Act (HIPAA) guidelines. 
8.2 Database Protection  
The database is secured with password protection. The informatics manager receives only 
coded information, which is entered into the database under those identification codes. 
Electronic communication with outside collaborators will involve only unidentifiable information. 


26 
 
8.3 Confidentiality during AE Reporting  
AE reports and annual summaries will not include subject-identifiable material. Each will include 
the identification code only. 
 
 
 


27 
 
References 
1. Allison, Paul D. (2001) Missing Data.  Thousand Oaks, CA:  Sage Publications.  
2. Horton N.J., Lipsitz S.R., and Parzen, M. (2003) A potential for bias when rounding in 
multiple imputation.  American Statistician 57:  229-232.    
3. Schafer, Joseph L. (1997) Analysis of Incomplete Multivariate Data.  London: Chapman 
& Hall. 
4. Paul D. Allison, University of Pennsylvania (2017) Multiple Imputation of Categorical 
Variables  Under the Multivariate Normal Model  
5. Charles W. Dunnett and Ajit C. Tamhane. A step-up multiple test procedure. Journal of 
the American Statistical Association, 87(417):162-170, 1992. 
6. Howard DR, Brown JM, Todd S, Gregory WM. Recommendations on multiple testing 
adjustment in multi-arm trials with a shared control group. Stat Methods Med Res. 2018 
May;27(5):1513-1530. doi: 10.1177/0962280216664759. Epub 2016 Sep 19. 

Prot_001.pdf: 
 
1 
 
APPROVED 
 
Apr 19, 2020 
 
INSTITUTIONAL REVIEW BOARD 
 
 
 
 
 
 
 
 
 
 
WHIP COVID-19 Study 
 
Version 1.1 
April 16, 2020 
 
Will Hydroxychloroquine Impede or Prevent COVID-19 
 
 
 
 
 
 
 
 


 
 
2 
 
 
Study Administration 
 
 
 
 
Sponsor: 
 
Henry Ford Health System 
2799 W. Grand Blvd. 
Center for Structural Heart Disease - CFP # 439 
Detroit, Michigan 48202 
(313) 916-8708 
 
Sponsor Contacts: 
 
Dee Dee Wang, MD 
Tel: 313-916-8708  
  Fax: 313- 916-28 19  
  Email: dwang2@hfhs.org 
 
 


 
3 
 
INVESTIGATORS (alphabetically): 
 
Babar Basir, DO, FACC, FSCAI 
Senior Staff Cardiology, Director of Acute Mechanical Support 
Tel: 313-916-2721 
Email: mbasir1@hfhs.org 
 
Paul Kilgore, MD, MPH, FACP 
Director of Research, Department of Pharmacy Practice 
Tel: 313-577-1215 
Email: paul.kilgore@wayne.edu 
 
Kathleen Maksimowicz-McKinnon, DO, MPH 
Senior Staff Rheumatology, Director of the Center for Vasculitis and Lupus 
Tel: 313-622-4470 
Email: kmckinn2@hfhs.org 
 
John E. McKinnon, MD, MSc 
Senior Staff Infectious Diseases, Co-Director of the Translational and Clinical Research Center 
Tel: 313-622-4309 
Email: jmckinn3@hfhs.org 
 
Matt Saval 
Group Practice Operation Director 
Tel: 313-972-9165 
Email: msaval1@hfhs.org 
 
William W. O’Neill, MD, FACC, FSCAI 
Senior Staff, Medical Director of the Center for Structural Heart Disease 
Tel: 313-916-3070 
Email: woneill1@hfhs.org 
 
Dee Dee Wang, MD, FACC, FSCAI 
Senior Staff Cardiology, Director of Structural Imaging 
Tel: 313-916-8708 
Email: dwang2@hfhs.org 
 
Marcus J. Zervos, MD 
Senior Staff, Division Head, of Infectious Diseases 
Tel: 313-673-9579 
Email: mzervos1@hfhs.org 
 
Research Staff 
 
Jenna Hudy 
Research Coordinator 
Tel: 313-916-9328 
Email: jhudy1@hfhs.org 
 
 
Mirna Kaafarani 
Research Coordinator 
Tel: 313-916-8583 
Email: MKaafar1@hfhs.org 
 
Laurie Marshall-Nightengale, MD, MSc 
Multi-Site Trials Clinical Coordinator 


 
 
4 
 
Tel: 313-916-4835 
Email: lmarsha6@hfhs.org 
 
Jun Ying Zhou 
Research Associate, McKinnon Laboratory 
Tel: 313-874-3162 
Email: jzhou1@hfhs.org 
 


 
5 
 
Study Synopsis 
 
 
 
Study Sponsor: 
Henry Ford Hospital, Detroit, Michigan 
Protocol Number: 
1410401 
Protocol Title: 
Will Hydroxychloroquine Impede or Prevent COVID-19: 
WHIP COVID-19 Study 
Indication: 
This is a prospective, multi-site study designed to evaluate whether the use of 
hydroxychloroquine in healthcare workers (HCW), Nursing Home Workers 
(NHW),  first responders (FR), and Detroit Department of Transportation bus 
drivers (DDOT) in SE, Michigan, can prevent the acquisition, symptoms and 
clinical COVID-19 infection. 
Objective: 
The primary objective of this study is to determine whether daily or weekly oral 
hydroxychloroquine (HCQ) therapy will prevent SARS-CoV-2 infection and 
COVID-19 disease in healthcare workers and first responders in SE, Michigan. 
Study Design: 
The study will randomize a total of 3,000 HCW, NHW, FR and DDOT bus 
drivers within Henry Ford Hospital System, the Detroit COVID Consortium in 
Southeast, Michigan. The participants will be randomized in a 1:1:1 blinded 
comparison of daily HCQ, weekly HCQ, or placebo. A fourth non-randomized 
comparator group of HCW, NHW, DDOT bus drivers, and FR who are currently 
on standard HCQ therapy will be recruited to assess the impact of weight-
based daily dosing of HCQ as compared to the randomized arms. 
Eligible participants who are asymptomatic for pre-specified signs and 
symptoms suggestive of COVID-19 infection will have a whole blood specimen 
obtained at study entry.  
Participants will be provided with weekly dosing of hydroxychloroquine 
(HCQ) 400mg po q weekly, daily dosing of HCQ 200mg po q daily following a 
loading dose of 400mg day 1, or placebo. Participants will receive monitoring 
at each study week visit to assess for the development of COVID-19 related 
symptoms, COVID-19 clinical disease, and medication side effects. At week 8 
or if diagnosed positive, participants will provide additional samples of whole 
blood and complete the final study questionnaire. 
 Data including demographic, clinical results, work duties, location of main 
work area and possible exposures in the community will be collected through 
questionnaires and EMR review.  Disease-specific, immunologic, and other 
serologic marker data will be obtained from stored samples. 
Subject Population: 
Approximately 3000 HCW, NHW,  FR and DDOT bus drivers, age 18-75 years, 
presenting at participating clinical sites without symptoms of respiratory tract 
infection, as outlined in the Inclusion/Exclusion section of this protocol.   


 
 
6 
 
Duration of Subject 
Participation: 
Each Participant’s involvement in the study will last 8 weeks. Subject 
participation is required after consent for sample collection, questionnaires, and 
study calls and EMR review of clinical testing for respiratory infections. 
Study Duration: 
Up to 3 months for enrollment, 2 years for testing and publications, starting 
immediately following approval by the HFHS Institutional Review Board (IRB) 
and The United States Food and Drug Administration (FDA). 


 
7 
 
 
Abbreviations/Definitions 
 
 
AE;  
 
Adverse Event 
C:  
 
Degrees Centigrade (Celsius) 
CAP:  
 
Community Acquired Pneumonia 
CFR:  
 
Code of Federal Regulations 
COVID-19:  
 
SARS-CoV-2 clinical coronavirus disease which may be diagnosed by 
clinical and/or laboratory methods 
CRL:  
 
Case Report Log 
DDOT 
 
Detroit Department of Transportation 
EMR: 
 
Electronic medical record 
FDA:  
 
Food and Drug Administration 
FR: 
 
First Responders 
HCW: 
 
Healthcare Workers 
ICF:  
 
Informed Consent Form 
ICH:  
 
International Conference on Harmonization 
IRB:  
 
Nursing Home Workers 
NHW: 
 
Institutional Review Board 
PI:  
 
Principal Investigator 
SAE:  
 
Serious Adverse Event 
SARS-CoVID -2:  
 
Severe acute respiratory syndrome coronavirus 2 virus 
SARS-CoVID-2 infection: 
Detection of SARS-CoVID-2 infection by laboratory testing, can be 
symptomatic or asymptomatic presentation 
SARS-CoVID-2 viremia: 
Detection of SARS-CoVID-2 virus in blood, serum or plasma 
 
SE: 
 
South East


 
 
8 
 
 
Table of Contents 
1 BACKGROUND ................................................................................................................... 9 
2 STUDY OBJECTIVE .......................................................................................................... 10 
3 STUDY LOCATIONS ........................................................................................................ 12 
4 STUDY DESIGN ................................................................................................................ 12 
4.1 
Use of Data .................................................................................................... 14 
4.2 
Study Duration .............................................................................................. 14 
5 STUDY MATERIALS ........................................................................................................ 14 
5.1 
The following materials will be needed at enrollment……. ............................... 14 
5.2 
The following materials needed for randomization visit ................................... 15 
5.3 
The following materials needed for the weekly visit…………………………………..15 
5.4 
The following materials needed for the week 8 end of study visit………………. 15 
6 
STUDY SUBJECTS ........................................................................................................ 16 
6.1 
Number of Subjects ....................................................................................... 16 
6.2 
Inclusion/Exclusion Criteria ......................................................................... 17 
6.2.1 Inclusion Criteria .......................................................................................... 17 
6.2.2 Exclusion Criteria.......................................................................................... 17 
6.3 
Participant Discontinuation.......................................................................... 18 
6.4 
Participant Withdrawal ................................................................................ 19 
7 
STUDY PROCEDURES .................................................................................................. 19 
7.1 
Screening and Enrollment ............................................................................ 19 
7.2 
Study Schedule of Events……………………..……………………………....20 
7.3 
Sample Collection and Handling……………………………………………...21 
8 
STATISTICS AND REPORTS……………………………………………………………21 
        8.1       Case Report Form (CRF) and Questionnaires……………...………………... 21 
        8.2       Reporting AE and SAE- Frequency…………………………………………...22 
        8.3       Statistical Analyses and Sample Size………………………………………….22 
9 
PARTICIPANT INVOLVEMENT ENDPOINT/FOLLOW-UP………………………….23 
10 
SAFETY CONSIDERATIONS…………………………………………………………...23 
10.1 
Definitions of Adverse Events……………...…………………………...………...24  
10.2 
Possible Risks & Benefits Associated with Study Procedure ........................... 25 
10.3 
Pharmacy ....................................................................................................... 27 
10.4 
Recording Requirements ................................................................................ 29 
 
11 
INVESTIGATOR OBLIGATIONS ................................................................................. 30 


 
9 
 
11.1 
Guidelines for the Conduct of the Study………………………………………30 
11.2 
Informed Consent……………………………………………………………...30 
11.3 
Confidentiality………………………………………………………………...31 
11.4 
Protocol Modification/Amendments………………………………………….31 
11.5 
Recording & Monitoring of Study Data………………………………………32 
11.6 
Direct Access to Source Data & Study Documents…………………………...32 
11.7 
Record Retention………………………………………………………………33 
12 
REFERENCES…………………………………………………………………………….38 
APPENDIX A: INVESTIGATOR ACKNOWLEDGEMENT................................................... 34 
APPENDIX B: APPROPRIATE TECHNIQUE FOR BLOOD DRAW………………………….34  
APPENDIX C: STUDY FLOWCHART .................................................................................... 39 


 
 
10 
 
1 BACKGROUND 
Community-acquired pneumonias (CAPs) can be due to viral or bacterial pathogens, and are one of the 
most common infectious diseases. Viral CAPs are most commonly caused by influenza A and B and other 
common cold viruses such as RSV, especially during winter months. Although their presentations can vary, 
only microbiological testing techniques can definitively identify the pathogen involved. In December 2019, 
a novel disease caused by a new virus now known as SARS-CoV-2, commonly referred to as COVID-19, was 
identified in Wuhan, China. Since then, the infection has spread worldwide, with over 663,828 cases 
identified and 30,822 deaths as of March 28, 2020 (Johns Hopkins Coronavirus Resource Center, 
https://coronavirus.jhu.edu/map.html). COVID-19 is a deadly pandemic which threatens the lives of 
millions of persons with mortality rates overall of 4.37%, but are highly very variable by region. For 
example, in Italy a crude mortality rate of 10.83% has been reported. In the United States, over 124,217 
cases and 2,185 deaths have been reported, with the State of Michigan now representing the fourth most 
affected state, having 4,658 confirmed cases and 111 deaths reported (Johns Hopkins Coronavirus 
Resource Center, March 28, 2020; https://coronavirus.jhu.edu/map.html). HCW are at high risk of 
exposure given the close proximity in which they care for patients (Bureau of Labor Statistics, Occupational 
Employment Statistics) in addition to the growing shortages in personal protective equipment (PPE), which 
are paralleling the rise in COVID-19 cases (1,2). Recent COVID-19 outbreaks have demonstrated that up to 
10-30% of HCW can become infected by the virus, and up to 85% may have asymptomatic/minimally 
symptomatic infection, promoting further spread of COVID-19 infection (2). Several epidemiological, 
societal and clinical interventions are currently ongoing to prevent the spread of COVID-19 disease, but to 
date, there are no published data on prevention strategies. This is a critical unmet need which must be 
addressed to preserve the population of active healthcare workers (HCW), nursing home workers (NHW), 
DDOT bus drivers, and first responders (FR) who are exposed to COVID-19 positive patients as part of their 
duties and represent the key component of  our clinical  response to this pandemic. 
 


 
11 
 
Chloroquine and hydroxychloroquine have demonstrated in-vitro efficacy in the treatment of COVID-19 
(3). In 2005, Vincent et al. similarly demonstrated that chloroquine was effective in preventing the spread 
of SARS-CoV-2 in cell culture(4). Chloroquine interferes with the terminal glycosylation of the cellular 
receptor, angiotensin-converting enzyme 2, which is thought to impede the receptor binding and infection 
of the cell. Chloroquine was first discovered in 1934, and has been used for treatment of malaria since 
1949 and other conditions such as systemic lupus erythematosus; and similarly, hydroxychloroquine (HCQ) 
has been used since 1955 (5,6). 
These agents have a well-known safety profile.  Multiple cohort studies have demonstrated the safety of 
HCQ in the lupus population, where it is routinely used even during pregnancy, with the only established 
contraindication for therapy being known retinopathy (7,8).  Furthermore, the American College of 
Rheumatology does not recommend routine glucose-6-phosphate dehydrogenase screening, as clinical 
data have not demonstrated any significant risk of associated hemolysis in numerous cohort studies in 
both lupus and rheumatoid arthritis (8). Current dosing of HCQ for rheumatologic disease is weight-based, 
with the upper limit of dosing established at 5 mg/kg/day. 
Malaria prophylaxis dosing of HCQ is given as 400mg po once a week for the duration of the exposure (5). 
Recent work by Gautret P et al demonstrated that doses of 600mg of  hydroxychloroquine showed 
significant reduction of viral carriage at day 6 as compared to controls in patients with COVID-19 (9). Other 
investigators demonstrated in-vitro activity of HCQ against SARS-COV-2 with an EC50= 5.47 uM (10). 
Unfortunately, no data exists on the efficacy of these medications as prophylaxis in the prevention of 
COVID-19.   
 
The aim of this study is to demonstrate whether the use of hydroxychloroquine can prevent SARS-CoVID-
2 infection and clinical COVID-19 disease in HCW, NHW,  DDOT bus drivers and FR . Preventing COVID-19  
transmission to HCW, FR, and DDOT bus drivers is a critical step in preserving the health care and first 
responder force, the prevention of COVID-19 transmission in health care facilities, with the potential to 


 
 
12 
 
preserve thousands of lives in addition to sustaining health care systems and civil services both nationally 
and globally.  If efficacious, further studies on the use of hydroxychloroquine to prevent COVID-19 in the 
general population could be undertaken, with a potential impact on hundreds of thousands of lives.  
 
2 STUDY OBJECTIVE 
The primary objective of this study will be to determine if the use of either daily or weekly 
hydroxychloroquine will lead to the prevention of SARS-CoV-2 infections and COVID-19 disease in 
HCW, NHW,  DDOT bus drivers and FR in SE, Michigan. 
2.1 Primary Aim 
1. To determine if the use of hydroxychloroquine as preventive therapy decreases the 
rate of acquisition of SARS-CoV 2 infections and clinical COVID-19 disease in Study 
Participants for each randomized treatment arm as compared to placebo. 
2.2 Secondary Aims 
1. Compare the rates of SARS-CoV 2 infections between the randomized treatment arms 
and the control arms to determine the effect of HCQ dose in the prevention of COVID-
19 viremia and disease. 
2. Compare the rates of SARS-CoV 2 infections in the non-randomized comparator arm 
to the randomized groups to assess the impact of chronic weight-based dosing of 
HCQ for COVID-19 prevention. 
3. To compare the rate of SARS-CoV 2 infections as measured by IgM/IgG in study 
participants receiving HCQ versus placebo. 
4. To compare the seroprevalence of SARS-CoV 2 IgM/IgG positive samples at study 


 
13 
 
entry and study conclusion in all participants receiving HCQ compared to those 
receiving placebo. 
5. To compare the development of clinical symptoms or COVID-19 diagnosis in 
participants presenting asymptomatically at study entry but identified as 
seropositive by serology at entry between the randomized treatment arms and 
comparator arm. 
6. To compare the clinical COVID-19 disease need for participants in each treatment 
arm to require emergency room visit, hospitalization or able to stay home without 
hospital care.  
7. To determine the safety and tolerability of HCQ dosing for preventive strategy 
against COVID-19. 
8.  To examine other clinical determinants contributing to the risk of SARS-CoV 2 
infection including demographics, work type and location, positive COVID-19 
partners, possible exposures and clinical symptoms. 
9. Examine the association between HCQ drug levels and development of COVID-19 
symptoms or positive test results. 
10. To identify immunologic, serological and inflammatory markers associated with 
acquisition and response to COVID-19 in both HCQ and placebo Participants 
developing laboratory or clinical confirmed disease. 
2.3 Primary Endpoint 
1. Difference in new cases of COVID-19 disease between randomized treatment arms. 
2.4 Secondary Endpoints 
1. The difference of SARS-CoV 2 infections between the randomized treatment arms 
and the control arms. 


 
 
14 
 
2. The difference of SARS-CoV 2 infections in the non-randomized comparator arm to 
the randomized groups. 
3. The rate of SARS-CoV 2 infections as measured by IgM/IgG seroconversion in study 
participants receiving randomized HCQ versus placebo. 
4. The seroprevalence of SARS-CoV 2 IgM/IgG positive samples at study entry and study 
conclusion in all participants receiving HCQ compared to those receiving placebo. 
5. Emergence of clinical symptoms or COVID-19 diagnosis in participants presenting 
asymptomatically at study entry but identified as seropositive by serology at entry 
between the randomized treatment arms and comparator arm. 
6. To examine the level of care needed by participants in each arm developing COVID-
19 as measured as requiring emergency room visit, hospitalization or able to stay 
home without hospital care.  
7. The safety and tolerability of HCQ dosing for preventive strategy against COVID-19 as 
measured by adverse events and serious adverse events. 
2.5 List of Outcomes 
1. Primary outcome: Clinical COVID-19 Disease with laboratory confirmation of 
infection 
2. Secondary outcomes: SARS-CoV-2 infections, clinical COVID-19 disease without 
laboratory confirmation, serology (IgM and IgG) positivity, SARS-CoV-2 viremia, 
adverse events related to study medication or procedures, HCQ blood levels, 
immunologic and serologic markers associated with SARS-CoV-2 infection and 
COVID-19 and COVID-19 disease related ED visits and hospitalizations.   


 
15 
 
3. STUDY LOCATIONS 
This study will be conducted through  at Henry Ford Health System, Detroit COVID Consortium and 
the Detroit Public Health building. The applicable Institutional Review Board (IRB) for each 
participating site will review and approve the study protocol and informed consent documents prior 
to any Participant enrollment. All HCW and NHW will be enrolled at one of the participating Henry 
Ford Health System (HFHS), Detroit COVID Consortium clinical sites. First responders and DDOT 
bus drivers will be enrolled at either the Detroit Public Health Building located at 100 Mack St. 
Detroit, MI 48201 or at participating HFHS sites. The total study duration is expected to be up to 2 
years, with Participants enrollment targeted to begin immediately following IRB and FDA approval. 
 
4. STUDY DESIGN 
The study will randomize a total of 3,000 HCW, FR, and DDOT bus drivers, age 18 to 75 years, 
through the Henry Ford Health System, Detroit COVID Consortium. HCW and NHW will include 
providers at both hospital/clinical settings and nursing homes. FR will include personnel working 
in both governmental, private or volunteer first responder services. DDOT bus drivers with the 
Detroit Department of Transportation.  The participants who meeting study entry criteria and are 
not on HCQ prior to study enrollment will be randomized in a 1:1:1 blinded comparison of daily 
or weekly hydroxychloroquine versus placebo for 8 weeks. 
A fourth non-randomized comparator group will be enrolled in the study comprising of HCW who 
are chronically on HCQ as part of their standard of care for their autoimmune disease(s). This will 
be an open enrollment group and will provide information of chronic weight-based daily therapy of 
HCQ effectiveness as a prophylactic/preventive strategy. These participants will continue on their 
therapy for the duration of the study.   
The trial has implemented a pragmatic, adaptive enrichment design, where the efficacy analysis will 
be performed based on patients with negative screen for COVID-19 related symptoms at the baseline 


 
 
16 
 
and the safety analysis will be based on all randomized patients given there may be lag time to get any 
future COVID-19 test results back after the time of the study enrollment. The primary outcome of the 
study will be difference in development of COVID-19 disease between randomized arms. As new 
assays become available for research use for COVID-19 testing, these will be included in subsequent 
amendments if needed. The trial is also designed to have one interim look when a half of patients 
have completed the 8 weeks assessments for an early treatment efficacy, or a possible reassessment 
of study sample-size if the estimation of placebo rate is inadequate. A DSMB will be assembled to 
review interim analysis results. The DSMB Chair will also be provided a site SAE report weekly for 
safety review. Depending on response to the study intervention, the DSMB may decide it is necessary 
to stop/continue the trial if 1) there are safety concerns at any point in the trial or 2) there is evidence 
of treatment efficacy at the interim analysis; or recommendation for trial modification as it may be 
suggested, or 3) to continue the trial as designed. The primary aims of the DSMB are to decide if the 
study is safe to continue at the interim analysis timepoint and to monitor serious adverse events 
during the trial.  
Participant eligibility will be assessed prior to study entry, and a screening questionnaire will be 
completed. Eligible asymptomatic participants will have study sample collections (whole blood) 
obtained at study entry. Clinical symptom data will be obtained at study screening and entry, to 
assess study eligibility focusing on the presence or absence of symptoms suggestive of COVID-19 
infection.  
The study's purpose and its potential risks and benefits will be explained to potential study 
Participants. Enrollment of study Participants will be done only after informed consent is 
obtained and a copy of the consent document is returned to the potential Participant. Consented 
Participants will be assigned a unique Subject ID that corresponds to the unique identifier 
assigned to the participant upon completion and submission of the online screening form. 
 


 
17 
 
In the event a Participant decides to withdraw consent before the baseline blood or study 
specimens can be collected, this Participant will be excluded from the study before they are 
randomized. 
Participants will have 8 scheduled study encounters (see schedule of events, section 7.2). 
Screening/baseline visit will include study screening, informed consent, and initial study 
questionnaires and specimen collections. At this visit, enrolled Participants will be provided with 
8 weeks of hydroxychloroquine (HCQ) or placebo pills based on their randomized study group. 
Participants will be asked to contact the study team if COVID-19 infection is established at any 
time during the study. For study weeks 1,2,3,5,6 &7, Participants will receive a monitoring 
questionnaire to assess for COVID-19 symptoms/diagnosis, adherence and medication side 
effects. These monitoring visits will be done by telephone and/or electronic encounters (virtual 
visits, email), whichever method the patient prefers to encourage adherence to the monitoring. 
Every effort will be made to obtain the weekly information from Participants and avoid missing 
timepoint information. Participants will have a +/- 3 day window to complete their scheduled 
study visits. As recommended in the FDA Guidance on Conduct of Clinical Trials of Medical 
Products during the COVID-19 Pandemic, updated on March 27, 2020, the approach of using 
electronic or virtual visits for study safety assessments will support study monitoring while 
increasing the safety for participants by reducing potential exposures to SARS-COV-2 while 
attempting to come to clinical areas for study visits, where no direct contact is needed as part of 
trial design.  
 The study Participant will have an in-house, face-to-face visit on week 4 of the study to obtain 
monitoring questionnaires to assess for COVID-19 symptoms/diagnosis, adherence and 
medication side effects, and collect study blood samples. At study week 8, participants will 
present for the final study visit and will provide additional samples of whole blood, as well as 
complete an end of study questionnaire. Participants who are determined to be positive for 


 
 
18 
 
COVID-19 by either study or clinical testing will complete the study at that timepoint. Every effort 
to obtain confirmatory test results for COVID-19 will be done, including patient self-report, at 
study evaluations if presenting with symptoms, and from supportive medical records or study 
testing.  At this point, participants having been diagnosed with COVID-19 will be asked if they 
would be willing, within 30 days of recovery, to present for a study visit to provide a blood sample 
and answer an end of study questionnaire than can be scheduled at a later time.  All participants 
will be monitored for safety 30 days post study completion. 
Any potential study Participant who screens positive for COVID-19 symptoms or tests positive for 
SARS-CoV 2 during screening or subsequently during the trial, will be referred to their respective 
providers for further testing and care. HFHS employees will be directly referred to employee 
health for further evaluation. 
Study questionnaires will obtain information on Participant demographics, clinical background, 
clinical symptoms, employment, work activities, location of main work area, known possible 
exposures to COVID-19 patients, potential medication side effects and adherence to study 
treatment regimens. Complete questionnaires are located in the appendix section.  
Additional laboratory studies will include plasma serologies, cellular & systemic inflammatory 
markers as well as other disease associated markers. Samples will be stored for future studies as 
new markers of SARS-COV-2 infection and COVID-19 disease may be yet to be identified.  
Samples will also be stored for potential future HCQ level testing. The testing will be done for 
samples from both randomized treatment arms and comparator arm subset of patients to assess 
their study compliance as compared to the medication adherence indicated in the study 
questionnaires. HCQ drug levels will provide further information regarding drug levels and their 
association with the effectiveness of the treatment strategies on prevention of symptom 
development and clinical & laboratory confirmed disease.   


 
19 
 
All collected specimens will be sent directly to the research laboratory for processing, analyses and 
storage. Patients who develop clinical symptoms for SARS-CoV-2 will have both clinical referral for 
testing and study blood collected. Additional testing for serology, immunology and other markers 
will be done later in the study. Samples will be stored in appropriately monitored – 80°C freezers or 
liquid nitrogen containers in the Division of Infectious Diseases and/or Translational and Clinical 
Research Center laboratories for testing.   
 
4.1  Use of Data 
The results of the investigational study will be used for the determination of the efficacy of 
the intervention strategy.  
The data generated during this study will support clinical trials for the prevention and 
monitoring of COVID-19 in HCW, FR, & DDOT bus drivers and will expand our knowledge of this 
disease.  Any data obtained during the course of the study that may potentially significantly 
impact the management and/or outcomes of the proposed therapies and monitoring for COVID-
10 will be made immediately available to the general health community with all related data.  
Barring these findings, data sharing will be planned at the completion of the study after all study 
plan analyses and sub-analyses have been completed.  
 
No personally identifiable testing for human DNA will be performed on any samples obtained from 
this study. 
 
4.2 
 Study Duration 
Each Participant’s involvement in the study will include direct contacts with study investigators 
which includes the following: Baseline screening, enrollment and sample acquisition; week 2-7 
monitoring questionnaire, and blood samples on week 4; and week 8 study termination 
questionnaire and blood sample acquisition. The Participant will receive their randomized 8 week 
study medication supply following enrollment and randomization.  The research pharmacy will 


 
 
20 
 
dispense medication to a dedicated study coordinator, who will then dispense the medication to 
the participant.  All transfer of medication will be recorded on a drug accountability log for the 
site and in the participants’ source binder. The total time for each participant in the study will be 
for 8 weeks from enrollment. For Participants with COVID-19 diagnosis will have an unplanned 
study visit after 4 weeks from diagnosis for final study assessment and blood draw. All patients 
may be contacted up to 30 days post completion of the study medication for safety monitoring. 
The study duration is estimated at 2 years for the completion of enrollment, data collection and 
analyses, laboratory testing to be completed, and dissemination/publication.  Initial findings of 
the study are expected to be completed within 6 months of study initiation. 
 
5 STUDY MATERIALS 
5.1 
The following materials will be needed at enrollment (in dedicated research 
exam room): 
5.1.1 Vials of Universal Transport Media 
5.1.2 Pre-printed labels with the site's assigned sample 
identification numbers for labeling the blood samples. 
5.1.3 Blood collection kits with appropriate whole blood vials. 
5.1.4 Cooler for sample transport to the laboratory for processing. 
5.1.5 Study screening questionnaire 
5.1.6 Informed consent 
5.1.7 Thermometers 
5.1.8 Medication Safety Sheet 
5.2 
The following materials are required for the randomization visit: 


 
21 
 
5.2.1 Study medication dispensed in pill blister pack 
5.2.2 Placebo medication dispensed in pill blister pack 
5.2.3 Randomization form 
5.2.4 Drug accountability log 
 
5.3 
The following materials needed for the week monitoring visits: 
 
Weeks 1,2,3,5,6 & 7 will be virtual visits (via telephone, telemedicine, electronic 
mail as preferred by the Participant) 
5.3.1 Questionnaire for adverse events and COVID-19 
symptomatology 
5.3.2 Call Log and Call Dialogue  
5.3.3 Referral if symptomatic and/or the participant has a 
significant AE/SAE (as indicated in Pharmacy section). 
5.3.4 AE/SAE monitoring document. 
5.3.5 Drug accountability log 
Week 4 visit will be a face-to-face visit in a dedicated research room/area. 
5.3.6 Week 4 will require the addition of blood draw materials as in 
section 5.1. 
 
5.4 
The following materials needed for the week 8 end of study visit (in dedicated 
research exam room): 
5.4.1 Questionnaire for adverse events and COVID-19 


 
 
22 
 
symptomatology. 
5.4.2 Referral if symptomatic and/or the participant has a 
significant AE/SAE (as indicated in Pharmacy section). 
5.4.3 AE/SAE monitoring document. 
5.4.4 Laboratory material as in 5.1 for sample collection and 
processing. 
5.4.5 Drug accountability log 
 
6 STUDY SUBJECTS 
 
 
6.1 
Number of Subjects 
Approximately 3000 HCW, FR, and DDOT bus drivers, age 18 to 75 years, without symptoms of 
respiratory tract infections and without a history of testing positive for SARS-CoV-2 will be 
prospectively enrolled and randomized at Henry Ford Health System, Detroit COVID Consortium 
or the Detroit Public Health Building.  The fourth non-randomized comparator arm will include 
Participants on chronic maintenance therapy with weight-based HCQ twice a day dosing for their 
autoimmune disease, which will be continued throughout the study. Enrollment in this group will 
be open as it will be a non-randomized treatment arm, with total numbers of HCW enrolled will 
be expected to be lower than the randomized groups. The total study duration is expected to be 
up to 2 years, with Participant enrollment targeted to begin in April 2020. 
Randomization Schema will be generated by the Biostatistician at Department of Public Health 
Sciences (PHS) at HFHS prior to the study enrollment. Randomization will be stratified by 
study site and level of risk of exposure in two levels. High risk includes healthcare personnel 
working in either hospital or nursing home settings (including environmental service) who 


 
23 
 
work in COVID-19 care areas, emergency rooms and intensive care units caring for COVID-19 
patients, nursing home HCW providing any direct patient care, first responders (FR) and DDOT 
bus drivers. Low risk group will include healthcare and supportive personnel who work in 
non-COVID-19 care areas, without direct patient contact, and those involved in administrative 
roles.  All physicians and clinical staff who are involved in the patient’s enrollment and follow-
ups will be blinded to the study treatments.  Once enrolled, each Participant will be assigned a 
unique identifier. This number, along with the assigned site number, will constitute the Subject 
ID. This process is defined by using the following format: 
 
- 
Site # 
Subject # 
 
Site # = 3-digit code for the site assigned by the investigators 
Subject # = 5-digit sequential number assigned by site personnel/investigators 
All subject-specific material (i.e., case report log and samples) must be labeled in accordance 
with this ID. 
 
6.2 
Inclusion/Exclusion Criteria 
To be enrolled in the study, each Participant must meet all of the following inclusion criteria and 
none of the following exclusion criteria: 
 
6.2.1 Inclusion Criteria 
1. 
Participant is willing and able to provide informed consent. 
2. 
Participant is 18-75 years of age. 
3. 
Participant does not have symptoms of respiratory infection, including 
cough, fevers (temperature >38.0C), difficulty breathing, shortness of 
breath, chest pains, malaise, myalgia, headaches, nausea or vomiting, or 
other symptoms associated with COVID-19. 


 
 
24 
 
4. 
Participant is willing to provide blood samples for the study. 
5. 
Subject agrees to all aspects of the study. 
6. 
The participant has no known allergies or contraindications (as stated in the consent 
form) to the use of hydroxychloroquine (HCQ) as noted in the exclusion criteria and 
Pharmacy sections.  
 
6.2.2 Exclusion Criteria 
1. Does not meet inclusion criteria. 
2. Participant unable or unwilling to provide informed consent. 
3. Participant has any of the symptoms above or screens positive for possible COVID-
19 disease.  
4. Participant is currently enrolled in a study to evaluate an investigational drug. 
5. Vulnerable populations deemed inappropriate for study by the site Principal 
Investigator. 
6. The participant has a known allergy/hypersensitivity or has a medication or co-
morbidity (including history of gastric bypass, epilepsy, cardiovascular disease or 
renal failure) that prevents the use of HCQ (see pharmacy section).  
7. The participant is a woman of childbearing age whose pregnancy status is unknown 
and is not willing to use 2 methods of contraception. 
8. The participant is pregnant or nursing. 
9. The participant was diagnosed with retinopathy prior to study entry. 
10. The participant has a diagnosis of porphyria prior to study entry. 


 
25 
 
11. The participant has renal failure with a creatinine clearance of <10 ml/min, pre-
dialysis or requiring dialysis.  
12. The Participant has a family history of Sudden Cardiac Death. 
13. The participant is currently on diuretic therapy using loop-diuretics. 
14. The participant has a history of known Prolonged QT Syndrome. 
15. The participant is already taking any of the following medications: Abiraterone 
acetate, Agalsidase, Amodiaquine, Azithromycin, Conivaptan, Dabrafenib, 
Dacomitinib, Dapsone (Systemic), Digoxin, Enzalutamide, Fusidic Acid (Systemic), 
Idelalisib, Lanthanum, Lumefantrine, Mefloquine, Mifepristone, Mitotane, Pimozide, 
QT-prolonging Agents, Stiripentol). See Pharmacy section. 
 
6.3 
Participant Discontinuation 
Participants may discontinue their participation in the study at any time. A Participant may be 
withdrawn from the study at any time at the discretion of the Investigator. Participants 
withdrawn from the study prior to randomization will not be included in the study. Using the  
intention to treat (ITT) approach, participants randomized but not completing the study will be 
included in the study analyses based on the treatment they were assigned and worse case (test 
positive) will be considered for those who withdraw early and clinical COVID-19 disease status 
cannot be confirmed.  
For this study, Participants may be discontinued from the randomized study drug if deemed to 
have developed a study drug related SAE. Safety follow up for up to 4 weeks after 
discontinuation will be done to determine clinical outcomes via direct communication with the 
Participant. Similarly, Participants who discontinue medications will be approached to assess 
any clinical outcomes during their planned 8 study week participation. Participants that are 


 
 
26 
 
discontinued from the study by the Investigator, are lost to follow up or decline further study 
involvement and withdraw their consent will not be approached after study discontinuation. 
 
6.4 
Participant Withdrawal  
A Participant will be considered unevaluable for the purposes of this study if: 
 
Participant withdraws consent for study participation before designated baseline 
samples have been obtained. 
 
Participant refuses specimen collection at study baseline. 
Subjects who are unevaluable will be withdrawn from the study and will not be included in the 
study analyses. 
 
7 STUDY PROCEDURES 
7.1 
Screening and Enrollment 
Research site staff will be notified of potential Participants (i.e., Participants meeting all inclusion 
criteria) through screening forms filled out by potential participants on the study website, or 
indirect contact (in person, electronic or telephone). Research site staff will be located at 
different sites within participating clinical institutions to facilitate Participant enrollment (e.g., 
points of entry). FR and DDOT bus drivers will be informed of the study through IRB approved 
communications received through their work or union resources or health department flyer. All 
FR and DDOT bus drivers will be screened and enrolled at a participating clinical institution or 
health department.  Research site staff trained in basic Human Research Subjects Protection will 
obtain informed consent from each Participant prior to enrollment and specimen collection in 
accordance with all applicable regulatory requirements. Those Participants wishing to participate 
will be asked to sign the Informed Consent Form (ICF) and will be provided with a copy for their 
records. The original form(s) will be maintained with the Participant’s study records. Study 


 
27 
 
investigators will receive reports on eligible and enrolled study Participants on a regular basis to 
monitor study enrollment and accrual.  
 
Consented Participants will be assigned a Subject ID that is recorded on the Case Report Log 
provided by the site investigator team.  The Principal Investigator (PI) at each clinical site will 
maintain a Participant Master Log that will associate the Subject ID to the Subject’s name and 
contact information. This log will remain at the clinical site and will remain confidential to the 
clinical site. 
 
Clinically asymptomatic Participants not on HCQ chronic therapy will be randomized into one of 
the three randomized arms of the study.  At that time, the research pharmacy will be notified of 
the subject randomization and they will prepare the 8-week supply of study medication.  This 
will be recorded on a drug accountability log in the pharmacy.  Pharmacy will notify study 
coordinators when medication is available for pick up and dispensing.  Research coordinator will 
pick up the study medication and schedule a drug dispensing study visit (baseline) with the 
subject.  At the drug dispensing study visit (baseline visit), the Participant will be given their 8-
week supply of medication, which will be recorded on their individual drug accountability 
log.  Subjects will be instructed to keep their medication blister pack and return it at the week 4 
study visit and at the end of the study for a study drug reconciliation. Participants will be asked 
about medication adherence during their virtual monitoring visits. Participants will have a +/- 3 
day window to complete their scheduled study visits. If a subject stops the study drug for any 
reason during the trial, the subject will be instructed to keep the remainder of their medication 
and return it to study personnel within 1 month for study drug reconciliation.  
 
Asymptomatic Participants on chronic HCQ therapy will continue on their current medication for 
the duration of the study. If during the study period, the Participant is unable to refill their 


 
 
28 
 
prescription, the Study team will assess the possibility of providing the HCQ treatment for period 
that the Participant is unable to fill their prescription or to the end of the study (whichever 
occurs first).  
 
 
 


 
29 
 
7.2 
Study Schedule of Events 
 
Case Report 
Forms 
 
Screening / 
Baseline 
 
Randomizationd 
Monitoring Weeks 
Study 
Withdrawal 
or Positive 
COVID-19 
Diagnosis 
Week 8 
End of 
Study 
As 
Needed 
1 
2 
3 
4 
5 
6 
7 
 
 
 
Pre-Screening 
Checklist 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Survey – Pt 
reported 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory – 
Blood Draw 
X 
 
 
 
 
X 
 
 
 
Xc 
X 
 
Randomizatio
n Form 
X 
 
 
 
 
 
 
 
 
 
 
 
Weekly 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
Xb 
X 
 
Blinded Drug 
Accountability 
Log 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE/SAE Log 
 
 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
X 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Protocol 
Deviation Log 
 
 
 
 
 
 
 
 
 
 
 
X 
Unblinding 
 
 
 
 
 
 
 
 
 
 
 
X 
Final Status 
 
 
 
 
 
 
 
 
 
xe 
Xe 
 
 
 
 
Note: a Virtual visits for monitoring will be done via telephone, video visits or electronic mail encounters, as 
preferred by the study participant to promote study compliance and reduce risks for participants to coming to 
the clinical settings and become exposed to COVID-19. b Study withdrawal evaluations due to COVID-19 
infection, patient preference or other reasons may be done either by virtual visits or clinic visits, depending on 
the participant clinical situation. c A study questionnaire and blood draw will be attempted on each HCW/FR 
who test or screen positive for COVID-19 by either study or clinical screening & testing. If study testing 
identifies potential active SARS-COV-2 infection during the study, the investigators will notify the Participant of 
the results and ensure that the Participant has access to appropriate follow up care. Participants will have a +/- 
3 day window to complete their scheduled study visits. d If the participant cannot receive his blister pack 
immediately after enrollment, the participant may return later on the date of enrollment or next day to 
receive their study medication. Clinical assessment will be the evaluation for symptoms during the encounter 
with the research personnel, any potential/ active participant describing, presenting or with clear symptoms of 
viral infection will be referred to their medical provider for care. e The final status form will be completed at 
week 8 or upon withdrawal or early termination.  


 
 
30 
 
7.3 
SAMPLE COLLECTION AND HANDLING 
Five (5) 10 ml blood tubes consisting of 4 EDTA and 1 Shield tubes of whole blood will be 
collected from each participant at the baseline/enrollment, week 4 and week 8 timepoints. The 
samples will be collected using standard aseptic procedures and will be stored in a 4°C 
refrigerator or cooler until transport to the research laboratory where the samples will be 
processed. Samples will be processed to serum plasma or cell components. Testing for SARS-
CoV 2 will be done for study entry samples. Remainder of the samples will be stored in -80°C 
for whole blood/serum plasma and cell samples will be stored in liquid nitrogen for future 
testing.   
 
8 Statistics and Reports 
8.1 Case Report Form (CRF) and Questionnaires 
Study investigators will provide CRLs to sites and must include the following information: 
 
Participant demographics, date/time of symptoms onset, and sample collection 
date must be recorded. 
 
The study entry/enrollment (baseline visit), drug dispensing visit, week 4 and 8 
visit, or at study withdrawal or confirmation of COVID-19 infection, 
questionnaire for each participant and submit for data entry upon completion. 
If a recording error is made, cross out the error will be crossed through with one stroke, 
initialed and dated, with the correct information entered next to the erroneous entry. 
 
The information required for completion of the CRL is as follows: 
Subject Information: 
 
Subject ID (3-digit site number and 4 digit4-digit Subject number) 
 
Subject Gender 
 
Subject age 


 
31 
 
 
Subject Consent Obtained (Yes/No) 
 
Date of Subject Consent (DD/MMM/YYYY) 
 
Diagnostic testing performed during the clinical visit and assay results if available 
 
Inclusion Criteria (Yes/No) -all criteria must be checked "yes" or Subject is not 
eligible 
 
Exclusion Criteria (Yes/No)-if any criteria is checked "yes", the Subject is not 
eligible 
 
Date of Onset of Symptom (DD/MMM/YYYY) if present 
 
Complete Questionnaire for each timepoint 
Sample Collection Information: 
 
Sample Collection Date (DD/MMM/YYYY) 
 
Standard of Care Method/ Results  
 
Comments (Print Comments) 
PI Signature and Date 
 
PI or Designee Signature and Date 
 
8.2 Reporting AE and SAE – Frequency 
Completed as participant reports for SAE and in the questionnaire for mild to moderate AEs only 
reported during planned study timepoints. 
 
8.3 Statistical Analyses and Sample Size  
The ITT will be used for testing the treatment efficacy based on patients who are SARS-CoVID-2 
viremia negative at the baseline.  The primary analysis will be to compare the rate of COVID-19 
disease for each  treatment group to the placebo group with a Mantel-Haenszel chi-square test 
with multiplicity adjustment using the Dunnett’s step up method(11,12). The  stratifying 


 
 
32 
 
variables will be those used for the randomization, site and  High vs. Low risk groups. The high 
risk group include healthcare personnel (including environmental service) who work in COVID-
19 care areas, emergency rooms and intensive care units caring for COVID-19 patients. First 
responders and DDOT bus drivers will be included as a high risk group. Low risk groups will 
include healthcare workers who work in non-COVID-19 care areas, without direct patient 
contact and those involved in administrative roles.   
 
  The DSMB chair will be provided with a weekly site SAE report to monitor safety.  An interim 
analysis will be done when a half of patients have completed the 8 weeks assessments for an 
early treatment efficacy or a possible reassessment of study sample-size if the estimation of 
placebo rate is inadequate.  Depending on response to the study intervention, the DSMB may 
decide it is necessary to stop/continue the trial if 1) there are safety concerns at any point in the 
trial or 2) there is evidence of treatment efficacy at the interim analysis; or recommendation for 
trial modification as it may be suggested, or 3) to continue the trial as designed. The DSMB will 
only stop the clinical trial for safety reasons. 
Secondary analyses will be performed to evaluate the comparisons between the randomized 
arms and the chronic HCQ treatment comparator arm. Additional analyses will include 
assessments of inflammatory markers in both plasma and leukocytes, clinical characteristics 
associated with risk for COVID-19 acquisition, disease specific markers and clinical symptoms, as 
well as virologic markers and sequencing of positive COVID-19 patients during the study. Safety 
and AE reporting will also be done as part of the study.  A detailed statistical analysis plan (SAP) 
will be written before the study is closed. 
Sample size/power calculation:   
With one planned interim analysis when 50% of the participants have completed their 8 week 
treatment and using an O’Brien-Fleming alpha spending method to ensure an overall type 1 


 
 
error of 0.05, the critical value for the interim analysis will be 0.0054 and the final critical value 
will be 0.0492.  With a sample size of 900 per group and alpha=0.0492, the power to detect a 
32% reduction in COVID-19 disease rate (10% vs 6.8%) between the placebo group and each 
HCQ treated group would be 87%.  Power calculations are also given for placebo rates of 8% and 
15% with a 32% reduction in COVID-19 disease rates for the HCQ treated groups. Assuming 5-
10% of patients will have SARS-CoVID-2 viremia positive at the baseline, we need 1000 per 
group with a total of 3000 patients to complete the trial.  
Power calculations using simulations for Dunnett’s step up method 
Assuming 900 per group and alpha=0.0492 
 
COVID-19 disease rate 
in placebo 
COVID-19 disease rate 
in treatment 
Power 
8% 
5.4% 
80% 
10% 
6.8% 
87% 
15% 
10% 
98% 
 
 
 
9 
PARTICIPANT INVOLVEMENT ENDPOINT/FOLLOW-UP 
All Participants who sign the Consent and Authorization Form and provide three (3) blood 
sample draws, complete the baseline and week 1- 8 assessments, or after acquiring COVID-19 
infection at any point during the study period are considered to have completed participation 
in this study.  Participants will be followed for 30 days after meeting study endpoint for safety 
purposes. No further follow-up by the study Investigator is planned for Participants involved 
in this study thereafter. Electronic medical records will be accessed to obtain information on 
any diagnostic testing done for COVID-19 as part of the Participants’ routine care which may 
lead to diagnosis of COVID infection, including but not limited to PCR, serologies, rapid 
diagnostic tests, and other related tests. 
 


 
 
34 
 
10 SAFETY CONSIDERATIONS 
10.1 
Definitions of Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a Participant administered an 
investigational product or undergoing a procedure, which does not necessarily have a causal 
relationship with the treatment. An AE can be any unfavorable and unintended sign, symptom, 
or disease temporally associated with the use of an investigational product, whether or not it is 
related to the investigational product. Development of COVID-19 disease will not be considered an 
adverse event as it is considered the study primary endpoint. 
 
A Serious Adverse Events (SAE) is any untoward medical occurrence that may present itself 
during a Subject’s participation in a clinical trial that: 
 
 
Results in death, 
 
Is life-threatening, 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization, may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the Participant and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Medical care and hospitalization secondary to development of 
COVID-19 disease are considered study endpoints for this prevention study.  
 
It should be noted that AEs that lead to hospitalization are considered SAEs.  However, elective 


 
 
hospital admissions not in response to an adverse event are not SAEs. 
 
Life-threatening means that the Participant was, in the view of the PI, at immediate risk of 
death from the reaction as it occurred.  This definition does not include a reaction that, had it 
occurred in a more serious form, might have caused death. Assessment of the cause of the 
event has no bearing on the assessment of the event’s severity. 
 
AEs will be considered to be study-related if the event follows a reasonable temporal sequence 
from a study-specific procedure and could readily have been produced by that study or 
medication procedure. Deaths, organ failures and other complications related to the Participants 
underlying conditions (including the disease or problem that caused the Participant to seek 
medical care), should not be considered study-related AEs. 
 
10.2 
Possible Risks & Benefits Associated with Study Procedures 
There is a potential health benefit to Participants by participating in this study, as the 
medication may help to prevent the acquisition or ameliorate the manifestations of COVID-19 
infection. The COVID-19 testing results obtained from testing completed by the study 
investigators will be made available to the Participants when available to the investigator. If any 
Participant has a positive COVID-19 test during the study, the Participant will be referred to 
their respective healthcare provider for additional testing and treatment as recommended by 
the local guidelines. HFHS employees will be referred directly to employee health.  First 
responders and DDOT bus drivers will be referred to their respective employee health services. 
Participants may also be referred to their primary care provider, if they choose so. Additional, 
secondary endpoint analyses and results will not be returned to the participating site and will 
not be used in the management of Participants. No personally identifiable testing for human 


 
 
36 
 
DNA will be performed on any samples obtained from this study. DNA testing on de-identified 
samples will be planned as a secondary study analyses to assess potential DNA markers of 
increased susceptibility to COVID-19 infection in our study population. 
Hydroxychloroquine (HCQ) is considered a safe and effective drug in the treatment of 
Rheumatoid arthritis, Systemic Lupus Erythematosus and other autoimmune diseases, as well as 
for the prevention of Malaria infection (6). The 2015 American College of Rheumatology 
guidelines do not recommend any routine laboratory testing or electrocardiogram monitoring 
for patients taking HCQ standard doses (up to 400mg maintenance dose) daily (8). Side effects of 
the medication are varied including gastrointestinal symptoms, skin and hair changes, muscle 
pains, an irregular heartbeat, and others as listed in Pharmacy section 10.3, with most being mild 
and of unknown incidence. Severe but rare side effects include drug allergic reaction, cardiac 
arrythmias with risk of death, hypoglycemia with concomitant hypoglycemic medications, visual 
changes, retinal disease and rarely blood cell count anomalies may occur. Participants with any 
potential medication associated drug-drug side effects and/or with any elevated risk factors 
associated with any significant HCQ side effects or toxicities, will be excluded from the study. 
 
The only study-related procedure that could impact Participant safety is the collection of three (3) 
planned blood draws. The anticipated risks of collecting a blood sample specimen may include 
slight pain, discomfort, and/or the possibility of bleeding or bruising at the site.  
 
Possible risk of loss of confidentiality could occur by obtaining study questionnaires and 
accessing the Participants’ electronic medical records to determine assay results from any 
clinical testing for COVID-19 that may have been performed during their clinic or emergency 
room visit includes potential exposure of confidential medical information. Investigators will 
keep a separate patient key linking MRN to the study ID and will not provide this information to 
the study sponsor unless required by law. All study and clinical information will be kept in 


 
 
secure electronic servers and in locked cabinets. Investigators will ensure that only the minimal 
amount of information needed for the study is accessed and recorded for study purposes. (See 
Confidentiality, section 11.3) 
 
10.3 
Pharmacy 
DOSE 
The once weekly randomized treatment arm will receive the proposed dose of 
hydroxychloroquine for prophylaxis of malaria is 6.5 mg/kg per dose (maximum of 400mg per 
dose) administered orally weekly on the same day of each week.  This is based on the 
recommended dose for prophylaxis of malaria(13).  
The daily hydroxychloroquine treatment arm will receive a 200mg oral dose daily following day 
1 dose of 400mg orally once. This dose represents approximately half the standard weight-based 
dosing recommended for management of autoimmune diseases and therefore less likely to 
produce side effects than standard of care. All treatment groups will receive placebo pills to have 
the patients take 2 pills a day. 
The randomized placebo arm will receive placebo pills made to resemble the daily dosing of 
HCQ. Similarly, the once a week treatment arm will receive placebo pills for the days not on HCQ 
medication. 
 
No specific dosage adjustments are required in patients with renal dysfunction or hepatic 
disease due to the lower dosing regimen in the intervention arms (14). 
 
Note, the elimination half-life of hydroxychloroquine sulfate estimated from 172 hours to 50 
days (15). Subjects may have prolonged exposure to hydroxychloroquine even after 
discontinuing the medication.  
 


 
 
38 
 
PRECAUTIONS AND CONTRAINDICATIONS 
Hydroxychloroquine is contraindicated in patients with hypersensitivity to hydroxychloroquine 
or related compounds.  
Caution should be exercised when using hydroxychloroquine in Participants with any of the 
following underlying conditions or risks:  
 
Cardiovascular disease: cardiomyopathy, with fatalities, has been reported. QT 
prolongation, ventricular arrhythmias, and torsades de pointes have been reported.  
Avoid use with other drugs that prolong QT interval.  
 
Dermatologic: severe exacerbation of psoriasis may occur. Other dermatologic reaction 
may occur.  
 
Endocrine and metabolic: severe hypoglycemia may occur in patients treated with 
antidiabetic medications.  
 
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia may 
occur, more commonly with prolonged use.  
 
Hepatic: Use with caution in patients with liver disease, alcoholism, or use of other 
hepatotoxic drugs. Dose adjustment may be necessary; however no specific dose 
guidelines are available.  
 
Musculoskeletal: proximal myopathy has been reported. Neurologic: neuropathy has 
been reported.  
 
Ophthalmic: Irreversible retinal damage has been reported as a rare complication of 
therapy. Increased risks include doses larger than 6.5mg/kg, duration of over 5 years, 
renal insufficiency, concomitant use of tamoxifen, or concurrent macular disease.  
 
Psychiatric: suicidal behavior has been rarely reported.  
 
DRUG-DRUG INTERACTIONS  


 
 
  
Hydroxychloroquine should not be used with certain drugs that are known to prolong QT 
syndrome. These include but are not limited to: 
 
 
Common drugs known to cause Torsades de Pointes 
Class 
Examples 
Antiarrhythmics 
Disopyramide, procainamide, quinidine, sotalol 
Macrolides 
Azithromycin, clarithromycin, erythromycin 
Fluoroquinolones 
Ciprofloxacin, levofloxacin, moxifloxacin 
Antifungals 
Fluconazole, ketoconazole, pentamidine, voriconazole 
Antipsychotics 
Haloperidol, thioridazine, ziprasidone 
Antidepressants 
Citalopram, escitalopram, 
Antiemetics 
Dolasetron, droperidol, granisetron, ondansetron 
Opioids 
Methadone 
Miscellaneous 
Cocaine, cilostazole, donepezil 
 
Other moderate drug interactions:  
Digoxin: may increase serum digoxin concentrations. 
Antacids or PPI may reduce HCQ absorption. 
 
PATIENT COUNSELING 
 
Counsel Participants that side effects of this medication may include vertigo, tinnitus, visual field 
defects, color vision abnormalities, nausea, vomiting, fatigue, decreased appetite, headaches, 
dizziness, and irritability. Participants taking antidiabetic medications will be counseled on the 


 
 
40 
 
risk of hypoglycemia and the associated symptoms.   Symptoms of toxicity (e.g. rash, visual 
changes) should be reported to a healthcare provider and to the investigators.  Participants will 
be made aware of the need to keep their study medications out of the reach of children. 
 
 
10.4 
Reporting Requirements 
Any medical occurrences that are observed during the study that the Investigator believes are 
serious AND qualify as either an unanticipated adverse event OR are related to study- 
specific procedures as defined above must be reported (by telephone or FAX) to the Study PI 
or Co-PI within 10 days to: 
Laurie Marshall-Nightengale, MD, MSc 
Research Coordinator 
Tel: 313-916-4835 
 
The applicable IRB must also be informed of the event in accordance with their procedures. The 
Investigator will then submit a detailed written report to Study Sponsor and the IRB no later than 
ten (10) days after the Investigator discovers the event. 
 
Study investigators will be responsible for reporting any reportable serious, unexpected, study-
related AEs from this study to the FDA and other applicable regulatory agencies. 
 
 
11 
INVESTIGATOR OBLIGATIONS 
11.1 
Guidelines for the Conduct of the Study 


 
 
The Investigator is responsible for ensuring that the study is conducted in accordance with the 
clinical protocol and in compliance with FDA regulatory requirements outlined in 21 CFR Parts 
11, 50, 54, 56 and 812, the Guidance for Industry - Good Clinical Practice: Consolidated 
Guidance (ICH-E6) April 1996, and the Declaration of Helsinki. 
 
The Investigator is also responsible for protecting the rights, safety and welfare of Participants 
under the Investigator’s care. 
 
11.2 
Informed Consent 
In accordance with guidelines as outlined in CFR 21, Part 50, the Investigator or designee will 
ensure that the Participant/Subject is provided full and adequate verbal and written 
information about the nature, purpose, possible risks and benefits, and costs of this 
investigational study.  A written informed consent form (ICF) will be provided to each 
participant describing this information. This form must be reviewed and approved by Study 
Sponsor, Investigators and the IRB before its use in the study. Each Participant must sign and 
date this form prior to their participation in the study. 
An original consent form for each Participant will be kept on file at the clinical site. A copy will 
also be given to the Participant or parent/legal guardian signing the form. 
 
11.3 
Confidentiality 
The Investigator and designees, employees, and agents involved with this study will comply 
with relevant state and federal laws relating to the confidentiality, privacy and security of 
Participant’s health information. Study data disclosures will be limited to the Sponsor, IRB, FDA 
or other authorized recipients as appropriate for the execution, analysis, review and reporting 
of this study. Such information shall not be used for any other purposes and will remain 


 
 
42 
 
confidential. 
 
11.4 
Protocol Modification/Amendments 
Deviations from the protocol will be documented throughout the duration of the study. 
Protocol deviations may include, but are not limited to the following: 
 
Participant is enrolled without meeting all inclusion criteria and/or meets one or 
more exclusion criteria; or 
 
Participant samples are not stored or handled within protocol specified timeframes 
and/or temperature requirements. 
 
Participant questionnaires are not fully completed prior to study entry. 
 
If preliminary or interim review of study data indicates that a revision to the protocol is 
required, an amendment to this protocol will be prepared and implemented upon agreement of 
the study investigators. If these changes or deviations affect the scientific accuracy of the 
investigational plan or the rights, safety, or welfare of human Participants, the IRB must be 
notified. Deviations from the protocol will must be documented on the Protocol Deviation 
Log. 
Protocol amendments may be introduced by the lead investigator team at any time after the 
start of the study to include new procedures or address new findings in the field. 
 
 
11.5 
Recording & Monitoring of Study Data 
All required study data will be recorded on a Source Document and later transcribed to the Case 
Report Logs provided by study investigators. The data recorded on the Case Report Logs is 
derived from study related source documents. The Investigator shall ensure that all data on the 


 
 
Study Report Logs is complete and accurate and consistent with source documentation. 
 
All data collections will be recorded/or legibly printed in indelible black or blue ink. Any errors 
will be crossed out with a single line and the correct entry made in indelible ink and initialed 
and dated by site personnel making the correction. 
A monitor may review the Case Report Forms for completeness and accuracy. Study data on 
the Study Report Forms may be verified against information on original source documents. 
Source documentation may include, but is not limited to, clinical records, intake forms, test 
result print outs, laboratory logs and may differ by site. The source documentation reviewed 
will be noted by the study monitor in each monitoring report.  The monitor will also check 
written informed consent forms and all study specific logs for completeness, accuracy and 
plausibility. 
 
11.6 
Direct Access to Source Data & Study Documents 
The Investigator and study site will permit trial-related monitoring, audits, IRB review and 
regulatory inspection by providing authorized personnel from Study Sponsor, its 
representatives, the IRB, the FDA and other appropriate regulatory agency direct access to all 
trial related data. 
 
Direct access is the permission to examine, analyze, verify and reproduce any records, source 
documents or reports that are important to the evaluation of a clinical study.  Any party with 
direct access should take reasonable precautions to maintain the confidentiality of the study 
Participants.  
 
11.7 
Record Retention 


 
 
44 
 
Copies of Study Report Forms, original ICFs, original source documents, study records, and 
reports must be maintained by the Investigator for a period of five (5) years after the 
investigation is terminated or completed, or for a period of two (2) years after the records are 
no longer required for the purposes of supporting a pre-market approval application or a 
notice of completion of a product development protocol. Study sponsor should be notified in 
writing at least 30 days prior to the disposal or transfer to another location or party, of any 
study records related to this protocol. 
 
 
 
 


 
 
12 
REFERENCES 
 
1. 
Bai Y, Yao L, Wei T et al. Presumed Asymptomatic Carrier Transmission of COVID-19. Jama 2020. 
2. 
Chang, Xu H, Rebaza A, Sharma L, Dela Cruz CS. Protecting health-care workers from subclinical 
coronavirus infection. The Lancet Respiratory medicine 2020;8:e13. 
3. 
Liu J, Cao R, Xu M et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in 
inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6:16. 
4. 
Vincent MJ, Bergeron E, Benjannet S et al. Chloroquine is a potent inhibitor of SARS coronavirus 
infection and spread. Virol J 2005;2:69. 
5. 
Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. 
Clinical reviews in allergy & immunology 2012;42:145-53. 
6. 
Goodman LS, Gilman, A., Hardman, J. G., Gilman, A. G., & Limbird, L. E. Goodman & Gilman's: The 
Pharmacological Basis of Therapeutics, Thirteenth Edition., 2018. 
7. 
Mohammad S, Clowse MEB, Eudy AM, Criscione-Schreiber LG. Examination of Hydroxychloroquine 
Use and Hemolytic Anemia in G6PDH-Deficient Patients. Arthritis care & research 2018;70:481-
485. 
8. 
Singh JA, Saag KG, Bridges SL, Jr. et al. 2015 American College of Rheumatology Guideline for the 
Treatment of Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, NJ) 2016;68:1-26. 
9. 
Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-
19: results of an open-label non-randomized clinical trial. International journal of antimicrobial 
agents 2020:105949. 
10. 
Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of 
Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2). Clinical infectious diseases : an official publication of the Infectious Diseases Society 
of America 2020. 
11. 
Tan KR AP. Travel-Related Infectious Diseases. In: Services USDoHaH, editor Travelers' Health 
Yellow Book, 2020. 
12. 
Sanofi-Aventis. Product Monograph Including Patient Medication Information PLAQUENIL 
(Hydroxychloroquine Sulfate Tablets USP). 2019. 
13. 
Lim HS, Im JS, Cho JY et al. Pharmacokinetics of Hydroxychloroquine and Its Clinical Implications in 
Chemoprophylaxis against Malaria Caused by Plasmodium vivax. Antimicrob Agents Ch 
2009;53:1468-1475. 
14.         1. 
Bai Y, Yao L, Wei T et al. Presumed Asymptomatic Carrier Transmission of COVID-19. Jama 
2020. 
2. 
Chang, Xu H, Rebaza A, Sharma L, Dela Cruz CS. Protecting health-care workers from subclinical 
coronavirus infection. The Lancet Respiratory medicine 2020;8:e13. 
3. 
Liu J, Cao R, Xu M et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in 
inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6:16. 
4. 
Vincent MJ, Bergeron E, Benjannet S et al. Chloroquine is a potent inhibitor of SARS coronavirus 
infection and spread. Virol J 2005;2:69. 
5. 
Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. 
Clinical reviews in allergy & immunology 2012;42:145-53. 
6. 
Goodman LS, Gilman, A., Hardman, J. G., Gilman, A. G., & Limbird, L. E. Goodman & Gilman's: The 
Pharmacological Basis of Therapeutics, Thirteenth Edition., 2018. 
7. 
Mohammad S, Clowse MEB, Eudy AM, Criscione-Schreiber LG. Examination of Hydroxychloroquine 
Use and Hemolytic Anemia in G6PDH-Deficient Patients. Arthritis care & research 2018;70:481-
485. 
8. 
Singh JA, Saag KG, Bridges SL, Jr. et al. 2015 American College of Rheumatology Guideline for the 
Treatment of Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, NJ) 2016;68:1-26. 


 
 
46 
 
9. 
Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-
19: results of an open-label non-randomized clinical trial. International journal of antimicrobial 
agents 2020:105949. 
10. 
Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of 
Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2). Clinical infectious diseases : an official publication of the Infectious Diseases Society 
of America 2020. 
11. 
Dunnett CW, Tamhane AC. A step-up multiple test procedure. Journal of the American Statistical 
Association 1992;8 (417):162-170. 
12. 
Howard DR, Brown JM, Todd S, Gregory WM. Recommendations on multiple testing adjustment in 
multi-arm trials with a shared control group. Statistical methods in medical research 
2018;27:1513-1530. 
13. 
Tan KR AP. Travel-Related Infectious Diseases. In: Services USDoHaH, editor Travelers' Health 
Yellow Book, 2020. 
14. 
Sanofi-Aventis. Product Monograph Including Patient Medication Information PLAQUENIL 
(Hydroxychloroquine Sulfate Tablets USP). 2019. 
15. 
Lim HS, Im JS, Cho JY et al. Pharmacokinetics of Hydroxychloroquine and Its Clinical Implications in 
Chemoprophylaxis against Malaria Caused by Plasmodium vivax. Antimicrob Agents Ch 
2009;53:1468-1475. 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
APPENDIX A: INVESTIGATOR  
Study Document 1 
 
 
Investigator Signature & Date:   
 
 
Investigator Name & Title (print):   
 
 
Name(s) of Co-Investigators:    
 
 
Address of Study Center:   
 
 
 
 
Telephone Number:   
 


 
 
48 
 
 
APPENDIX B: APPROPRIATE TECHNIQUE FOR BLOOD DRAW 
Proper collection of a quality throat specimen from each Participant is critical. 
 
 
Three (3) blood specimens will be collected from each Participant using the sterile procedure as 
routine standard of care. A total of five (5) 10 mL tubes of whole blood will be collected at each 
timepoint. Avoid contaminating the specimens when collecting samples. Do not touch the top of the 
tubes or the sample collection site without gloves and protective equipment. 
 
A. Procedures/Study Protocol 
 
1. The phlebotomist or trained research assistant to perform the venous blood draw will inspect the 
participant’s arms and hands for a vein of a reasonable size. This is most often the medial cubital vein, 
although other veins on the forearm and back of the hand can be used.    
  
2. Once a suitable vein has been selected by the phlebotomist, the participant will be asked to sit or lie 
down in a position that provides the phlebotomist access to the vein and that is comfortable for the 
participant.    
  
3. The skin superficial to the vein will be cleaned with an alcohol wipe.  
  
4. A tourniquet will be applied 5-10 cm above the intended site of the venous puncture.    
  
5. Blood samples will be collected using a closed, vacutainer system.  The grey rubber end of the vacutainer 
needle is exposed and screwed onto the vacutainer tube holder.  The needle is then unsheathed and 
inserted through the skin and into the vein at an angle of 15-30 degrees.  
  


 
 
6. Blood tubes can then be inserted into the tube holder and onto the hold. The vacuum in the tube will 
draw the blood.  A full tube can be disengaged, and a new tube can be added. The number of tubes to be 
used varies depending on the number and type of analyses to be performed.    
  
7. Upon completion of the blood draw, the tourniquet will be removed, and the needle will be withdrawn 
from the vein quickly.   
  
8. Cotton will be pressed on the site of venous puncture.    
  
9. Participant will be asked to sit still and apply pressure to stop the bleeding and reduce the risk of 
bruising.  
  
10. The phlebotomist will disengage the needle from the holder directly into the sharp’s disposal.   
  
11. If a plasma sample is being collected the blood samples will be gently inverted to mix anticoagulant.  
  
12. Once the bleeding has subsided or stopped (approximately 2-3 min), a bandage will be applied over the 
puncture and the participant will be asked to sit quietly for up to 10 minutes.  
  
13. The phlebotomist will inform the participant there may be bruising at the site of the puncture for the 
next few days, to keep the puncture area clean and dry to promote rapid healing, and no heavy lifting for 
24 hours to prevent further bruising.    
  
14. The participant will be thanked for their participation.    
  
  


 
 
50 
 
B. EQUIPMENT  
  
• 21 gauge needle for each participant with closed vacutainer system   
• Blood collection tubes for each participant   
• Tourniquet  
• Box of nitrile/vinyl gloves (Do not use latex gloves due to allergies/sensitivities.)  
• Alcohol wipes, cotton balls/swabs, bandages  
• Pillow/pad for raising arm to comfortable elevation  
• Apple/orange juice and snacks for fasting participants  
• Disposable, single use materials or equipment are to be used whenever possible   
• Any reusable materials or equipment must be cleaned and disinfected with alcohol-based sanitizers before 
use with another participant  
     
C. DESCRIPTION TO STUDY PARTICIPANTS  
1. Each individual (i.e., study participant) is to be asked in-person, by telephone, or by email if they are:   
• comfortable having blood drawn, and allergic/have sensitivities to rubbing alcohol.   
2. Individuals who indicate in any way they are uncomfortable with the procedure and/or are 
allergic/sensitive to rubbing alcohol will be asked not to participate in the study.  
3. In the information-consent letter participants must be informed:   
 
the blood will only be drawn by a trained and experienced phlebotomist who has been delegated to 
conduct the procedure by a physician.  
 
the phlebotomist will insert a needle into a vein in their arm similar to giving a blood sample in a lab 
that may be requested by their family physician/doctor during a routine physical or a check-up.  
 
the procedure requires wiping an area of the skin with rubbing alcohol and puncturing a suitable vein on 
the inside surface of their elbow with a 21-gauge needle.    
 
Participant will be instructed to wear a loose shirt or a short sleeve shirt as the most commonly used vein 


 
 
for blood collection is located on the inside surface of their elbow.    
 
Participant may ask any questions that they may have about the procedures at any time or ask to stop the 
procedure at any time.  
  
 
 
 
 


 
 
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APPENDIX D: STUDY FLOW CHART 
 
 
 
 
Note: * Only study week 4 will be a clinic research visit with blood draw performed at that visit and refill of the 
participant randomized medications. Weeks 1,2,3,5,6 & 7 will be done via telephone, virtual visit or electronic 
mail, as preferred by the patient.