Conditions: Corona Virus Infection Acute Respiratory Distress Syndrome SARS-CoV Infection Coronavirus Coronavirus Infections
Keywords: COVID-19 Corona Virus SARS-COV-2 Coronavirus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1312
Healthy volunteers: no

Brief summary:
Study Objective:

1. To test if post-exposure prophylaxis with hydroxychloroquine can prevent symptomatic COVID-19 disease after known exposure to the SARS-CoV-2 coronavirus.
2. To test if early preemptive hydroxychloroquine therapy can prevent disease progression in persons with known symptomatic COVID-19 disease, decreasing hospitalizations and symptom severity.

Detailed description:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging viral infection causing COVID19. The current strategy uses a public health model of identifying infected cases, isolation, and quarantine to stop transmission. Once exposed, observation is standard-of-care. Therapy is generally not given to persons who are not hospitalized. The doses of hydroxychloroquine being used are within the normal standard FDA-approved doses.

Hydroxychloroquine may have antiviral effects against SARS-COV2 which may prevent COVID-19 disease or early preemptive therapy may decrease disease severity. This trial will use a modification of standard malaria dosing of hydroxychloroquine to provide post-exposure prophylaxis to prevent disease or preemptive therapy for those with early symptoms. People around the the United States and Canada can participate to help answer this critically important question. No in-person visits are needed.

This trial is targeting 5 groups of people NATIONWIDE to participate:

1. If you are symptomatic with a positive COVID-19 test within the first 4 days of symptoms and are not hospitalized; OR
2. If you live with someone who has been diagnosed with COVID-19, with your last exposure within the last 4 days, and do not have any symptoms; OR
3. If you live with someone who has been diagnosed with COVID-19, and your symptoms started within the last 4 days; OR
4. If you have had occupational exposure with known exposure to someone with lab-confirmed COVID-19 within the last 4 days and do not have symptoms; OR
5. If you have had occupational exposure with known exposure to someone with lab-confirmed COVID-19 within the last 4 days AND have compatible symptoms starting within the last 4 days;

You may participate if you live anywhere in the United States (including territories) or in the Canadian Provinces of Quebec, Manitoba, Alberta, or Ontario.

For information on how to participate in the research trial, go to covidpep.umn.edu or email covid19@umn.edu for instructions. Please check your spam folder if you email.

In Canada, for trial information, please go to: www.covid-19research.ca

Arms:
arm 1: Participants in this arm will receive the study drug. arm 2: Participants in this arm will receive a placebo treatment.

Interventions: intervention 1: Hydroxychloroquine intervention 2: Placebo
Intervention descriptions: intervention 1: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days intervention 2: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days

Protocol document:
Prot_SAP_000.pdf: 
COVID-19 PEP RCT 
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i 
 
Post-exposure Prophylaxis or Preemptive Therapy for SARS-
Coronavirus-2: A Pragmatic Randomized Clinical Trial  
 
Short Title: COVID-19 PEP RCT 
 
 
UMN IRB Number: STUDY00009267 
FDA IND: 148257 
ClinicalTrials.gov: NCT04308668 
Principal Investigator: David R Boulware 
 
Draft or Version Number: 2.3 
24 April 2020  
 
 
 
 
 
CONFIDENTIAL 
This document is confidential and the property of the University of Minnesota.  No part of 
it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the principal investigator. 


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STATEMENT OF COMPLIANCE 
This protocol will utilize a single institutional review board (IRB) registered with the Office of 
Human Research Protections (OHRP) and issued a Federal Wide Assurance (FWA). The 
research will be reviewed and approved by the IRB and will be subject to continuing review [45 
CFR 46.103(b)]. 
 
 
 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable US federal regulations and ICH guidelines. 
 
Site Investigator: 
 
Signed: 
 
Date: 
4/24/2020 
 
Name 
Title 
 
 
 


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TABLE OF CONTENTS 
 
Page 
1 
Key Roles 
1 
2 
Background Information and Scientific Rationale 
2 
2.1 
Background Information 
2 
2.2 
Rationale 
7 
2.3 
Potential Risks and Benefits 
8 
2.3.1 
Potential Risks 
8 
2.3.2 
Known Potential Benefits 
9 
3 
Objectives 
10 
3.1 
Study Objectives 
10 
3.2 
Study Outcome Measures 
10 
3.2.1 
Primary Outcome Measures 
10 
3.2.2 
Secondary Outcome Measures 
10 
4 
Study Design 
11 
4.1 
Design 
11 
4.2 
Study participant duration 
12 
4.3 
Study procedures 
12 
4.4 
Individually identifiable health information: 
12 
4.5 
Substudies (if applicable) 
12 
5 
Study Enrollment and Withdrawal 
13 
5.1 
Subject Inclusion Criteria 
13 
5.2 
Subject Exclusion Criteria 
13 
5.3 
Treatment Assignment Procedures 
14 
5.3.1 
Randomization Procedures 
14 
5.3.2 
Reasons for Withdrawal 
15 
5.3.3 
Handling of Withdrawals 
15 
5.3.4 
Termination of Study 
15 
6 
Study Intervention/Investigational Product 
16 
6.1 
Study Product Description 
16 
6.1.1 
Acquisition 
16 
6.1.2 
Formulation, Packaging, and Labeling 
16 


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6.1.3 
Drug Description: 
16 
6.1.6 
Product Storage and Stability 
18 
6.2 
Dosage, Preparation, and Administration of Investigational Product 
18 
Drug/Device Handling: 
18 
6.3 
Modification of Investigational Product for a Participant 
18 
6.4 
Accountability Procedures for the Investigational Product: 
18 
6.5 
Assessment of Subject Compliance 
18 
6.6 
Concomitant Medications/Treatments 
18 
7 
Study Schedule 
19 
7.1 
Screening 
20 
7.2 
Enrollment/Baseline 
20 
7.3 
Follow-up 
20 
7.4 
Final Study Visit 
21 
7.5 
Early Termination Visit 
21 
7.6 
Unscheduled / Sick Visit 
21 
8 
Study Procedures/Evaluations 
22 
8.1 
Clinical Evaluations 
22 
8.2 
Laboratory Evaluations 
22 
9 
Assessment of Safety 
23 
9.1 
Specification of Safety Parameters 
23 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
23 
9.2.1 
Adverse Events 
23 
9.2.2 
Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) 
23 
9.2.3 
Serious Adverse Events (SAEs) 
23 
9.2.4 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
23 
9.3 
Reporting Procedures 
23 
9.3.1 
Serious Adverse Events 
23 
9.3.2 
Regulatory Reporting 
24 
9.3.3 
Reporting of Pregnancy 
25 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
25 
9.5 
Safety Oversight (DSMB) 
25 
10 
Clinical Monitoring 
26 


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11 
Statistical Considerations 
27 
11.1 
Study Hypotheses 
27 
11.2 
Sample Size Considerations 
27 
11.3 
Planned Interim Analyses 
28 
11.4 
Final Analysis Plan 
29 
12 
Source Documents and Access to Source Data 
31 
13 
Quality Control and Quality Assurance 
31 
14 
Ethics/Protection of Human Subjects 
32 
14.1 
Ethical Standard 
32 
14.2 
Institutional Review Board 
32 
14.3 
Informed Consent Process 
32 
14.3.1 
Informed Consent/Assent Process (in Case of a Minor) 
32 
14.4 
Exclusion of Women, Minorities, and Children 
33 
14.5 
Subject Confidentiality 
33 
14.6 
Future Use of Stored Specimens 
33 
15 
Data Handling and Record Keeping 
34 
15.1 
Data Management Responsibilities 
34 
15.2 
Data Capture Methods 
34 
15.3 
Types of Data 
34 
15.4 
Timing/Reports 
34 
15.5 
Study Records Retention 
34 
15.6 
Protocol Deviations 
34 
16 
Publication Policy 
34 
17 
Literature References 
35 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CFR 
Code of Federal Regulations 
COVID19 
coronavirus disease 2019 
SRS-CoV 
SARS coronavirus                      
(i.e. circa 2003) 
SARS-CoV-2 
SARS coronavirus 2                   
(i.e. circa 2019) 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDS 
Investigational Drug Services 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PCR 
Polymerase chain reaction 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
US 
United States 
WHO 
World Health Organization 
 
t 


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Summary 
Full Title: 
Post-exposure prophylaxis or Preemptive Therapy for coronavirus: 
A Pragmatic Randomized Clinical Trial 
Short Title: 
COVID-19 PEP RCT 
Clinical Phase: 
III 
Sponsor: 
Investigator-Initiated Protocol, University of Minnesota 
Principal Investigator: David R Boulware, MD MPH 
Accrual Ceiling 
3000 
Study Population 
• 
Adult Household contacts or Healthcare workers exposed to 
persons with COVID-19 disease within 4 days (n=1500), or 
• 
Non-hospitalized adults with symptomatic COVID-19 disease 
within 4 days of onset (n=1500) 
Objective 
1) Test if hydroxychloroquine can prevent development of 
COVID-19 disease after known exposure to the SARS-CoV2 
virus. 
2) Test if early preemptive therapy in non-hospitalized adults with 
symptomatic COVID-19 disease can prevent disease 
progression and hospitalization  
Study Design 
Double-blind, randomized placebo-controlled clinical trial 
Internet-based trial driven by self-report. 
Study medicine delivered by FedEx to consented participants. 
Follow up through 14 days, with SAEs followed up to 90 days 
Intervention Arm: 
Hydroxychloroquine 200mg tablet.   


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800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600 
mg once a day for 4 consecutive days (5 days in total) 
(This is a modified malaria dosing for hydroxychloroquine) 
Control Arm: 
Placebo 4 tabs once, followed in 6 to 8 hours by 3 tabs, then 3 
tabs once a day for 4 consecutive days (5 days in total) 
Primary Endpoint in 
Asymptomatic Cohort 
● Incidence of COVID-19 disease within 14 days among those 
who are asymptomatic with known exposure 
Primary Endpoint in 
Symptomatic Cohort 
● Change in symptom severity score (visual analog scale 0-10) 
over 14 days 
Secondary Endpoints 
1. Incidence of Hospitalization for COVID-19 or death 
2. Incidence of confirmed SARS-CoV-2 detection 
3. Incidence of possible COVID-19 symptoms 
4. Incidence of all-cause study medicine discontinuation 
5. Severity of symptoms at Day 5 and 14 by visual analog scale 
6. Ordinal Scale of COVID-19 disease maximum severity at day 
14 among those who are symptomatic at trial entry 
 
Duration of 
Participation 
Recruitment and follow up will be internet-based. 
●       14 days of active participation 
• 
 Up to 90 days follow up for those with COVID-19 diagnosis to 
assess final outcome or dried blood spot collection for 
antibody serologies. 
Inclusion Criteria 
●       Exposure to COVID-19 within 4 days, either as: 
○ Occupational exposure, or 
○ Household contact.  
OR 
● Individual with symptomatic COVID-19 disease confirmed by 
PCR+ or by compatible symptoms with exposure to known 
PCR+ case with <=4 days of symptoms. 
 
●       Age >=18 years of age 
●       Provision of Informed Consent 
Exclusion Criteria 
• 
Current hospitalization 
• 
Allergy to chloroquine or hydroxychloroquine 
• 
Prior retinal eye disease 
• 
Concurrent malignancy requiring chemotherapy 
• 
Known Chronic Kidney disease, Stage 4 or 5 or dialysis. 


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• 
Known glucose-6 phosphate dehydrogenase (G6PD) 
deficiency. 
• 
Known Porphyria 
• 
Weight <50 kg 
• 
Structural or ischemic heart disease 
• 
Personal or family history of QT prolongation 
• 
Current use of: hydroxychloroquine, chloroquine, mefloquine, 
or cardiac medicines of: amiodarone, digoxin, dofetilide, 
flecainide, procainamide, propafenone, or sotalol 
• 
Current use of QT prolonging medicines, including 
azithromycin (Refer to protocol for full list). 
Stratification 
Randomization will be stratified by baseline status of COVID-19 
disease vs. asymptomatic with exposure.  
Analyses will be separate for asymptomatic vs. symptomatic 
cohorts 
Statistical 
Assumptions 
● 10% attack rate for close contracts (or 10% progression of 
disease to hospitalization among those symptomatic at entry) 
● Comparison of Proportions by Fisher’s Exact test for disease 
incidence;  
● Comparison of ordinal scale of disease severity by 
proportional odds model 
● N=621 sample per arm has   90% power to detect a 50% 
relative risk reduction (i.e. <5.0%) in disease incidence or 
50% decrease in the ordinal disease severity (to <4.25% 
disease incidence and <1% hospitalization).  
● 20% dropouts, inflates sample size to n=750 per arm 
 


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Schematic of Study Design: 
 
 
 
For participants who develop symptomatic disease, they will be followed for up to 90 
days to assess final outcome status in the event of hospitalization.  
 
Stratification is based on symptom status at baseline 
1. 1500 asymptomatic healthcare workers or household contacts exposed to COVID-19 
2. 1500 symptomatic COVID-19 outpatients 
 
 


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KEY ROLES 
Individuals: 
 
 
Principal Investigator:  David R. Boulware MD, MPH, CTropMed 
 
Co-Investigator: Sarah Lofgren, MD 
Co-Investigator: Alison Galdys, MD 
Co-Investigator: Matthew Pullen, MD 
Co-Investigator: Radha Rajasingham, MD 
Co-Investigator: Caleb Skipper, MD 
Medical Monitor: Mahsa Abassi, DO MPH 
Pharmacologist: Melanie Nicol, PharmD, PhD 
Biostatistician: Kathy H Hullsiek, PhD 
Associate Statistician: Ananta Bangdiwala, MS 
Associate Statistician: Nicole Engen, MS 
 
Institution:  
Division of Infectious Diseases, Department of Medicine, University 
of Minnesota, Minneapolis, MN 
 
 
 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
Significance of Research Question/Purpose: 
 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging 
viral infection causing COVID19. The current strategy uses a public health model of identifying 
infected cases, isolation, and quarantine to stop transmission.  Once exposed, observation is 
standard-of-care. 
No effective therapy currently exists for treatment.  The lack of effective therapy 
diminishes persons presenting post-exposure for self-quarantine. Having an effective post-
exposure prophylaxis, even if only partially effective, may additionally create synergy for the 
public health strategy of case identification and isolation – if a safe prophylaxis is available. 
People who develop COVID-19 disease generally develop signs and symptoms, 
including mild respiratory symptoms and fever, after an average of 5-6 days after 
exposure (i.e. mean incubation period). The range of the incubation period is between 1 
to 14 days.[1] 
Most people infected with the COVID-19 virus have mild disease and recover. 
Approximately 80% of laboratory-confirmed patients have had mild to moderate disease, 
which includes non-pneumonia and pneumonia cases, 14% have severe disease, and 
6% are critically ill with respiratory failure, shock, and/or multiple organ dysfunction [1]. 
Preliminary Data: 
Chloroquine has in vitro activity in cell lines against SARS-CoV and SARS-CoV2. In a 
Vero E6 cell line, the half-maximal effective concentration (EC50) activity of chloroquine was 
1.13 μM against SARS-CoV2 [2]. Hydroxychloroquine is functionally equivalent as chloroquine.   
Another compound under treatment trials, remdesivir (Gilead) had an EC50 of 0.77 μM 
[2].  Remdesivir (Gilead) is not FDA-approved and in limited quantities.  Hydroxychloroquine is 
FDA-approved and globally is inexpensive.  Chloroquine is no longer broadly available in the 
USA. 
Existing Literature: 
Several drugs, such as ribavirin, interferon, lopinavir-ritonavir, corticosteroids, have been 
used in patients with SARS or MERS, although the efficacy is poorly understood as a gold 
standard randomized clinical trial has not been conducted. 
After the original 2003 SARS outbreak, screening of compounds was performed.  The 
Special Pathogens Branch of the Division of Viral and Rickettsial Diseases at the Centers for 
Disease Control and Prevention (CDC) in Atlanta, Georgia investigated chloroquine. 


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CDC investigators reported that post-infection chloroquine treatment was 
effective in vitro at preventing the spread of SARS-CoV infection in an in vitro cell-based 
system [3].  Vincent et al reported: 
“In order to investigate the antiviral properties of chloroquine on SARS-
CoV after the initiation of infection, Vero E6 cells were infected with the virus and 
fresh medium supplemented with various concentrations of chloroquine was 
added immediately after virus adsorption. Infected cells were incubated for an 
additional 16–18 h, after which the presence of virus antigens was analyzed by 
indirect immunofluorescence analysis. When chloroquine was added after the 
initiation of infection, there was a dramatic dose-dependent decrease in the 
number of virus antigen-positive cells (Fig. 2A). As little as 0.1–1 μM chloroquine 
reduced the infection by 50% and up to 90–94% inhibition was observed with 33–
100 μM concentrations (Fig. 2B). At concentrations of chloroquine in excess of 1 
μM, only a small number of individual cells were initially infected, and the spread 
of the infection to adjacent cells was all but eliminated. A half-maximal inhibitory 
effect (EC50) was estimated to occur at 4.4 ± 1.0 μM chloroquine (Fig. 2C). 
These data clearly show that the addition of chloroquine can effectively reduce 
the establishment of infection and spread of SARS-CoV if the drug is added 
immediately following virus adsorption.” [3] 
Figure 2. Post-infection chloroquine treatment reduces SARS-CoV. 
 


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Vincent et al also reported: “Since we observed antiviral effects by chloroquine 
immediately after virus adsorption, we further extended the analysis by adding chloroquine 3 
and 5 h after virus adsorption and examined for the presence of virus antigens after 20 h. We 
found that chloroquine was still significantly effective even when added 5 h after infection (Fig. 
3); however, to obtain equivalent antiviral effect, a higher concentration of chloroquine was 
required if the drug was added 3 or 5 h after adsorption.” [3] 
  
Further experiments demonstrated that chloroquine impaired the terminal glycosylation 
of angiotensin-converting enzyme-2 (ACE2) receptor, which is the binding site for the envelope 
spike glycoprotein of SARS-CoV and SAR-CoV2 [3]. 
Conversely, chloroquine did not have activity against Middle East respiratory syndrome 
coronavirus (MERS-CoV), which may be related to 
MERS binding to CD26 receptor protein [4]. 
 
In a March 9, 2020 publication,  
hydroxychloroquine was found to have greater activity 
than chloroquine [5]. The SARS-CoV-2 EC 50 values 
for hydroxychloroquine were 6.14 μM at 24 hours 
and 0.72 μM at 48 hours, [5]. Conversely, 
chloroquine EC50 values were >100 μM at 24 hours 
and 18.01 μM at 48 hours [5]. This inhibition assay 
was performed with Vero cells using an infectious 
dose of 100 plaque forming units. 
Figure 3 displays the antiviral activities of 
hydroxychloroquine for treatment or prophylaxis 
against SARS-CoV-2 in vitro [5].  
 
 


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Existing Clinical Data  
There is accumulating clinical data on treatment of hospitalized patients with COVID-19 
infection with chloroquine or hydroxychloroquine.  These data have been summarized by 
Pastick et al. as of April 15, 2020 [6].  To date, there is no conclusive evidence of clinical benefit 
of hydroxychloroquine for treatment of hospitalized patients.   
There have been no studies of early therapy or preventative therapy.  
 
Reference 
Overall Findings 
Limitations 
Study 
design 
Number of 
patients 
Treatment 
regimen 
Severity of illness 
(As reported) 
Location 
Outcomes 
HCQ 
Control 
 
Hydroxychloroquine (HCQ) 
Chen J, et 
al. [7] 
No statistically significant differences in 
conversion rate by day 7 (86.7% vs. 
93.3%, p>0.05).  
No difference in clinical outcomes between 
groups. 
Full article only 
available in 
Chinese.  
 
Not peer-reviewed. 
 
Small sample size. 
Randomize
d controlled 
trial 
15 
15 
400mg HCQ for 
5 days  
Unknown severity; 
patients had 
symptoms for 6-7 
days 
Shanghai, 
China 
At two weeks, all 
patients had negative 
viral nucleic acid tests.   
Gautret et 
al. [8] 
In unadjusted analyses, there were 
significantly reduced viral titers in the HCQ 
arm at day 6 (70% compared to 12.5% 
PCR negative, p<0.001).  
 
All six patients receiving HCQ and 
azithromycin were SARS-CoV-2 negative 
on day 6.  
Study design. 
 
Small sample 
size/underpowered. 
 
Exclusion of six 
patients from 
analysis (no 
intention to treat 
analyses).   
 
Lack of long-term 
outcomes. 
Non-
randomized
, non-
blinded, 
open-label 
trial 
26 
16 
600mg HCQ for 
10 days 
17% were 
asymptomatic 
 
61% had upper 
respiratory 
symptoms 
 
22% had chest CT 
confirmed 
pneumonia 
Marseille, 
France 
Six patients in the 
treatment arm were 
excluded from analysis 
(one died, three 
required ICU 
admission, one 
withdrew, one was lost-
to-follow-up).  


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6 
Chen Z, et 
al. [9] 
Time to clinical recovery and cough 
remission were shortened in the HCQ 
group; resolution of pneumonia was higher 
in the HCQ group (80.6% vs. 54.8%) 
 
Two HCQ patients had mild adverse 
reactions (rash, headache). 
Small sample size.  
 
Not peer-reviewed. 
Randomize
d, parallel-
group trial 
31 
31 
400mg HCQ for 
5 days 
Mild illness 
(PaO2/FiO2 >300 
mmHg) with chest 
CT confirmed 
pneumonia  
 
Wuhan, 
China 
Four patients in the 
control group 
developed severe 
illness (not defined).  
Molina et 
al. [10] 
 
8/10 had positive nasopharyngeal swabs at 
days 5-6 (80%, 95% CI: 49-94). 
Small sample size.  
 
Not peer-reviewed. 
Prospective 
open-label 
study 
 
11 
0 
600mg HCQ for 
10 days + 
azithromycin 
500mg x1, then 
250mg 
10/11 were receiving 
supplemental O2 
Paris, 
France 
One patient died, two 
were transferred to the 
ICU, one had 
medications stopped 
secondary to QTc 
prolongation. 
Gautret et 
al. [11] 
Reduced nasopharyngeal viral titers at day 7 
(83% negative) and 8 (93%).  
 
Mean length of hospitalization of 5 days. 
Study design. 
Small sample size.  
Short follow-up time. 
Not peer-reviewed. 
Non-
randomized
, non-
blinded, 
open-label 
trial 
80 
0 
600mg HCQ for 
10 days + 
500mg, 
followed by 
250mg 
azithromycin 
5% were 
asymptomatic 
54% had pneumonia 
92% of patients had 
a low national early 
warning score 
(NEWS) and mild 
disease 
Marseille, 
France 
Sixty-five (81.3%) 
patients survived to 
hospital discharge. 
Three patients required 
ICU admission and one 
died.  
 
Chloroquine (CQ) 
Gao J et 
al. [12] 
CQ was stated to be superior to standard 
of care treatment in preventing 
exacerbation of pneumonia, reducing days 
to conversion rate, and shortening time to 
clinical recovery. 
Combined patients 
from various 
ongoing studies.  
 
No statistical 
methodology.  
Interim 
report 
100 
0 
Not reported, 
likely varied 
from trial to trial.  
NA 
Qingdao, 
China 
NA 
 
 
 


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2.2 
Rationale 
Current standard of care is observation and quarantine after exposure to COVID19.   
As of March 6, 2020, the CDC estimates that the transmission of SARS-CoV2 after a U.S. 
household close contract is 10.5% (95%CI, 2.9 to 31.4%) [13].  Among all close contacts, the 
SARS-CoV2 transmission rate is estimated at 0.45% (95%CI, 0.12 to 1.6%) by the CDC. These 
estimates are based on monitoring of travel-associated COVID19 cases. Conversely, in a 
setting with community transmission, the secondary attack rate in China was 35% (95%CI, 27-
44%) based on 48 transmissions among 137 persons in 9 index patients. 
Chloroquine or Hydroxychloroquine may have antiviral effects against SARS-COV2 which may 
prevent COVID19 disease or early preemptive therapy may ameliorate disease severity.  This 
trial will use a modification of standard malaria dosing of hydroxychloroquine to provide post-
exposure prophylaxis / preemptive therapy.  
Standard malaria treatment dosing is: 
● 800mg once, then 400mg in 6-8 hours, then 400mg daily x 2 days (3 days in total). 
We propose to dose for SARS-CoV-2 post-exposure prophylaxis at: 
● 800mg once, then 600mg in 6-8 hours, then 600mg daily x 4 days (5 days in total).  
The projected levels achieved will be approximately 4.4 µM which is at or above the half 
maximal effective concentration (EC50) where 50% viral inhibition would occur.  A delayed start 
to prophylaxis will be occurring -- based on the intrinsic delay from the exposure to case 
notification to trial enrollment, and to receipt of the first medication dose.  Thereby, higher doses 
may be necessary as seen in the CDC study [3]. Thus a malaria loading dose sequence will be 
used, but with higher daily doses thereafter to target reaching the above the EC50.  
As the incubation period is 2-14 days with a mean incubation period of 5-6 days, we seek to 
deliver post-exposure prophylaxis by the morning of day 4 at the latest. (<=3 days is an 
inclusion criteria).  We recognize this may turn “post-exposure prophylaxis” into more of a 
“preemptive therapy” for some subjects who rapidly develop disease after trial randomization. If 
hydroxychloroquine does not prevent disease for some, preemptive therapy may ameliorate the 
COVID19 disease severity. Attenuated disease may in turn be associated with reduced rates of 
transmission. 
 


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2.3 
Potential Risks and Benefits 
2.3.1  Potential Risks 
Short-term use of hydroxychloroquine is well-tolerated with a safe track record since 
1955. The most common reported side effects include: 
● headache, dizziness, ringing in your ears; 
● nausea, vomiting, stomach pain; 
● loss of appetite, weight loss; 
● mood changes, feeling nervous or irritable; 
● skin rash or itching; or 
● hair loss. 
GI side effects are minimized when taken with a meal or with milk. Antacid medications 
should be spaced apart by at least 4 hours.  
 
Potential adverse effects by system, as listed on the FDA package insert: 
○ 
Eye: “Chloroquine retinopathy” is a rare side-effect of chronic use after multiple years 
of use. This has not occurred with <1 year of continuous use. 
 
○ 
Dermatologic Reactions: Bleaching of hair, alopecia, pruritus, skin and mucosal 
pigmentation, photosensitivity, and skin eruptions (urticarial, morbilliform, lichenoid, 
maculopapular, purpuric, erythema annulare centrifugum, Stevens-Johnson 
syndrome, acute generalized exanthematous pustulosis, and exfoliative dermatitis). 
 
○ 
Hematologic Reactions: Various blood dyscrasias such as aplastic anemia, 
agranulocytosis, leukopenia, anemia, thrombocytopenia (hemolysis in individuals 
with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency). 
 
○ 
Gastrointestinal Reactions: anorexia, nausea, vomiting, diarrhea, and abdominal 
cramps. Isolated cases of abnormal liver function and fulminant hepatic failure. 
 
○ 
Cardiac Reactions: Long-term use (>1 year) has been associated with the 
development of cardiomyopathy and arrhythmias.  Specifically, chronic use has been 
associated with a mean +25msec prolongation of the QT interval after a median use 
of 3.5 years in patients with autoimmune diseases.  In a 2018 review of short term 
antimalarial treatment trials (n=1076 with chloroquine), no serious cardiac adverse 
events were reported among 35,548 participants [14] 
 
○ 
Allergic Reactions: Urticaria, angioedema, and bronchospasm have been reported 
 
○ 
Central Nervous System Reactions: Irritability, nervousness, emotional changes, 
nightmares, psychosis, headache, dizziness, vertigo, tinnitus, nystagmus, nerve 
deafness, convulsions, ataxia 
○ 
Miscellaneous Reactions: Weight loss, lassitude, exacerbation or precipitation of 
porphyria and non-light-sensitive psoriasis. Possible Hypoglycemia in persons with 
diabetes 
 


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On 24 April 2020, FDA issued a caution: 
 
FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of 
the hospital setting or a clinical trial due to risk of heart rhythm problems 
Close supervision is strongly recommended 
 
“The FDA is aware of reports of serious heart rhythm problems in patients with COVID-
19 treated with hydroxychloroquine or chloroquine, often in combination with 
azithromycin and other QT prolonging medicines.  We are also aware of increased use 
of these medicines through outpatient prescriptions.  Therefore, we would like to remind 
health care professionals and patients of the known risks associated with both 
hydroxychloroquine and chloroquine. We will continue to investigate risks associated 
with the use of hydroxychloroquine and chloroquine for COVID-19 and communicate 
publicly when we have more information.” 
 
“Hydroxychloroquine and chloroquine can cause abnormal heart rhythms such as QT 
interval prolongation and a dangerously rapid heart rate called ventricular tachycardia.  
These risks may increase when these medicines are combined with other medicines 
known to prolong the QT interval, including the antibiotic azithromycin, which is also 
being used in some COVID-19 patients without FDA approval for this condition.  Patients 
who also have other health issues such as heart and kidney disease are likely to be at 
increased risk of these heart problems when receiving these medicines.” 
 
Mitigation of Risk:  The inclusion / exclusion criteria exclude cardiac risk factors, 
chronic kidney disease, and anti-arrhythmia medicines. On 24 April, additional QT 
prolonging medicines are excluded.    
 
2.3.2 Known Potential Benefits 
● There are no known benefits in humans for preemptive treatment.  
● In vitro antiviral activity against SARS-CoV and SARS-CoV2 viruses. 
● Chloroquine and Hydroxychloroquine have a long history of safe, effective 
use as an antimalarial, both acutely and long-term use. 
● Chloroquine is being used therapeutically for severe COVID-19 disease in 
China and Korea.  
● Commonly used as a chronic medication for autoimmune disorders 
(rheumatoid arthritis, systemic lupus erythematosus). 
● Recent studies have shown potential broad antiviral effects in vitro at 
dosages below currently recommended clinical dosing, reducing risk of 
potential adverse effects listed above. 
 
 


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3 
OBJECTIVES 
3.1 
Study Objectives 
To determine if hydroxychloroquine is effective at prevention of COVID-19 disease or 
reducing disease severity. 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
 
Asymptomatic Cohort 
● 
Incidence of COVID-19 disease within 14 days (among those asymptomatic 
at baseline) 
Symptomatic Cohort 
• 
Change in symptom severity score (visual analog scale 0-10) over 14 days 
3.2.2 Secondary Outcome Measures 
● Incidence of hospitalization or death 
● Incidence of confirmed SARS-CoV-2 detection 
● Incidence of symptoms compatible with COVID-19 (possible disease) 
● Incidence of all-cause study medicine discontinuation or withdrawal 
● Incidence of adverse reactions 
● Symptom severity on day 5 or 14 via visual analog scale 
● Ordinal Scale of COVID-19  Disease Severity at day 14 (among those 
who are symptomatic at trial entry)  
Illness without hospitalization 
Hospitalization (or post-hospital discharge) 
Hospitalization with ICU stay or Death 
 
Assessment of outcome measures will be primarily by self-report.  As necessary, 
COVID19 disease will be verified from public health records, medical records, or death 
certificates. The primary endpoints are different for the two cohorts (those who are 
asymptomatic with known exposure; or those who are symptomatic at trial entry), and 
analyses will be done separately for the two cohorts. 
The primary analysis will use PCR+ confirmed disease.  However if the absence of 
sufficient testing supplies continues then outpatients will not be offered SARS-CoV-2 
testing unless they are sick enough to be hospitalized.  In that case an alternate a priori 
planned analysis will define incident COVID19 disease as a composite of SARS-CoV-2 
PCR+ confirmed result OR symptomatic disease (i.e. possible) COVID-19 in those 
without testing.   


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4 
STUDY DESIGN 
 
There are two strata: 1) asymptomatic healthcare workers or household contacts 
exposed to COVID-19 (n=1500); 2) symptomatic COVID-19 disease (n=1500). Follow 
up will occur up to 90 days for those with symptomatic COVID-19 disease who become 
hospitalized.  
 
4.1 DESIGN 
Randomized, double-blind, placebo-controlled clinical trial, parallel design 
 
• 
Intervention Arm: Hydroxychloroquine 800 mg orally once (4 tablets), followed in 6 to 8 
hours by 600 mg (3 tabelts), then 600 mg once a day for 4 consecutive days (5 days in 
total) 
• 
Control Arm: Vitamin Placebo 4 tablets orally once, followed in 6 to 8 hours by 3 tablets, 
then 3 tablets once a day for 4 consecutive days (5 days in total) 


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4.2 
Study participant duration 
● 14 days consisting of internet-based virtual visits 
● For participants ill with COVID-19 disease who are hospitalized (an SAE), 
observational follow up will extend to up to 90 days to assess final outcome status of 
their SAE.  
● Pregnant women have their fetal outcome assessed postpartum to exclude a 
teratogenic SAE. 
4.3 
Study procedures 
• 
All procedures will consist of internet-based questionnaires completed by self-report. 
• 
Informed consent is provided to access medical records to verify information, as 
necessary. 
• 
Optional: blood spot will be collected at approximately day 14. 
• 
Optional: daily cardiac monitoring with remote EKG reads of QTc interval. 
4.4 
Individually identifiable health information:  
Name, date of birth, addresses, and phone number will be collected so as to prescribe 
study medication. Email addresses will be collected for communication. If participants 
are hospitalized, the hospitalization date will be collected. 
4.5 
Substudies (if applicable) 
Additional sub-studies will undergo separate IRB approval, and these studies will involve 
separate informed consent. Consented participants will be queried as to if they wish to 
participate in future research.   
1) Serology for Coronavirus Antibodies: New Participants will be offer an optional 
participation in self-collection of dried blood spots in order to measure serologies for 
antibodies. Participants who have already been consented and entered the trial, will 
be approached for amendment of consent.  The purpose of serology testing is two-
fold: First, to verify infection. Second, the prevalence of antibodies will be compared 
among symptomatic and asymptomatic persons with a scientific question of how 
many asymptomatic persons seroconvert after a high risk exposure in the absence of 
symptomatic illness.  The exact serology methodology to be conducted will be 
determined, based on availability and diagnostic performance. Blood spot collection 
materials (e.g. 18g lancet, filter paper, bandaid, instructions, and return envelope).  
(Optional) 
2) Cardiac Monitoring with handheld EKG to check cardiac QTc interval once daily for 
the first 7 days as a safety substudy. (Optional) 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Participants will undergo screening via internet-based forms. The screening and 
inclusion criteria will be based on self-report.  
5.1 
Subject Inclusion Criteria 
● Exposure to a COVID19 case within <=4 calendar days as either:  
○  Occupational exposure (healthcare worker, first responder, etc.) 
○ Household contact 
OR  
● Symptomatic COVID-19 disease  
○ Confirmed diagnosis with PCR+ SARS-CoV-2 within <=4 days of symptom onset  
OR 
○ Individual with compatible symptoms with exposure to known PCR+ SARS-CoV-
2 case within 14 days AND compatible symptoms of fever, cough, or shortness of 
breath (and no available /pending testing for the individual)* 
● >= 18 years of age 
● Provision of informed consent 
5.2 
Subject Exclusion Criteria 
● Current Hospitalization 
● Contraindication or allergy to hydroxychloroquine 
● Retinal eye disease 
● Concurrent malignancy requiring chemotherapy 
● Known glucose-6 phosphate dehydrogenase (G-6-PD) deficiency 
● Known chronic kidney disease, stage 4 or 5 or receiving dialysis 
● Known Porphyria  
● Weight < 50 kg 
● Structural or ischemic heart disease 
● Personal or Family history of prolonged QT 
● Current use of: hydroxychloroquine, chloroquine, or cardiac medicines of: flecainide, 
Tambocor; amiodarone, Cordarone, Pacerone; digoxin or Digox, Digitek, Lanoxin; 
procainamide or Procan, Procanbid, propafenone, Rythmal;  or sotalol. 
● Current use of QT prolonging medicines of:  
○ Antimicrobials: levofloxacin, ciprofloxacin, moxifloxacin, azithromycin, 
clarithromycin, erythromycin, ketoconazole, itraconazole, or mefloquine 
○ Antidepressants: amitriptyline, citalopram, desipramine, escitalopram, 
imipramine, doxepin, fluoxetine, wellbutrin, or venlafaxine 
○ Antipsychotic or mood stabilizers: haloperidol, droperidol, lithium, quetiapine, 
thioridazine, ziprasidone 
○ Methadone 
○ Sumatriptan, zolmitriptan 


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Rationale for inclusion / exclusion criteria:  
* As of 20 March 2020, testing is limited in many U.S. states and locales due to 
insufficient supplies. Thus, outpatient testing may not be available. A person with known 
exposure to a confirmed COVID-19 case with subsequent compatible symptoms is 
eligible for enrollment, if testing is not available. If a symptomatic person tests negative 
for SARS-CoV-2, they are not eligible for enrollment.  
Mean Incubation period is ~5.2 days, thus we wish to limit enrollment to those with a 
higher risk of progression and deliver study medicine in a time period to intervene to 
prevent disease or ameliorate disease (i.e. start of study medicine by <=4 days after 
exposure). The current (as of March 17, 2020) delays in testing makes this window 
particularly tight, and it may need to be relaxed in the future via protocol amendment. 
In clinical practice of tropical medicine, chloroquine or hydroxychloroquine are 
prescribed without any baseline laboratory testing or monitoring.   
Chronic use of hydroxychloroquine for >1 year can cause retinopathy or 
cardiomyopathy, thus persons with baseline conditions will be excluded.  Study medicine 
is excreted via the kidney with dose reduction recommended in CrCl <30 cc/min (Stage 
4 Kidney Disease).  G-6-PD deficiency is listed as a caution on the FDA label. G-6-PD 
testing is not routinely performed in clinical care prior to giving hydroxychloroquine 
prescriptions (unlike with primaquine).  Medication exclusions are for possible drug-drug 
interactions, particularly with cardiac arrhythmia medicines with a caution on the FDA-
package insert. 
On April 20, 2020, FDA mandated exclusion of structural or ischemic heart disease; or 
personal or family history of prolonged QT. 
On April 24, 2020, FDA issued a caution for QT prolongation in persons with heart 
disease, chronic kidney disease, or taking other QT prolonging medicines. 
 
5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
Participants will be randomized via permuted block randomization. Randomization 
will be recorded on an electronic log by the pharmacy. Study investigators and 
subjects will be blinded.  There will be separate randomization schedules for the 
two cohorts (asymptomatic with exposure or symptomatic).  
Masking Procedures 


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Participants will be provided masked study medicine, shipped by courier (e.g. 
FedEx). The intervention vs. placebo will not be identical; however, participants 
and outcome assessors will be masked to their assignment. 
5.3.2 Reasons for Withdrawal 
 
Participants may withdraw at any time point at their discretion.   
5.3.3 Handling of Withdrawals 
Withdraws will be counted as failures for the secondary endpoint of completion of 
study medication.  
Participants who discontinue study medication will still be asked to complete the 
follow up visit schedule. 
5.3.4 Termination of Study  
This study may be prematurely terminated if there is sufficient reasonable cause, 
including but not limited to: 
● Unexpected, significant, or unacceptable risk to subjects 
● Interim analyses by the DSMB. 
● Insufficient compliance with protocol requirements 
● Data are not sufficiently complete and/or not evaluable 
● Regulatory authorities decide that study should be terminated 
If the study is prematurely terminated for harm, current subjects will complete follow up, 
and no further subjects will be enrolled.  If the study is terminated due to benefit, then 
the study will immediately convert into an open-label prospective cohort to collect further 
observational data on the safety and efficacy of the intervention, up to the IRB approved 
recruitment limit. 
 
 


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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
6.1.1 Acquisition 
 
 
FDA-approved formulation of hydroxychloroquine will be purchased. 
6.1.2 Formulation, Packaging, and Labeling 
The study medicines will be packaged by the MHealth Investigational Drug 
Services.  Dispensed medications will be delivered by courier (e.g. Fedex) to 
study participants. 
Labels will include: “Caution: New Drug – Limited by Federal Law to 
investigational use.  Keep out of reach of children.” 
6.1.3 Drug Description:  
Hydroxychloroquine sulfate  
 
6.1.4 Formulation: 200mg tablet ( = 
155 mg base of chloroquine) 
6.1.5 Pharmacokinetics: 
● Absorption: Rapid and 
almost completely 
● Distribution: Widely distributed into body tissues 
● Metabolism: Partially hepatic to main metabolyte of desethylchloroquine 
● Excretion: Urine (>=50% as unchanged drug); acidification of urine 
increases elimination 
● Cmax = 1.2 nmol/mL = 1.2 µmol/L = 1.2 µM  at 400mg single dose.[15]  
● Tmax = 2.4 hours 
● T1/2 = 172 + 39 hours = 7.1 +1.6 days 
● AUClast = 75.4 + 47 nmol/h/mL 
● This Cmax is in the therapeutic window for SARS-COV2 activity. 
● Steady state doses for 400mg dose is 974 µg/L = 2.24 µM [16], thus a 
600mg dose should generate approximately 3.4 µM , which is above the 
EC50 of viral inhibition of 1.3 µM (EC50 = 50% inhibition; however, the 
more inhibition the better, likely). 
 
Population PK parameter modeling: 5 day regimen  


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Figure courtesy of Dr. Mahmoud Al-Kofahi of College of Pharmacy, Univ. of Minnesota  
 
The EC50 has been reported as 0.72 µM [5], although this is not a precise 
measurement, and should be view with a range of error present (but not reported). The 
EC50 is the point of 50% maximal inhibition, so more drug would be better (balanced 
against toxicity and drug supply). The percentage of persons achieving a 24 hour level 
above the EC50 is as follows (Figure). 
 
 


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6.1.6 Product Storage and Stability 
 
Store at room up to 30° C (86° F). Dispense in a tight, light-resistant container. 
 
6.2 
Dosage, Preparation, and Administration of Investigational 
Product 
Drug/Device Handling:  
Hydroxychloroquine or placebo will be dispensed by the MHealth Investigational Drug 
Service (IDS) Pharmacy.  To do so, study investigators will send a prescription to the 
IDS Pharmacy, the pharmacy will randomize the subject, and dispense the appropriate 
study medicine. The medicine will then be provided to research volunteers via FedEx / 
courier delivery in the United States. 
6.3 
Modification of Investigational Product for a Participant 
With mild side effects, participants will be instructed to split the 3 tablet daily dosing into 
multiple times per day. 
In the event of substantial side effects, participants may discontinue the study 
medication and stay in the study to complete follow up. 
6.4 
Accountability Procedures for the Investigational Product: 
 
Accountability will be via self-report at the day 5 virtual visit. 
6.5 
Assessment of Subject Compliance 
 
Adherence will be via self-report at day 5 virtual visit.  
6.6 
Concomitant Medications/Treatments 
Participants may receive other concomitant medications or therapies, and will be asked 
to report these in regards to other therapies received on day 1, day 14, and in the event 
of hospitalization. 
 


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7 
STUDY SCHEDULE 
 


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7.1 
Screening  
● Baseline screening for eligibility 
● Informed consent by self-administered  
● This will be performed via a web-based form. Eligibility criteria will be by self-report. 
7.2 
Enrollment/Baseline 
Randomization (Day 0) 
● Participants will be randomized by a computer-generated algorithm using a permuted 
block randomization sequence. 
● Randomization will be stratified by symptomatic vs. asymptomatic status at baseline. 
● Investigational pharmacy will dispense the masked study medicine  
● Study personnel will then FedEx study medicine to the participant 
● Participant will be sent an email to expect medication to arrive by 10:30am  
7.3 
Follow-up  
 
Day 1 Virtual visit 
● Verify receipt of study medicine 
● Clinical status check-in 
○ Participant starts study medicine (4 tabs), then 3 tabs in 6-8 hours, 
then 3 tabs daily.  
● Query for SARS-CoV-2 testing 
● Query for symptom status (0-10 visual analog scale of symptom severity) 
● Query for hospitalization or SAEs 
● Query for medication-related side effects / AEs 
 
Day 3 Virtual visit  
● Query for symptom status (0-10 visual analog scale of symptom severity) 
● Query for hospitalization or SAEs 
● Query for medication-related side effects / AEs 
 
Day 5 Virtual visit 
● Query for symptom status (0-10 visual analog scale of symptom severity) 
● Assessment of adherence by self-report 
● Completion of study medicine, which has a ~7 day half-life 
● Query for study medicine side effects since enrollment 
● Query for SARS-CoV-2 testing 
● Query for hospitalization or SAEs 
 
Day 10 Virtual visit  
● Query for symptom status (0-10 visual analog scale of symptom severity) 
● Query for SARS-CoV-2 testing 


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● Query for SARS-CoV-2 testing 
● Query for hospitalization or SAEs 
 
7.4 
Final Study Visit 
● Day 14 Visit 
● Query for symptom status (0-10 visual analog scale of severity) 
● Query for study medicine side effects since enrollment 
● Query for SARS-CoV-2 testing 
● Query for hospitalization or SAEs 
● Query for pregnancy status 
● Final outcome assessment 
● Assess other medicines used during study period 
● Optional dried blood spot collection, return in pre-paid envelope.  
 
If participations have a SAE prior to the final study visit (e.g. hospitalization), the 
final resolution of the event will be followed until resolution or up to 90 days. The 
hospitalization eCRF will be sent in 14 days interval to assess clinical outcome / 
resolution of the hospitalization. Pregnancies will be followed through delivery to 
assess for any teratogenic SAE. 
7.5 
Early Termination Visit 
If participants develop new / worsening symptoms of coronavirus, they will be directed to 
their healthcare provider and/or local public health authority for clinical care. We will 
follow up of hospitalized patients for resolution of their SAE for up to 90 days to assess 
their final outcome. Participants will be sent the Hospitalization eCRF 14 days after 
hospitalization is reported with repeats in 14 day intervals until the participant is 
discharged from the hospital.  
7.6 
Unscheduled / Sick Visit  
Subjects will be provided a central email contact: faq.covid19@gmail.com as a contact 
point for questions or concerns.  This email will forward to an on-call study physician 
who will call the participant to resolve their concerns.  
 
 


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STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
 
Clinical evaluations are by self-report. 
8.2 
Laboratory Evaluations 
SARS-COV-2 positivity is by self-report. Informed consent asks for access to medical 
records.  
Follow up PCR testing within 14 days is asked on followed questionnaires. Pending test 
results at 14 days or during hospitalization will be queried for final results with repeat 
survey sent at day 28.   
Informed consent will request permission to contact local public health authorities or their 
medical provider in the event of lost to follow up or COVID19 disease. 
There is no incentive to be dishonest, and we believe healthcare workers in particular 
will take their responsibilities seriously.  
An optional dried blood spot collection will be offered at day 14.  At time of informed 
consent, participants may opt into this collection.  The dried blood spots will be used for 
future serology testing. Participants who opt into this testing will be mailed: i) 
instructions; ii) Whatman filter paper for dried blood spot collection; iii) one time use 
lancet; iv) return envelope.  
Participants who have entered the trial prior to dried blood spot being offered and are 
<90 days from study entry will be contact with the option for dried blood spot testing of 
their antibody serology. 
 
 
 
 


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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Hydroxychloroquine has a track record of safety since its FDA-approval in 1955.  As an 
already, FDA-approved medicine, this trial is designed as a pragmatic trial in the setting 
of a public health emergency.  
9.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.2.1 Adverse Events 
Hydroxychloroquine has an excellent safety track record, being first FDA-approved in 
1955.  Adverse events will not be captured, unless they result in hospitalization. See 
Serious Adverse Events below.   
Expected adverse events would include normal events within the general population as 
well COVID19-related disease events which may include need for hospitalization, 
pneumonia, respiratory failure, sepsis, and death.  
9.2.2 Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) 
 
Not applicable  
9.2.3 Serious Adverse Events (SAEs) 
 
Hospitalization or death are protocol-defined endpoints. 
SAEs (e.g. hospitalizations) will be followed for up to 90 days to assess final outcome. 
9.2.4 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
 
Not applicable 
9.3 
Reporting Procedures 
9.3.1 Serious Adverse Events 
An AE or suspected adverse reaction is considered a serious adverse event (SAE) if it 
results in any of the following outcomes:  


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● Death 
● Life-threatening adverse event (as below)  
● Hospitalization 
● Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
● Congenital anomaly/birth defect.   
● Important medical events that may not result in death, but are life-threatening, or 
require hospitalizations may be considered serious when, based upon appropriate 
medical judgment they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.   
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
 Life-threatening adverse events: An AE is considered “life-threatening” if, in the view of 
either the site principal investigator or sponsor, its occurrence places the patient or 
subject at immediate risk of death.  It does not include an AE that, had it occurred in a 
more severe form, might have caused death. For life threatening AEs, subjects would be 
recommended /expected to be hospitalized.  
 
Based on the known safety track record of hydroxychloroquine, this pragmatic protocol 
will focus on death, life-threatening AEs, and hospitalizations.  Incapacity / permanent 
disability is a possibility with COVID19, but this is not associated with 
hydroxychloroquine. In the event of incapacity, the subject would be expected to be 
hospitalized.   
 
Hydroxychloroquine and chloroquine are not known to cause teratogenic events and are 
viewed as safe in pregnancy, especially with short term use.  With this trial’s sample 
size, this will not further delineate this risk.  COVID19 disease may indeed be 
teratogenic. For women who are pregnant, we will ask to follow them through the end of 
their pregnancy, and they will be sent a follow up eCRF at 1 month post-partum based 
on their reported estimated date of delivery as provided at the day 14 study visit.  
 
Thus, the hospitalization or death secondary endpoint will capture relevant SAEs. For 
those with ongoing hospitalization at the day 14 study visit, participants will be queried in 
14 day intervals with the hospital eCRF to assess their final clinical outcome. 
 
9.3.2 Regulatory Reporting  
As hydroxychloroquine is an FDA-approved medicine being used at standard dosing, 
reporting to regulatory authorities will occur in summary format after each DSMB reports 
and at a frequency of at least annually.  


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Serious unexpected suspected adverse reactions (SUSARs) which are not expected 
with COVID-19 nor listed in the FDA package insert will be reported to the IRB.  
Those SUSARS which are deemed by an independent medical monitor to be related to 
the study medicine will be reported to the FDA and IRB. 
 
9.3.3 Reporting of Pregnancy 
Chloroquine and hydroxychloroquine are not known to be teratogenic. Chloroquine and 
hydroxychloroquine can accumulate in neonatal eyes.  Conversely, the risk of severe 
COVID-19 infection is unknown, but likely is a heightened risk in pregnant women. The 
CDC states, “We do not have information on adverse pregnancy outcomes in pregnant 
women with COVID-19. Pregnancy loss, including miscarriage and stillbirth, has been 
observed in cases of infection with other related coronaviruses (SARS-CoV and MERS-
CoV) during pregnancy. High fevers during the first trimester of pregnancy can increase 
the risk of certain birth defects.”   
Thus, the risk/benefit would favor the enrollment of women who may be or are pregnant, 
so as to not discriminate against pregnant women. 
For women who are pregnant, we will ask to have follow through the end of their 
pregnancy to assess outcome of the pregnancy via a brief survey.  
9.4 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
Participants who are hospitalized for COVID-19 or SAEs will have up to 90 day follow up 
conducted to assess their final outcome.  Management will be as per the participant’s 
local healthcare provider. 
9.5 
Safety Oversight (DSMB) 
A data and safety monitoring board (DSMB) will oversee the trial.  The quorum will 
include three members and a biostatistician.  The PI will be a non-voting observer, 
providing input as requested.  See the DSMB charter for more details. 
 
 
 
 
 
 


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10 
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial 
subjects are protected and that the reported trial data are accurate, complete, and 
verifiable. Clinical monitoring also ensures that conduct of the trial is in compliance with 
the currently approved protocol/ amendment(s), ICH, GCP, and with applicable 
regulatory requirement(s) and Sponsor requirements. Clinical monitoring will also verify 
that any critical study procedures are completed following specific instructions. 
Monitoring will be the responsibility of the University of Minnesota.  
 
The automated logic of the REDCap database system will enable complete records. All 
data are by self report.   
 
 
 


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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
We hypothesize that hydroxychloroquine is superior to placebo for preventing progression to 
COVID-19 disease among those who are asymptomatic. 
We hypothesize that hydroxychloroquine is superior to placebo for preventing progression 
among those with symptomatic mild COVID19 disease preventing hospitalization/death.  
11.2 Sample Size Considerations 
Two cohorts  of 1500 subjects each:   
1) Asymptomatic persons exposed to COVID-19 disease (750 in placebo, 750 in intervention);  
2) Symptomatic outpatient COVID-19 disease (750 in placebo, 750 in intervention). 
 
Assuming 90% power, a two-sided alpha = 0.05 and loss to follow-up up to 20%, for each 
cohort the planned sample size is 750 participants per arm based on the following assumptions:   
• 10% transmission rate from COVID-19 cases to close contacts 
• For those with symptomatic illness the proportions at day 14 in the placebo group are 
90%, 8% and 2%, respectively for illness without hospitalization, hospitalization with ICU 
stay or death, and hospitalization with an ICU stay or death.   
 
The estimated transmission rates are uncertain.  Table 1 below (for the asymptomatic cohort 
with exposure) shows that we are well powered to detect even a smaller (40%) relative 
reduction in the incidence of COVID 19 with 80% power for transmission rates of at least 10% 
with placebo.  Table 2 (for the symptomatic group) shows that we are well powered to detect a 
common odds ratio of 0.6-0.75 under the assumption that the control proportions for illness 
without hospitalization, hospitalization without ICU stay or death and hospitalization with ICU 
stay or death are 90%, 8% and 2%, respectively.   
 
 
 
 


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Table 1.  Sample Size Table for Asymptomatic Participants (Healthcare worker or 
household contact) With Exposure 
Estimated 
transmission rate 
with placebo 
Estimated 
transmission rate 
with drug 
Percent relative 
reduction in 
transmission rate 
Sample size 
(per arm) with 
90% power 
Sample size 
(per arm) with 
80% power 
10% 
5% 
50% 
621 
474 
6% 
40% 
1014 
771 
12% 
6% 
50% 
509 
389 
7.2% 
40% 
831 
632 
15% 
7.5% 
50% 
398 
304 
9% 
40% 
648 
493 
 
Table 2.  Sample size table for participants with symptomatic disease, assuming that the 
control proportions are 90% illness with no hospitalization, 8% hospitalization with no ICU stay 
or death and 2% hospitalization with ICU stay or death. 
Log Odds Ratio 
Odds Ratio 
Sample size (per 
group) with 90% 
power 
Sample size (per 
group) with 80% 
power 
0.60 
1.82 
805 
601 
0.65 
1.91 
697 
521 
0.70 
2.01 
610 
456 
0.75 
2.12 
539 
403 
 
11.3 Planned Interim Analyses  
A Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be provided at 
each DSMB report for the primary outcome for each cohort  The O’Brien-Fleming boundaries 
will be truncated at alpha = 0.001 (|Z| > 3.09).   For each cohort, interim analyses are separately 
planned at 25%, 50% and 75% of trial enrollment.   
 
As enrollment may be brisk, the timing of interim analyses may be altered at PI discretion based 
on that pace of enrollment.  It may be possible that the trial is fully enrolled by the time day 14 
outcomes are available for the first 25% enrolled. In this case, any further analyses would be 
related as to when to release interim results.   


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At the first DSMB review, the stopping boundary is unlikely to be crossed. The purpose of this 
early review will assess the trends for safety/efficacy and allow for the DSMB to determine the 
probable timing of further reviews based on the pace of enrollment.  
Should a stopping boundary be crossed, we would recommend an analysis to determine 
whether the findings are consistent across secondary endpoints, such that a clear answer is 
achieved. Starting with the 2nd DSMB review (at approximately 50% enrollment) the DSMB will 
be given the conditional power for both cohorts under both the study design parameters and the 
current data.   If the conditional power is less than 20% then trial discontinuation may be 
considered.   
In the event of early halting due to efficacy of the intervention, the study will immediately 
convert to an open label observational cohort of hydroxychloroquine prescribed to all 
consented participants in the relevant cohort.  
In the event of early halting due to futility of no effect, a protocol modification will be 
made to alter the intervention.  
Based on the public health situation, the DSMB has the prerogative to alter the stopping rules. 
Sample Size Re-estimation:  
At time of ~50% enrollment, a sample size re-estimation should occur based on the disease 
transmission rate in the control group.  The a priori assumption (based on limited data) is 10% 
transmission risk.  The new sample size estimation will take into account the updated 
transmission rate with no treatment and will be powered to detect a 50% relative reduction in 
outcome.   
 
11.4 Final Analysis Plan 
 
Primary outcome analyses (intention to treat): 
 
Asymptomatic Cohort Primary Analysis: 
Those with asymptomatic exposure:  Incidence of COVID 19 disease by day 14 will be 
assessed via Fisher’s Exact Test. 
 
Symptomatic Cohort Primary Analysis: 
Those with symptomatic disease at study entry:  For a summary metric of the change in 
symptom severity over 14 days, a longitudinal change over time repeated measures mixed-
regression model will estimate the treatment effect by study arm. Subjects without symptoms 
are coded as a zero severity. Persons hospitalized or dead are coded as 10 severity. 


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Participants who become symptomatic with COVID19 on Day 1 before receiving the 
study medicine will be described with the symptomatic cohort. 
Secondary Analyses: 
For the asymptomatic with exposure cohort, the primary analysis (intention to treat) will 
be repeated for participants who received at least one dose of the study medicine. 
● Secondary endpoints will be assessed via Fisher’s Exact test and median (with 
interquartile ranges) as appropriate.   
● Those with symptomatic disease at study entry:  Proportional odds models will be used 
to assess the ordinal scale for disease severity at day 14 (illness without hospitalization,   
hospitalization without ICU stay or death, or hospitalization with ICU stay or death).  
● Severity of overall symptoms at Day 0, 1, 5, and 14 is recorded on a 0-10 visual analog 
scale.  Severity of symptoms at Day 5 will be compared first as a categorical analysis 
(no symptoms vs. symptoms) via Fisher’s Exact Chi Square.   
○ Second among those with symptoms, the 0-10 visual analog scale severity data 
will be compared via independent two-sample t test.  If data are non-normally 
distributed, then data will be compared via Mann-Whitney U by study arm.  
A priori subgroup analyses will include assessment by: 
● Confirmed SARS-CoV-2 disease or disease exposure 
● Healthcare worker vs. Household contact 
● Days from Exposure 
● Decile of age 
● Sex as a biological variable 
● Censored subjects, who became symptomatic before receipt of the first dose of study 
medicine on D#1, will be separately analyzed and reported.  
 
Handling of withdrawn subjects. 
If there is a large lost to follow up / study discontinue rate, then the primary endpoint for the 
asymptomatic cohort would have a secondary analysis to assess incidence as a 3-category 
analysis of: i) no disease, ii) incident disease, or iii) unknown.   
 
Similarly, the symptomatic cohort would add a fourth category of unknown. 
 
Participants who stop taking the study medicine but who agree to be followed for 14 days will be 
assessed as intent-to-treat. On Day 14, we will ask for other medications or vitamins that were 
taken during the study period. 
 
Screened Persons  
Persons who are screened but not enrolled will be summarized in CONSORT diagrams and 
other descriptive summaries of their COVID-19 related information – with all data de-identified.  


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA 
Source documents will include internet forms self-completed by participants directly entered into 
a RedCAP database.   
This protocol is based on self-report. 
This internet-based protocol is meant to enable a large number of participants to be recruited, 
quickly as well as maintain the safety of the research staff.  In person visits, create a public 
health  
Participants will be asked to provide consent to obtain medical records from their healthcare 
provider or public health official, if there is the need to verify outcomes – for SARS-CoV-2 test 
results or hospitalizations.  
 
 
 
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study medications will be commercially procured U.S. FDA-approved hydroxychloroquine or 
under ANDA #210959 following Good Manufacturing Practice. 
 
 
 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (International Conference on Harmonization guidelines), Declaration of Helsinki, and 
International Ethical Guidelines for Biomedical Research Involving Human Subjects, applicable 
U.S. government regulations and institutional research policies and procedures. All investigators 
must have received human subject protection and GCP training prior to human subject 
involvement. 
14.2 Institutional Review Board 
Prior to the initiation of the study, the protocol, all informed consent forms and the 
participant Information materials will be submitted to and approved by the single IRB of record.  
Likewise, any future amendments to the study protocol will be submitted and approved by the 
IRB before implementation.  This protocol and any amendments will undergo review and 
approval by the Human Subjects Board at the University of Minnesota under DHHS Assurance 
FWA00000312.  
14.3 Informed Consent Process 
● Written informed consent will be obtained via an English-language, internet-based web 
form. If potential participants have questions, they may contact faq.covid19@gmail.com  
to reach a study staff member to answer their questions about research, either via email 
or a phone call. 
● After completion of reading the form, participants will be assessed for comprehension, 
querying: 
○ Concept of Randomization to hydroxychloroquine or vitamin placebo 
○ Whether hydroxychloroquine is known to be effective in preventing disease 
○ Duration of the study? (14 days) 
○ Duration of taking the study medicine (5 days) 
○ When follow up surveys will be sent (Days 1, 3, 5, 10 and 14) 
○ If hydroxychloroquine can be shared? (No) 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) 
● Persons under 18 years of age are not eligible to participate. COVID19 has 
negligible mortality in children <10 years, and rate of progression to symptomatic 
disease may likely be different. Furthermore, pediatric dosing is weight based, 
making remote administration more complicated with fixed dose 200mg tablets.  


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14.4 Exclusion of Women, Minorities, and Children  
● Persons under 18 years of age are not eligible to participate. COVID19 has 0% 
mortality in children and young adults.   
● Non-English speaking adults are not eligible as the webpage and consents will 
only be available in English. 
14.5 Subject Confidentiality 
● Interaction will be via internet-based RedCAP ECRFs conforming to required 
U.S. privacy and server security standards. 
● Clinical data will be entered into a study specific database by designated staff on 
a regular basis from completed electronic Case Record Forms (eCRF). Access to 
database will be given to authorized personnel only (members of the immediate 
study team). eCRF and trial documents will be kept in a secure database.  
● Documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to 
any unauthorized third party, without prior written approval of the participant 
except as necessary for monitoring by the IRB or public health authorities  
● No participant identifying information will be disclosed in any publication or at any 
conference activities arising from the study. 
14.6 Future Use of Stored Specimens 
● No specimens are to be stored for future research.   
 
 


COVID-19 PEP RCT 
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15 
DATA HANDLING AND RECORD KEEPING 
15.1 Data Management Responsibilities 
Investigators will maintain a REDCAP database of study records.  
Survey forms will be self-completed by study participants.  
15.2 Data Capture Methods 
● Data will be obtained via internet-based REDCAP forms. 
15.3 Types of Data 
● Participants will be asked to provide data regarding COVID19 exposure timing 
and location. They will also be asked to provide ongoing symptom reports during 
the follow-up period. 
15.4 Timing/Reports 
● An enrollment progress report will be generated monthly 
○ Participants Enrolled 
○ Participants on study 
○ Participants completed the study 
○ Lost to Follow Up 
○ Cumulative COVID19 (pooled, both arms) 
○ Cumulative Hospitalizations (pooled, both arms) 
● A data safety monitoring board (DSMB) will review data after every 100 
participants complete 14 days of follow-up. 
● De-identified data will be shared with the research team members for analysis. 
15.5 Study Records Retention 
● No paper documents will be retained or stored. 
● Digital records will be kept in a secure server setting. 
15.6 Protocol Deviations 
 
Protocol violations will be reported to the IRB of record.  
16 
PUBLICATION POLICY 
 
Publication will be expeditiously made with a full, de-identified data made available. 


COVID-19 PEP RCT 
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35 
 
17 
LITERATURE REFERENCES 
1. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 
2020. Available at: https://www.who.int/docs/default-source/coronaviruse/who-china-
joint-mission-on-covid-19-final-report.pdf  
2. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the 
recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30: 269-71. 
3. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS 
coronavirus infection and spread. Virol J 2005; 2: 69. 
4. Cong Y, Hart BJ, Gross R, et al. MERS-CoV pathogenesis and antiviral efficacy of 
licensed drugs in human monocyte-derived antigen-presenting cells. PLoS One 2018; 
13: e0194868. 
5. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, 
Lu R, Li H, Tan W, Liu D. In vitro antiviral activity and projection of optimized dosing 
design of hydroxychloroquine for the treatment of severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 202. In Press. doi: 10.1093/cid/ciaa237. 
6. Burke RM, Midgley CM, Dratch A, Fenstersheib M, Haupt T, Holshue M, Ghinai I, 
Jarashow MC, Lo J, McPherson TD, Rudman S, Scott S, Hall AJ, Fry AM, Rolfes MA. 
Active monitoring of persons exposed to patients with confirmed covid-19 - United 
States, January-February 2020. MMWR Morb Mortal Wkly Rep. 2020;69:245-6. 
7. Lim HS, Im JS, Cho JY, Bae KS, Klein TA, Yeom JS, Kim TS, Choi JS, Jang IJ, Park 
JW. Pharmacokinetics of hydroxychloroquine and its clinical implications in 
chemoprophylaxis against malaria caused by Plasmodium vivax. Antimicrob Agents 
Chemother. 2009;53:1468-75. PMCID: 2663072. 
8. Carmichael SJ, Charles B, Tett SE. Population pharmacokinetics of hydroxychloroquine 
in patients with rheumatoid arthritis. Therapeutic Drug Monitoring. 2003;25:671-81. 
9. Haeusler IL, Chan XHS, Guerin PJ, White NJ. The arrhythmogenic cardiotoxicity of the 
quinoline and structurally related antimalarial drugs: A systematic review. BMC Med. 
2018;16:200. PMCID: PMC6220451. 


COVID-19 PEP RCT 
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36 
SUPPLEMENTS / APPENDICES 
 
APPENDIX A: SCHEDULE OF EVENTS 
 
Overview of Procedures 
 
Participants with ongoing SAE / hospitalization at day 14 will be 
followed until hospital discharge or up to day 90 for final resolution. 
Screen
•Person emails covid19@umn.edu
•Auto-Response sends Study Info Sheet
•URL links to Screening eCRF
Consen
t
• Screening for Inclusion/Exclusion 
• If eligible -> Informed Consent Form
• Assessment of Comprehension
• Signing online consent form
Enroll
•Prescription order sent to IDS Pharmacy
•IDS Pharmacy Randomizes Subject
•Study Staff to FedEx Study Medicine
Day +1
• Email with URL to eCRF to verify:
• Receipt of med
• Symptom status / AEs, 
• Day 3 survey if symptomatic
Day +3 
• Email with URL link to eCRF to verify:
• Symptom status; 
• Hospitalization status; AEs
Day +5
• Email with URL link to eCRF to verify:
• Symptom status; testing status
• Hospitalization status; AEs
• Medications
Day 
+10
•Email with URL link to eCRF to verify:
•Symptom status; testing status
•Hospitalization status; AEs 
Day 
+14
•Email with URL link to eCRF to verify:
•Symptom status; testing status
•Hospitalization status; AEs
•Inquiry if future contact for research? 
•Return dried blood spot


COVID-19 PEP RCT 
Version 2.3 
 
24 April 2020 
37 
 
1. 
Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 
2020. 
2. 
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the 
recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30: 269-71. 
3. 
Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS 
coronavirus infection and spread. Virol J 2005; 2: 69. 
4. 
Cong Y, Hart BJ, Gross R, et al. MERS-CoV pathogenesis and antiviral efficacy of 
licensed drugs in human monocyte-derived antigen-presenting cells. PLoS One 2018; 
13: e0194868. 
5. 
Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized 
Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020; In Press. 
6. 
Pastick KA, Okafor EC, Wang F, et al. Review: Hydroxychloroquine and Chloroquine for 
Treatment of SARS-CoV-2 (COVID-19). Open Forum Infectious Diseases 2020; 
ofaa130. 
7. 
Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients 
with common coronavirus disease-19 (COVID-19). Journal of Zhejiang University 2020. 
8. 
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. Int J 
Antimicrob Agents 2020; 105949. 
9. 
Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: 
results of a randomized clinical trial. medRxiv 2020. 
10. 
Molina JM, Delaugerre C, Goff JL, et al. No Evidence of Rapid Antiviral Clearance or 
Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in 
Patients with Severe COVID-19 Infection. Médecine et Maladies Infectieuses 2020. 
11. 
Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination 
of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day 
follow up: A pilot observational study. Travel Med Infect Dis 2020; 101663. 
12. 
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent 
efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci 
Trends 2020; 14: 72-3. 
13. 
Burke RM, Midgley CM, Dratch A, et al. Active Monitoring of Persons Exposed to 
Patients with Confirmed COVID-19 - United States, January-February 2020. MMWR 
Morb Mortal Wkly Rep 2020; 69: 245-6. 
14. 
Haeusler IL, Chan XHS, Guerin PJ, White NJ. The arrhythmogenic cardiotoxicity of the 
quinoline and structurally related antimalarial drugs: a systematic review. BMC Med 
2018; 16: 200. 
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 Chemother 2009; 53: 1468-75. 
16. 
Carmichael SJ, Charles B, Tett SE. Population Pharmacokinetics of Hydroxychloroquine 
in Patients With Rheumatoid Arthritis. Therapeutic Drug Monitoring 2003; 25: 671-81. 
 


Post-exposure Prophylaxis or Preemptive Therapy for  
SARS-Coronavirus-2:  A Pragmatic Randomized Clinical Trial 
 
 
Statistical Analysis Plan 
06 May 2020 
 
 


Protocol Version, Date 
Primary Endpoint 
Protocol Version 1.0, March 17, 2020 
Incidence of COVID19* 
Protocol Version 2.0; March 20,  2020 
Incidence of COVID19 
Protocol Version 2.1, March 26, 2020 
Incidence of COVID19 
Protocol Version 2.2; March 27, 2020 
Incidence of COVID19 
Protocol Version 2.3, April 24, 2020 
Incidence of COVID19 
* Incidence of COVID19 disease, defined on March 17 and thereafter as: “The primary analysis 
will use PCR+ confirmed disease.  However if the absence of sufficient testing supplies 
continues then outpatients will not be offered SARS-CoV-2 testing unless they are sick enough 
to be hospitalized.  In that case an alternate a priori planned analysis will define incident 
COVID19 disease as a composite of SARS-CoV-2 PCR+ confirmed result OR symptomatic 
disease (i.e. possible) COVID-19 in those without testing.”   
 
I. 
Prophylaxis study primary outcome 
a. The primary outcome will be presented for the treatment and control groups as 
proportions, and compared with Fisher’s Exact tests. 
 
b. The primary outcome will be presented for subgroups formed by contact type 
(household contact and healthcare workers), age groups (18-35, 36-50 and > 
50), sex, and days from exposure. These are apriori subgroups defined in the 
Version 1.0 of the protocol. 
 
c. Participants who are randomized into the prevention trial, but who become 
symptomatic on Day 1 before receiving the study medicine will be censored from 
the prevention cohort and analyzed with the companion treatment cohort.  
 
d. The primary outcome will be presented by subgroups formed by COVID test 
results (confirmed positive vs. other), age groups (18-35, 36-50, > 50), sex, and 
days from exposure onset to entry. These are apriori subgroups defined in the 
Version 1.0 of the protocol. 
e. Medication adherence is captured on study day 5.  Another subgroup of interest 
is comparing the treatment groups for change in symptom severity score after 
day 5 by adherence reported at day 5 (<= 75% versus > 75%).    
 
 
II. 
Secondary outcomes  
a. Secondary outcomes for incidence will be presented as proportions and 
compared between the treatment groups with Fisher’s Exact tests. 
b. Symptom severity scores were recorded with the online participant surveys at 
days 3, 5, 10 and 14 only for those who responded “yes” to “Any symptoms 
experienced”.   


i. Visual analog scale (0-10) for “overall symptom severity” is collected via a 
digital slider bar, which is marked with “0 = no symptoms”; 5 (placed in 
the middle); and “10 = severe symptoms” 
 
ii. For those who responded “no” to “Any symptoms experienced” the 
symptom severity score for that visit is assigned as zero. 
iii. For those hospitalized or with deaths, their symptom severity was scored 
as 10 if they did not respond to the visit survey.   
iv. Analysis is by Kruskall Wallis tests among those with symptoms at day 
14. 
 
 
Clarifications (24 May 2020): 
 
Participants with missing outcome data are still included in the denominator, as the trial 
is performed as an intent to treat analysis. 
 
Sensitivity analyses were performed excluding participants with missing data from the 
denominator as well as including participants with missing data as events. 

ICF_001.pdf: 
Page 1 of 11    
Version Date:  24 April 2020 
Title of Research Study:  Post-exposure Prophylaxis or Preemptive Therapy for 
SARS-Coronavirus-2: A Pragmatic Randomized Clinical Trial 
 
Investigator Team Contact Information:  
For questions about research appointments, the research study, research results, or 
other concerns, call the study team at:  
Investigator Name:  David Boulware, MD 
Investigator Affiliation: Division of 
Infectious Diseases and International 
Medicine, Department of Medicine, 
University of Minnesota 
To Contact the Research Study 
Personnel with Questions or concerns, 
please email:  XXXXXXXX@gmail.com  
 
Supported By: This research is supported by the University of Minnesota. 
 
Key Information about This Research Study 
The following is a short summary to help you decide whether or not to be a part of this research 
study. More detailed information is listed later on in this form. 
What is research? 
 
 
Doctors and investigators are committed to your care and safety. There are important 
differences between research and treatment plans:  
● The goal of research is to learn new things in order to help groups of people in the 
future. Investigators learn things by following the same plan with a number of 
participants, so they do not usually make changes to the plan for individual research 
participants. You, as an individual, may or may not be helped by volunteering for a 
research study.   
● The goal of clinical care is to help you get better or to improve your quality of life. 
Doctors can make changes to your clinical care plan as needed. 
 
Research and clinical care are often combined. One purpose of this informed consent document 
is to provide you clear information about the specific research activities of this study.  
 
 
Why am I being asked to take part in this research study? 
We are asking you to take part in this research study because either you have a confirmed 
diagnosis of COV-19 disease OR have been exposed to SARS-coronavirus-2 from someone 
who has COVID-19 disease.  
 
What should I know about a research study? 
● Whether or not you take part is up to you. 
● You can choose not to take part. 
● You can agree to take part and later change your mind. 
● Your decision will not be held against you. 
● You can ask all the questions you want before you decide.  
 


Page 2 of 11    
Version Date:  24 April 2020 
Why is this research being done? 
The first objective is to determine whether a medication can be given to prevent COVID-19 
disease in people who have been exposed to the virus but who are asymptomatic.  The concept 
is called “post-exposure prophylaxis” — a method where medication is given to prevent an 
infectious disease after someone has contact with another infected person.  This strategy has 
proven useful for diseases like influenza and bacterial meningitis. 
The second objective is to determine if a medication can treat symptomatic mild COVID-19 
disease to decrease the severity of illness, shorten duration of illness, and prevent 
hospitalization. 
COVID-19 disease is caused by a virus called severe acute respiratory syndrome 
coronavirus 2, or SARS-CoV-2 for short.  Currently COVID-19 is infecting people across the US 
but no FDA-approved treatments are yet available.  There are trials starting to test experimental 
treatments for ill, hospitalized patients; however, our study is proposing to prevent disease in 
people who have been exposed to COVID-19 or treat mild to moderate disease in people who 
are not hospitalized. 
It is unknown whether you will receive any direct benefit by participating in the study, as we 
do not know if the study medication successfully treats or prevents disease yet.  However, the 
data collected will be helpful in knowing how to manage COVID-19 disease moving forward.  
The drug being investigated is called hydroxychloroquine (hi-drox-ee-klor-o-kwin), which is 
typically used to treat malaria and sometimes autoimmune diseases.  It is not a new drug, 
having been first approved in 1955.  Laboratory tests have demonstrated that it has activity 
against the SARS-CoV-2 virus. 
How long will the research last? 
We expect that you will be in this research study for 14 days. If you develop symptoms of 
COVID-19 or become hospitalized, we will follow you until your symptoms resolve.  
 
What will I need to do to participate? 
You will be asked to fill out an online form. We will send you the investigational drug by 
FedEx to be received tomorrow morning.  You will need to take the drug for 5 days.  We send 
you a brief internet-based survey about any symptoms or hospitalizations that you experienced.  
No blood sample collections or visits to the doctor’s office are required.   You will need to: 
● Take the study medicine for five days.  
o The first day you will take 4 tablets by mouth, then  
o 6-8 hours later take 3 tablets, then  
o Take 3 tablets once daily for 4 more days (5 days in total) 
The hydroxychloroquine dose is similar to what is given for malaria treatment but 
higher daily doses of 3 tablets instead of 2 tablets.  
● We will have a short follow up email survey for you to complete on: 
o Day 1 (to confirm you have received the medicines) 
o Day 3  
o Day 5  
o Day 10  
o Day 14  


Page 3 of 11    
Version Date:  24 April 2020 
o An Additional survey at Day 21 if you are hospitalized or have pending 
test results at day 14. If still hospitalized at day 21, we will send follow up 
surveys every 2 weeks until you are discharged. 
More detailed information about the study procedures can be found under “What happens 
if I say yes, I want to be in this research?” 
Is there any way that being in this study could be bad for me? 
Hydroxychloroquine is a relatively safe drug which has been used for the prevention of 
malaria for over 60 years.  However, like all drugs, side effects and adverse reactions are 
possible.  Specific details are described later in the document.  Some pre-existing medical 
conditions will prevent you from entering the study, such as if you have an abnormal heart 
rhythm. The dose being used and the short duration of hydroxychloroquine used in our study 
should also reduce the chance of an adverse event. 
There has been substantial media attention on the potential dangers of abnormal heart 
rhythms when using very high dose chloroquine (2x higher than what is being used in our trial) 
with azithromycin OR using high dose hydroxychloroquine with azithromycin. On April 24, the 
FDA issued a caution: “The FDA is aware of reports of serious heart rhythm problems in 
patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination 
with azithromycin and other QT prolonging medicines.” 
 Our trial is using he normal FDA-approved dosing range of hydroxychloroquine WITHOUT 
azithromycin.  The risk of having an abnormal heart rhythm is increased if one has: 
 
an abnormal heart rhythm, such as prolonged QT syndrome 
 
underlying heart disease 
 
chronic kidney disease. 
 
currently receiving medicines which prolong the QT interval. 
All of these conditions are excluded from trial participation.  Three interim analysis to date 
have not revealed any safety concerns.  
Aside from possible medication side effects, there are no direct harms of this internet-based 
study.  As there is no known way to prevent or treat COVID-19 disease, there are no standard 
medicines that other people are receiving in your situation.  Any personal medical information 
collected will be kept confidential.   
More detailed information about the risks of this study can be found under “What are the 
risks of this study?  Is there any way being in this study could be bad for me? (Detailed 
Risks)” and in the “What happens to the information collected for the research?” section 
Will being in this study help me in any way? 
We cannot promise any benefits to you or others from your taking part in this research.  
However, possible benefits from study participation include preventing COVID-19 disease or 
reducing the severity of COVID-19 disease.  There is also an important benefit to others and the 
medical community at large, as a medication that proves effective in preventing or reducing the 
severity of COVID-19 could have worldwide importance. 
More detailed information about the benefits of this study can be found under “Will being in 
this study help me in any way? (Detailed Benefits)” 


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What happens if I do not want to be in this research? 
As there are currently no FDA-approved medications for the treatment or prevention of 
COVID-19 disease, there are no known alternatives other than deciding not to participate in this 
research study.  Deciding not to participate in the trial will otherwise not affect your ability to 
receive supportive medical care from a doctor or hospital if you were to become sick.  If you did 
develop COVID-19 disease, you would likely remain eligible for any treatment trial that was 
ongoing at a hospital.  
 
If you wish to stop taking the study medicine, you may do so; however, the investigators would 
ask to continue to follow you to collect your clinical outcome through Day 14 – do you become 
ill? Do you become hospitalized? 
 
Detailed Information About This Research Study 
The following is more detailed information about this study in addition to the info listed above. 
How many people will be studied? 
We expect up to 2500 people may be in this research study. 
 
What happens if I say “Yes, I want to be in this research”? 
You will first answer an online questionnaire about your health history to determine if you 
can participate in this study.  If you are deemed eligible and consent for study participation, then 
you will be randomly assigned to receive either 
hydroxychloroquine or a vitamin, which you will 
take for 5 days.  Once assigned, the medication will 
be sent by FedEx overnight to you.  You are to start 
the medication as soon as you receive it.  Then you 
will fill out a survey on Days 1, 3, 5, 10, and 14 
reporting any COVID-19 symptoms, medicine side 
effects, or hospitalizations that have occurred. 
The experimental treatment you get will be 
chosen by chance, like flipping a coin.  Neither you 
nor the research study doctor will choose what 
experimental treatment you get. You will have an 
equal (50%) chance of being given either 
treatment.  Neither you nor the study doctor will 
know which experimental treatment you are getting.  
No in-person visits or blood draws are required.  
All data will be collected by you reporting 
information in online questionnaires.   
If you do become ill with COVID-19 
symptoms or your symptoms worsen, you 
should contact your local doctor and/or local 
Department of Health.   
Please call your doctors for medical care.  If you 
become sick, we would recommend continuing the 
study medication, unless directed by your local 
doctor. 


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What are my responsibilities if I take part in this research? 
If you take part in this research, you will be responsible for:  
1. Check tomorrow to make sure you receive the shipped medication at ~10:30am Mon-Sat 
(via Fedex) 
2. Take your medication each day  
3. Fill out at least five online questionnaires on Day 1, 3, 5, 10, and 14.  Each survey 
should take ~2 minutes to complete on average.  
4. If you do become symptomatic or are hospitalized, we will send additional surveys 2 
weeks later (Day 28) to ask how long it took you to recover. 
There are two optional sub-studies that you may participate in of: 
 
Checking for antibodies at Day 14 via the collection of a dried blood spot and returning 
 
Cardiac monitoring with daily electrocardiograms (EKGs) to assess for any change in 
heart rhythm.  
More details on these sub-studies are on the final two pages. 
What happens if I say “Yes”, but I change my mind later? 
 
If you take part in this research study, and want to leave, you should tell us.  Your choice not 
to be in this study will not negatively affect your right to any present or future medical care. 
 
If you stop the study, you should continue to follow the direction of your own doctor or public 
health officials.  
 
If you stop participating in the research study, information about you that has already been 
collected may not be removed from the study database. This is per U.S. FDA rules. 
 
If you have severe side effects from the study medicine and wish to stop the 
medicine, you may stop the medicine and still remain in the study.  You’re ongoing 
participation in reporting these side effects is very important. Even if you do not take the 
study medicine or stop the study medicine, we would like for you to complete the 
follow up surveys, please. 
 
If you stop being in the research, you will be asked if the investigators can continue to 
collect information from you about your clinical outcome through 14 days. You may choose 
to decline.  
 
What are the risks of being in this study?  Is there any way being in this 
study could be bad for me? (Detailed Risks) 
● The main side effects of hydroxychloroquine include nausea (and upset stomach), 
decreased appetite, headache, rash, itching, and blurred vision.  Central nervous system 
effects can include: ringing in the ears, irritability, nervousness, emotional changes, 
nightmares, or vertigo. All these symptoms  should resolve once the drug is stopped.  
Dividing up the doses into multiple doses per day can decrease gastrointestinal side effects, 
such as nausea.  
● More serious reactions are rare but possible; typically these occur in people taking the drug 
for much longer periods of time than as directed in this study, generally for >1 year.  These 
include vision damage, heart rhythm problems, low blood sugar, and muscle weakness.  


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Persons with psoriasis may experience temporary skin worsening while taking the 
medication.   
● Persons with diabetes should be aware that hydroxychloroquine may lower their blood 
sugars, and you should monitor your blood sugars frequently.  
● Persons with a previous allergy to chloroquine or hydroxychloroquine should avoid the drug. 
● Persons with Glucose-6-phosphate deficiency (G6PD), a blood disorder, may have 
increased risk of hemolytic anemia when taking hydroxychloroquine. Symptoms of hemolytic 
anemia include fatigue, shortness of breath, pale skin, and yellowing of skin or eyes.    
● Persons with existing eye disease of the retina should not take hydroxychloroquine.  Long-
term use >1 year can be associated with rare retinal eye problems. Eye problems have not 
been reported with short-term use.  
● Persons taking medications for abnormal heart rhythms may be ineligible for the study (more 
information below).  Long term use >1 year has been associated with prolongation of the 
heart QT interval.  Very high doses (2x higher than what is being used in this study) can be 
toxic or when used in combination with azithromycin – thi scna prolong the QT interval.  
o 
The QT interval is a feature on the electrocardiogram (i.e, “EKG”) that can 
provide valuable information. When the QT interval is longer than normal, this 
indicates that the heart muscle is taking longer than normal to recharge. If the QT 
interval is very long, the heart can develop fast beats, which can be potentially 
dangerous. 
o 
Azithromycin is prohibited in this study because of the concern for causing 
abnormal heart rhythms. 
● Persons with porphyria cutanea tarda may develop fever and liver injury with high dose 
hydroxychloroquine use, such as given in this study. Persons with known porphyria are 
excluded. 
● Persons with epilepsy or an otherwise low seizure threshold may be at greater risk of 
seizures while receiving hydroxychloroquine. 
● Persons with structural heart disease, ischemic heart disease, or an abnormal heart rhythm 
called QT prolongation are not eligible to participate.  
● Persons taking medications for significant heart rhythm problems are ineligible for the study 
due to increased risk for heart rhythm abnormalities.  The most common medications are: 
● 
Flecainide (Tambocor) 
● 
Procainimide (Procan) 
● 
Propafenone (Rythmol) 
● 
Amiodarone (Cordarone, Pacerone) 
● 
Quinidine  
● 
Digoxin  
● Other medicines which can prolong the heart QT interval – and are prohibited -- are:  
● 
Antimicrobials: levofloxacin, ciprofloxacin, moxifloxacin, azithromycin, 
clarithromycin, erythromycin, ketoconazole, itraconazole, or mefloquine 
● 
Antidepressants: amitriptyline, citalopram, desipramine, escitalopram, 
imipramine, doxepin, fluoxetine, wellbutrin, or venlafaxine 
● 
Antipsychotic or mood stabilizers: haloperidol, droperidol, lithium, quetiapine, 
thioridazine, ziprasidone 
● 
Methadone 


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● 
Sumatriptan, zolmitriptan 
Due to avoidance of any possible increased risk of harm, if you are currently using these 
medicines, you are not eligible to participate.  
● Some persons will receive a vitamin instead of hydroxychloroquine.  Oral vitamins are 
considered safe, though can occasionally cause upset stomach. The vitamin being given will 
not interfere with any current vitamin that you may take.  
● There is a risk that you may have a bad outcome with COVID-19 disease.  This risk exists 
whether you are in the trial or not.  We cannot predict for sure who will have mild or severe 
disease after infection from the virus.  However, we do have evidence that persons >65 
years old may be at higher risk for more severe disease. It is unlikely that this trial will 
worsen that risk in any way. 
● There is some risk of a data breach involving the information we have about you.  We 
comply with the University’s data security standards to secure your information and minimize 
risks.  
 
What do I need to know about reproductive health and/or sexual activity if I 
am in this study?   
Pregnant women may participate in the trial.   
 
Hydroxychloroquine is Pregnancy Category: C – Use with caution if benefits outweigh risks. 
Hydroxychloroquine crosses the placenta. Animal studies show evidence of fetal harm when 
used in high doses and for prolonged durations with associated neurological disturbances and 
interference with hearing, balance, and vision in the fetus.  There is no data in animals that short 
term use, such as for the treatment of malaria (or as in this study), causes fetal toxicity.  
 
In humans, a 2009 comprehensive review of the published literature reported that 
hydroxychloroquine is not associated with any increased risk of congenital defect, spontaneous 
abortion, fetal death, pre-maturity, or decreased numbers of live births in pregnant women with 
autoimmune diseases.  
 
The effect of SARS-CoV-2 on pregnancy is not known.  The U.S. Food and Drug Administration 
(FDA) recommends contraception use for all women of childbearing potential for the next 6 
weeks. This is recommended but not required for your participation.  
 
If you are or become pregnant while participating in this research study, we ask to be able to 
send you a short survey ~1 month after your delivery to collect information on the outcomes of 
your pregnancy.  
 
Breastfeeding: Small amounts of hydroxychloroquine enter into breast milk. Small studies have 
reported no harmful effects in infants whose mothers' breastfed while taking hydroxychloroquine 
with no evidence of vision, hearing, or growth problems in infants who were followed up to one 
year of age. 
 
Will it cost me anything to participate in this research study? 
Taking part in this research study will not lead to any costs to you.  You will not be charged for 
the study medications or the cost to ship them to you. 
What happens to the information collected for the research, including my 


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health information? 
We try to limit the use and sharing of your information, including research study records, any 
medical records and any other information about you, to people who have a need for this 
information.  But we cannot promise complete confidentiality.   
 
If you participate in this study, your information, including your health information, will be used 
and shared for purposes of conducting this research.  As described later in this Consent Form, 
your information may also be used and shared for publishing and presenting the research 
results.   If you sign this Consent Form, you are giving us permission to use and share your 
health information for these purposes. We ask for access to your medical records to verify test 
results and review hospitalizations, you are giving permission to any health care providers who 
are treating you to share your medical records with us.   
 
What health information will be made available? 
 
Health information about you to be used and shared for the research includes those items 
checked by the research team below: 
 
☒ Your medical records, which may include records from hospital and clinic visits, emergency 
room visits, medical history and physical exams, medications, progress notes, lab and 
pathology reports.  These records may be used and shared for as long as this research 
continues. We will limit any request to 5 days prior and 90 days after study entry. 
☒ Information collected as part of this research study, including research procedures, research 
visits, and any optional elements of the research you agree to, all as described in this Consent 
Form.  This information might not be part of your medical record, and may include things like 
responses to surveys and questionnaires, and information collected during research visits 
described in this Consent Form. 
Who will access and use my health information? 
If you agree to participate in this study, your information will be shared with: 
● The University of Minnesota research team and any institutions or individuals 
collaborating on the research with us; 
● Others at the University of Minnesota and M Health/Fairview who provide support for the 
research or who oversee research (such as the Institutional Review Board or IRB which 
is the committee that provides ethical and regulatory oversight of research at the 
University, systems administrators and other technical and/or administrative support 
personnel, compliance and audit professionals (Such as the Quality Assurance Program 
of the Human Research Protection Program (HRPP)) , individuals involved in processing 
any compensation you may receive for your participation, and others); 
● The research sponsor(s), any affiliates, partners or agents of the sponsor(s) involved in 
the research, organizations funding the research, and any affiliates, partners or agents 
of the funding organization(s) involved in the research, including state health 
departments; 
● Organizations who provide accreditation and oversight for research and the research 
team, and others authorized by law to review the quality and safety of the research (such 
as U.S. government agencies like the Food and Drug Administration, the Office of 


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Human Research Protections, the Office of Research Integrity, or government agencies 
in other countries); and 
 
The sponsor, monitors, auditors, the IRB, the University of Minnesota Research 
Compliance Office and other University compliance units, the US Office of Research 
Integrity (ORI), the US Office for the Protection of Human Research Protections (OHRP), 
the US Food and Drug Administration (FDA) may be granted direct access to your 
medical records to conduct and oversee the research. By signing this document, you are 
authorizing this access. We may publish the results of this research. However, we will 
keep your name and other identifying information confidential. Specifically, your records 
may be audited to determine whether all information provided by you is correct.  
 
Additional sharing of your information for mandatory reporting 
If we learn about any of the following, we may be required or permitted by law or policy to report 
this information to authorities: 
● Current or ongoing child or vulnerable adult abuse or neglect; 
● Communicable, infectious or other diseases required to be reported under Minnesota’s 
Reportable Disease Rule; 
● Certain wounds or conditions required to be reported under other state or federal law; or 
● Excessive use of alcohol or use of controlled substances for non-medical reasons during 
pregnancy. 
 
How will my information be used in publications and presentations? 
We may publish the results of this research in scientific, medical, academic or other journals 
or reports, or present the results at conferences.  Information that makes it easy to identify you 
(such as your name and contact information, and medical records number) will not be part of 
any publication or presentation.  If you have an extremely unique or rare condition that is not 
shared by many others, it is possible that some people may be able to determine your identity 
even without these identifiers. 
What will be done with my data and specimens when this study is over? 
Your data will not be used for any future research after this study is complete. 
 
Do I have to sign this Consent Form and give my permission to make my information, 
including my health information, available for use and sharing? 
No, you do not have to sign this Consent Form.  But if you do not sign, you will not be able 
to participate in this research study.  Treatment available outside of the study, payment for such 
treatment, enrollment in health insurance plans and eligibility for benefits will not be impacted by 
your decision about signing this Consent Form. 
Does my permission for making my health information available for use and sharing ever 
expire? 
Yes, we will limit collection of data to 90 days from entering the study.  
May I cancel my permission for making my health information available for use and 
sharing? 
Yes.  You may cancel your permission at any time by writing to the researcher at the email 
address on the first page of this Consent Form.  If you cancel your permission, you will no 


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longer be in the research study. If you cancel your permission, any health information about you 
that was already used and shared may continue to be used and shared for the research study 
and any optional elements of the study to which you agree in this Consent Form.  
What happens to my health information after it is shared with others? 
When we share your information with others as described in this Consent Form, privacy 
laws may no longer protect your information and there may be further sharing of your 
information.   
Will I be able to look at my records? 
The research team will allow you to see the information collected for this study.  
 
A description of this clinical trial is available at: www.ClinicalTrials.gov/ct2/show/NCT04308668 
as required by U.S. Law. This Web site will not include your name or any other direct identifiers 
such as your contact information. The Web site may include a summary of the results of this 
research. You can search this Web site at any time. 
 
Will I receive research test results? 
When the study is complete, we will email a summary of results to all participants’ email 
addresses. You will not know if you got the hydroxychloroquine or the vitamin.   
 
If you participate in the optional dried blood spot collection to check for antibodies at Day 14, 
we seek to return results to you within 4-6 weeks.  
Will I be compensated for my participation?  
There is no payment for study participation. The study medicine will be provided free of charge.  
 
Whom do I contact if I have questions, concerns or feedback about my 
experience? 
This research has been reviewed and approved by an IRB within the Human Research 
Protections Program (HRPP) at the University of Minnesota. To share feedback privately with 
the HRPP about your research experience, call the Research Participants’ Advocate Line at 
612-XXX-XXXX  (Toll Free: 1-888-XXX-XXXX) or go to z.umn.edu/XXXXXX.  You are 
encouraged to contact the HRPP if:  
● Your questions, concerns, or complaints are not being answered by the research team. 
● You cannot reach the research team at XXXXXXX@gmail.com (please email study 
related questions here first) 
● You want to talk to someone besides the research team. 
● You have questions about your rights as a research participant. 
● You want to get information or provide input about this research. 
 
Will I have a chance to provide feedback after the study is over?  
The Human Research Protections Program (HRPP) may ask you to complete a survey that 
asks about your experience as a research participant. You do not have to complete the survey if 
you do not want to. If you do choose to complete the survey, your responses will be 
anonymous.   
If you are not asked to complete a survey, but you would like to share feedback, please 
contact the study team or the HRPP. See the “Investigator Contact Information” of this form for 


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study team contact information and “Whom do I contact if I have questions, concerns or 
feedback about my experience?” of this form for HRPP contact information. 
What happens if I am injured while participating in this research? 
In the event that this research activity results in an injury, you should seek first aid and 
emergency treatment from your healthcare provider, as needed.  Care for such injuries will be 
billed in the ordinary manner, to you or your insurance company.  If you think that you have 
suffered a research related injury let the study physicians know right away.   
If you develop new or worsening symptoms concerning for COVID19 
disease (such as fever, cough, shortness of breath, sore throat, 
muscle aches, or fatigue) you should call your healthcare provider or 
local health department for testing and further instructions.  
Your signature documents your permission to take part in this research.  You will be provided a 
copy of this signed document. 
 
 
_______________________________________________      __________________ 
Signature of Participant                                                                   Date 
 
_______________________________________________ 
Printed Name of Participant