Clinical trial NCT04328467
Conditions: COVID-19 Corona Virus Infection ARDS Acute Respiratory Distress Syndrome
Sponsor: University of Minnesota
Start date: 2020-04-06; Completion date: 2020-07-13
Enrollment: 1483 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Objective: To determine if pre-exposure prophylaxis with hydroxychloroquine is effective for the prevention of COVID-19 disease.

Detailed description:
The current standard of care is observation and quarantine after exposure to COVID-19. There is no approved treatment or prophylaxis for COVID-19.

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%). 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 COVID-19 disease or reduce disease severity. It is not known at what dosing hydroxychloroquine may be effective for pre-exposure prophylaxis.

Arms: arm 1: 400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks arm 2: 400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks arm 3: Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks
Interventions: intervention 1: Hydroxychloroquine intervention 2: Placebo
Intervention descriptions: intervention 1: Hydroxychloroquine; 200mg tablet; oral intervention 2: Placebo; tablet; oral

Protocol documents:
Prot_SAP_000.pdf: 
PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
1 
 
                
Pre-exposure Prophylaxis for SARS-Coronavirus-2: A 
Pragmatic Randomized Clinical Trial  
 
Short Title: PREP COVID-19 
 
 
UMN IRB Number: STUDY00009414 
ClinicalTrials.gov: NCT04328467 
Principal Investigator: Radha Rajasingham MD 
 
Draft or Version Number: 1.0 
27 March 2020  
 
 
 
 
 
CONFIDENTIAL 
This document is confidential and the property of the University of Minnesota and 
consortia members.  No part of it may be transmitted, reproduced, published, or used by 
other persons without prior written authorization from the principal investigator. 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
2 
 
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. 
 
 
Signed: 
 
 
 
Site Investigator: 
 
Radha Rajasingham, MD 
Assistant Professor of Medicine 
 
Date: 
March 26, 2020 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
3 
 
TABLE OF CONTENTS 
 
Page 
1 
Key Roles 
12 
2 
Background Information and Scientific Rationale 
13 
2.1 
Background Information 
13 
2.2 
Rationale 
16 
2.3 
Potential Risks and Benefits 
17 
2.3.1 
Potential Risks 
17 
2.3.2 
Known Potential Benefits 
18 
3 
Objectives 
20 
3.1 
Study Objectives 
20 
3.2 
Study Outcome Measures 
20 
3.2.1 
Primary Outcome Measure 
20 
3.2.2 
Secondary Outcome Measures 
20 
4 
Study Design 
21 
4.1 
Design 
21 
4.2 
Study participant duration 
21 
4.3 
Study procedures 
22 
4.5 
Substudies 
Error! Bookmark not defined. 
5 
Study Enrollment and Withdrawal 
24 
5.1 
Subject Inclusion Criteria 
24 
5.2 
Subject Exclusion Criteria 
24 
5.3 
Treatment Assignment Procedures 
25 
5.3.1 
Randomization Procedures 
25 
5.3.2 
Masking Procedures 
25 
5.3.3 
Reasons for Withdrawal 
25 
5.3.4 
Handling of Withdrawals 
25 
5.3.5 
Termination of Study 
25 
6 
Study Intervention/Investigational Product 
26 
6.1 
Study Product Description 
26 
6.1.1 
Acquisition 
26 
6.1.2 
Formulation, Packaging, and Labeling 
26 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
4 
 
6.1.3 
Drug Description: 
26 
6.1.4 
Formulation: 
26 
6.1.5 
Pharmacokinetics: 
26 
6.1.6 
Product Storage and Stability 
27 
6.2 
Dosage, Preparation, and Administration of Investigational Product 
27 
6.3 
Modification of Investigational Product for a Participant 
27 
6.4 
Accountability Procedures for the Investigational Product: 
27 
6.5 
Assessment of Subject Compliance 
28 
6.6 
Concomitant Medications/Treatments 
28 
6.7 
Screening 
30 
6.8 
Enrollment/Baseline 
30 
6.9 
Follow-up 
30 
6.10 
Final Study Visit 
30 
6.11 
Early Termination Visit 
30 
6.12 
Unscheduled Visit 
31 
7 
Study Procedures/Evaluations 
32 
7.1 
Clinical Evaluations 
32 
7.2 
Laboratory Evaluations 
32 
8 
Assessment of Safety 
33 
8.1 
Specification of Safety Parameters 
33 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
33 
8.2.1 
Adverse Events 
33 
8.2.2 
Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) 
33 
8.2.3 
Serious Adverse Events 
33 
8.2.4 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
33 
8.3 
Reporting Procedures 
33 
8.3.1 
Serious Adverse Events 
33 
8.3.2 
Regulatory Reporting 
34 
8.3.3 
Reporting of Pregnancy 
35 
8.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
35 
8.5 
Safety Oversight (DSMB) 
35 
9 
Clinical Monitoring 
35 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
5 
 
10 
Statistical Considerations 
37 
10.1 
Study Hypotheses 
37 
10.2 
Sample Size Considerations 
37 
10.3 
Planned Interim Analyses 
38 
10.4 
Final Analysis Plan 
39 
11 
Source Documents and Access to Source Data/Documents 
41 
12 
Quality Control and Quality Assurance 
41 
13 
Ethics/Protection of Human Subjects 
42 
13.1 
Ethical Standard 
42 
13.2 
Institutional Review Board 
42 
13.3 
Informed Consent Process 
42 
13.3.1 
Informed Consent/Assent Process (in Case of a Minor) 
42 
13.4 
Exclusion of Women, Minorities, and Children 
43 
13.5 
Subject Confidentiality 
43 
13.6 
Future Use of Stored Specimens 
43 
14 
Data Handling and Record-Keeping 
44 
14.1 
Data Management Responsibilities 
44 
14.2 
Data Capture Methods 
44 
14.3 
Types of Data 
44 
14.4 
Timing/Reports 
44 
14.5 
Study Records Retention 
44 
14.6 
Protocol Deviations 
44 
15 
Publication Policy 
45 
16 
Literature References 
45 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
6 
 
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 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
7 
 
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 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
US 
United States 
WHO 
World Health Organization 
 
 
 
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
8 
 
Summary 
Full Title: 
Pre-exposure prophylaxis for coronavirus: A Pragmatic 
Randomized Clinical Trial 
Short Title: 
PREP COVID-19 
Clinical Phase: 
III 
Sponsor: 
Investigator-Initiated Protocol, University of Minnesota 
Principal 
Investigators: 
Radha Rajasingham, MD 
 
Accrual Ceiling 
3500 
Study Population 
Healthcare workers at high risk for exposure to COVID-19 cases 
Objective 
Test if pre-exposure prophylaxis with hydroxychloroquine can 
prevent development of COVID-19 disease  
Study Design 
Double-blind, randomized clinical trial 
Internet-based trial driven by self-report. 
Study medicine delivered by courier to consented participants. 
Intervention Arms: 
Hydroxychloroquine 200mg tablet.   
1. 400 mg orally once, followed by 400mg 6 to 8 hours later, 
thereafter 400mg weekly for the duration of follow up, up to 
12 weeks 
2. 400mg orally once, followed by 400mg 6 to 8 hours later, 
thereafter 400mg twice weekly for the duration of follow up, 
up to 12 weeks 
Control Arm: 
Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, 
thereafter two tabs weekly or twice weekly for the duration of 
follow up, up to 12 weeks 
Primary Endpoint 
● COVID-19-free survival  
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
9 
 
Secondary 
Endpoints 
1. Incidence of confirmed SARS-CoV-2 detection 
2. Incidence of possible COVID19 symptoms 
3. Incidence of all-cause study medicine discontinuation 
4. Ordinal Scale of COVID-19 Disease maximum severity if 
COVID-19 diagnosed 
5. Incidence of Hospitalization for COVID-19 or death 
6. Incidence of study medication-related side effects  
Duration of 
Participation 
●       Recruitment and follow up will be internet-based. 
        
All patients will be followed for at least 4 weeks. Recruitment is 
expected to take 4 weeks, for a total study duration of 8 weeks. 
But the total study duration will depend on the actual rate of 
enrollment. Study drug will be given for a maximum of 12 weeks.  
Inclusion Criteria 
●       Healthcare worker, at high risk of COVID-19 exposure: 
● Persons primarily working in emergency 
departments (physicians, nurses, ancillary staff, 
triage personnel) 
● Persons primarily working in intensive care units 
(physicians, nurses, ancillary staff, respiratory 
therapists)  
● Persons performing aerosol generating procedures: 
ex. Anesthesiologists, nurse anesthetists (CRNAs) 
● First responders: ex. EMTs, paramedics 
●       Age >=18 years of age 
●       Provision of Informed Consent 
Exclusion Criteria 
●    Active COVID-19 disease 
● Confirmed prior COVID-19 disease 
●    Current fever, cough, shortness of breath 
●       Contraindication or allergy to chloroquine or 
hydroxychloroquine 
●       Prior retinal eye disease 
●       Known Chronic Kidney disease, Stage 4 or 5 or dialysis. 
●       Known glucose-6 phosphate dehydrogenase (G-6-PD) 
deficiency. 
●       Weight <40 kg 
●       Current use of hydroxychloroquine or cardiac medicines of 
flecainide, amiodarone, digoxin, procainamide, or 
propafenone 
●       Current use of medications with known significant drug-drug 
interactions: artemether, lumefantrine, mefloquine, 
tamoxifen, or methotrexate. 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
10 
 
Statistical 
Assumptions 
● 10% transmission rate for high-risk healthcare workers with 
no treatment 
 
● Alpha = 0.025 (to account for two treatment groups vs. 
placebo comparisons) 
● Assuming 15% lost to follow up in the placebo group and 5% 
lost to follow up in each treatment group 
● N=3500 has   80% power to detect a hazard ratio of 0.65, 
using a two-sided log-rank test 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
11 
 
Schematic of Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At the close of the study, any participant with ongoing illness will continue 
to be assessed for up to a total of 90 days after the common closing date.  
 
 
 
 
Potential participants screened by internet-based 
questionnaire. Internet-based informed consent obtained. 
 
Screening 
Randomization 
Day 0 
 
Intervention 
Arm 1 
Intervention 
Arm 2 
Placebo 
 
Hydroxychloroquine 
weekly 
Hydroxychloroquine 
twice weekly 
 
Placebo  
weekly 
Or twice weekly 
 
 
 
Weekly clinical assessment 
Assessment of final outcome measures 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
12 
 
1 
KEY ROLES 
Principal Investigator:  Radha Rajasingham MD 
Co-Investigator: Sarah Lofgren, MD 
Co-Investigator: David R. Boulware MD, MPH 
Co-Investigator: Archana Bhaskaran 
Co-Investigator: Akram Khan, MD 
Co-Investigator: Matthew Pullen, MD 
Co-Investigator: Bryan Wolf, MD 
Co-Investigator: Caleb Skipper, MD 
Co-Investigator: Peter Li, MD 
Pharmacologist: Melanie Nicol, PharmD, PhD 
Co-Investigator: Ingrid Mayer, MD 
Biostatistician: Kathy H Hullsiek, PhD 
Co-Investigator: Justin Balko, PharmD, PhD 
Associate Statistician: Ananta Bangdiwala, MS 
Co-Investigator: Brian Rini, MD 
Associate Statistician: Nicole Engen, MS 
 
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
13 
 
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 COVID-19. 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 for self-quarantine. Having an effective pre-exposure 
prophylaxis for healthcare workers at high risk of contracting COVID-19, 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.2 
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-CoV2.3 Hydroxychloroquine is functionally equivalent as chloroquine.   
Another compound under treatment trials, remdesivir (Gilead) had an EC50 of 0.77 μM.3  
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. 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
14 
 
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.4  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.”4 
Figure 2. Post-infection chloroquine treatment reduces SARS-CoV. 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
15 
 
 
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.”4 
  
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. 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
16 
 
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.5 
 
In a March 9, 2020 publication, 
hydroxychloroquine was found to have greater activity 
than chloroquine.6 The SARS-CoV-2 EC 50 values for 
hydroxychloroquine were 6.14 μM at 24 hours and 
0.72 μM at 48 hours.6 Conversely, chloroquine EC50 
values were >100 μM at 24 hours and 18.01 μM at 48 
hours.6 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.6  
In a March 18, 2020 publication, 
hydroxychloroquine was found to be less toxic than 
chloroquine with slightly lower, but similar potency.7 
At MOI of 0.01, 0.02, 0.2, and 0.8, the EC50 of 
hydroxychloroquine was 4.51, 4.06, 17.31, and 12.96 μM respectively compared to 2.71, 3.81, 
7.14, and 7.36 μM for chloroquine.  
On March 20, 2020, a clinical study from France reported improved viral clearance in 20 
patients treated with 600 mg per day of hydroxychloroquine for 6 days compared to 16 controls.8 
By 6 days, 70% of those in the hydroxychloroquine group had negative viral PCR on 
nasopharyngeal swab compared to 13% in the control group. However, the authors noted an 
additional 6 subjects on hydroxychloroquine that were removed from the analysis because they 
did not complete therapy- 5 of these were still viral PCR positive at the time of drop-out. Without 
an adequately powered, randomized clinical trial, the efficacy of hydroxychloroquine against 
COVID-19 disease remains to be seen but these data are encouraging in regards to a potential 
antiviral effect.  
 
2.2 
Rationale 
The current standard of care is observation and quarantine after exposure to COVID-19.  There 
is no approved treatment or prophylaxis for COVID-19.  
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%).9 Among all close contacts, the SARS-


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
17 
 
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 COVID-19 disease or reduce disease severity. It is not known at what dosing 
hydroxychloroquine may be effective for pre-exposure prophylaxis.  
We propose to dose for SARS-CoV-2 pre-exposure prophylaxis at: 
1. 400mg once weekly (with a loading dose) 
2. 400mg twice weekly (with a loading dose) 
 
Study recruitment is expected to take 4 weeks, and all participants will be followed for a 
minimum of 4 weeks. If study recruitment is slower than anticipated, the study medications will 
be given for a maximum of 12 weeks.  
 
The projected levels achieved will be approximately 0.72 uM which is at the half-maximal 
effective concentration (EC50) where 50% viral inhibition would occur.  Given chloroquine’s and 
hydroxychloroquine’s long half-time, a steady-state concentration may take days to achieve.   
Thereby, a loading dose may be necessary as seen in emergency prophylactic use of 
hydroxychloroquine or chloroquine for anti-malarial purposes.4  
If hydroxychloroquine does not prevent disease for some, it may reduce COVID-19 disease 
severity. Attenuated disease may, in turn, be associated with reduced rates of transmission. 
2.3 
Potential Risks and Benefits 
2.3.1  Potential Risks 
The 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; 
● 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.  
Long-term use of hydroxychloroquine at its accepted prophylactic dose is also well-
tolerated.  


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
18 
 
In our recent post-exposure study of hydroxychloroquine, where hydroxychloroquine is 
given at high dose (800mg) daily for 5 days, 70% of participants reported no side effects. 
The most common side effects, reported in ~30% of participants were GI-related 
symptoms such as nausea or vomiting.  
 
In this study, we are using lower dose (400mg) weekly or twice weekly. We expect even 
fewer side effects, if any.  
 
● 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. 
Furthermore, based on the recommendation by the American Academy of 
Ophthalmology, screening for retinopathy is warranted with dosing higher than 
5 mg/kg/day. The proposed dosing in this trial is order of magnitudes lower. 
○ 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. 
○ Allergic Reactions: Urticaria, angioedema, and bronchospasm have been 
reported 
○ CNS 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. 
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-CoV-2 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). 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
19 
 
● 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. 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
20 
 
3 
OBJECTIVES 
3.1 
Study Objectives 
To determine if pre-exposure prophylaxis with hydroxychloroquine is effective at 
prevention of COVID-19 disease. 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measure 
● COVID-19-free survival  
 
3.2.2 Secondary Outcome Measures 
● Incidence of confirmed SARS-CoV-2 detection 
● Incidence of symptoms compatible with COVID19 (possible disease) 
● Incidence of all-cause study medicine discontinuation or withdrawal 
● Ordinal Scale of COVID-19 Disease Severity (for those who develop 
COVID-19) 
○ No illness 
○ Illness with outpatient observation 
○ Hospitalization (or post-hospital discharge) 
○ Hospitalization with ICU stay or death 
● Incidence of hospitalization or death 
● Self-reported adherence 
● Self-reported study medication side effects 
 
 
Primary outcome of COVID-19-free survival will be confirmed by positive test. 
Assessment of other outcome measures will be primarily by self-report.  As necessary, COVID-
19 disease will be verified from public health records, medical records, or death certificates.  
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
21 
 
4 
STUDY DESIGN 
 
 
4.1 DESIGN 
Randomized, double-blind clinical trial, parallel design. This is an event-driven trial. 
Subjects will be followed until study termination. Study drug will be prescribed for up to 
12 weeks.  
4.2 
Study participant duration 
● Weekly internet-based virtual visits for the duration of follow up 
● Study drug is prescribed to be taken for up to 12 weeks 
● For participants ill with COVID-19 disease at the common closing date for the 
study, observational follow up will extend to up to 90 days after the common 
closing date to assess final outcome status. 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
22 
 
● Pregnant women have their fetal outcome assessed post-partum.  
4.3 
Study procedures 
4.3.1 Screening 
● Baseline screening for eligibility via self-administered questionnaire 
● Informed consent 
 
4.3.2 Randomization 
● Participants will be randomized at the investigation pharmacy 
● The investigational pharmacy will dispense masked study medicine 
(hydroxychloroquine or placebo)  
● The study medicine will be shipped to participants to arrive ~1 day after 
enrollment 
 
4.3.3 Day 1 Virtual visit 
● Verify receipt of study medicine 
● Clinical status check-in 
● Begins taking study medicine (2 tabs), then 2 tabs in 6-8 hours 
● Query for symptom status 
● Query for hospitalization or SAEs 
 
4.3.4 Weekly Virtual visit 
● Clinical status check-in for COVID-19 symptoms 
● Assessment of adherence and side effects by self-report 
● Continue study medicine up to 12 weeks 
● Query for study medicine side effects since enrollment 
● Query for SARS-CoV-2 testing 
● Query for hospitalization or SAEs 
 
4.3.5 Study termination virtual visit (to be completed on or shortly after the 
common closing date for the study) 
● Clinical status check-in for COVID-19 symptoms 
● Query for study medicine adherence and side effects since enrollment 
● Query for SARS-CoV-2 testing 
● Query for hospitalization or SAEs 
● Query for pregnancy status 
● Final outcome assessment 
 
4.4 
Individually identifiable health information: Name, date of birth, 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. 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
23 
 
4.5 
Sub studies  
Participants in Minneapolis, MN, Portland, OR, and Nashville TN, will have the 
opportunity to participate in an optional sub-study evaluating peripheral blood 
correlatives. Please see full details in Appendix A.  
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
24 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
Participants will undergo screening via internet-based google forms. The screening and 
inclusion criteria will be based on self-report.  
 
5.1 
Subject Inclusion Criteria 
● A healthcare worker at high risk for COVID-19 exposure (defined below)  
● >= 18 years of age 
● Provision of informed consent 
5.2 
Subject Exclusion Criteria 
●    Active COVID-19 disease 
● Confirmed prior COVID-19 disease 
●    Current fever, cough, shortness of breath 
●       Contraindication or allergy to chloroquine or hydroxychloroquine 
●       Prior retinal eye disease 
●       Known Chronic Kidney disease, Stage 4 or 5 or dialysis. 
●       Known glucose-6 phosphate dehydrogenase (G-6-PD) deficiency. 
●       Weight <40 kg 
●       Current use of hydroxychloroquine or cardiac medicines of flecainide, amiodarone, digoxin, 
procainamide, or propafenone 
●       Current use of medications with known significant drug-drug interactions: 
artemether, lumefantrine, mefloquine, tamoxifen or methotrexate. 
 
Rationale for inclusion / exclusion criteria:  
Healthcare workers at high risk for COVID-19 exposures include: 
● Persons primarily working in emergency departments (physicians, nurses, 
ancillary staff, triage personnel) 
● Persons primarily working in intensive care units (physicians, nurses, ancillary 
staff, respiratory therapists)  
● Persons performing aerosol generating procedures: ex. Anesthesiologists, nurse 
anesthetists (CRNAs) 
● First responders: ex. EMTs, paramedics 
 
In clinical practice of tropical medicine, chloroquine or hydroxychloroquine are 
prescribed without any baseline laboratory testing or monitoring.   
Age criteria are meant to increase the propensity to follow up and minimize dropouts. 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
25 
 
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. 
 
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.  
5.3.2 Masking Procedures 
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. 
5.3.3 Reasons for Withdrawal 
Participants may withdraw at any time point at their discretion.   
5.3.4 Handling of Withdrawals 
Withdraws will be counted as failures for the secondary endpoint of completion of 
study medication.  
5.3.5 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 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
26 
 
● 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. 
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 Investigational Drug Services.   
Dispensed medications will be delivered by courier (e.g. FedEx) to study 
participants. 
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.[5,7]  
● 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 trough concentrations for 400mg twice-weekly dosing is 
expected to be above 0.72 μM, which is above the EC50 of viral inhibition. 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
27 
 
 
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 
 
6.2.1 Drug/Device Handling: Hydroxychloroquine or placebo will be dispensed by 
the investigational Pharmacy.  To do so, study investigators will send a 
prescription to the Pharmacy, the pharmacy will randomize the subject, and 
dispense the appropriate study medicine. The medicine will then be provided 
to research volunteers via courier delivery in the United States. 
6.3 
Modification of Investigational Product for a Participant 
With mild side effects, participants may be instructed to split the 2 tablet weekly dosing 
into multiple times on the same day (for example, one tablet in the morning, followed by 
one tablet at night). 
In the event of substantial side effects, participants may discontinue the study 
medication. 
In the event of the development of acute kidney injury with creatinine clearance <30 
mL/min, the dose should be reduced by half.  
6.4 
Accountability Procedures for the Investigational Product: 
 
Accountability will be via self-report at weekly virtual visits. 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
28 
 
6.5 
Assessment of Subject Compliance 
Adherence will be via self-report at weekly virtual visits.  
6.6 
Concomitant Medications/Treatments 
Participants may receive other concomitant medications or therapies and will be asked 
to report these. 
 
 
 
Study Schedule 
 
 
 
 
Screen 
 
Person emails covid19prep@umn.edu 
Auto-Response sends Study Info Sheet 
URL links to Screening eCRF 
 
Consent 
 
Screening for Inclusion/Exclusion  
If eligible -> Informed Consent Form 
Assessment of Comprehension 
Signing online consent form
 
Randomize 
 
Prescription order sent to Pharmacy 
Pharmacy Randomizes Subject 
Study Staff to courier Study Medicine 
 
Day +1 
 
Email with URL to eCRF to verify: 
Receipt of med 
Symptom status  
 
Weekly 
 
Email with URL link to eCRF to verify: 
Symptom status; testing status 
Hospitalization status; medication side effects  
Assess medication adherence 
 
Termination 
 
Email with URL link to eCRF to verify: 
Symptom status; testing status 
Hospitalization status; medication side effects, adherence 
Inquiry if future contact for research?  


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
29 
 
 
 
 
 
 
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
30 
 
 
6.7 
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. 
6.8 
Enrollment/Baseline 
6.8.1 Randomization (Day 0) 
● Participants will be randomized by a computer-generated algorithm using 
a permuted block randomization sequence 
● Investigational pharmacy will dispense the masked study medicine (12 
week supply) 
● Study personnel will then courier study medicine to the participant 
● Participant will be sent an email to expect the medication to arrive the 
following day 
6.9 
Follow-up  
● Day 1 Visit 
○ Participant will confirm receipt of study medication  
 
● Weekly visits  
○ Participant clinical status check-in 
○ Assess adherence to study medication and side effects 
6.10 Final Study Visit 
● Participant clinical status check-in 
● Assess adherence to study medicine 
 
6.11 Early Termination Visit 
If participants develop symptoms of coronavirus, they will be directed to their healthcare 
provider and/or local public health authority. We request to follow up hospitalized 
healthcare workers with suspected COVID-19 up to 90 days beyond the closing date to 
assess final outcomes.  


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
31 
 
6.12 Unscheduled Visit  
Subjects will be provided a central email contact: faq.covid19prep@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.  
Additionally, email communications will contain a URL for a sick visit web-form that 
participants can note their current development of symptoms of medication side effects.  
This will be the same follow-up eCRF sent on weekly visits.  This can be completed 
multiple times.  
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
32 
 
7 
STUDY PROCEDURES/EVALUATIONS 
7.1 
Clinical Evaluations 
Clinical evaluations will be by self-report. 
7.2 
Laboratory Evaluations 
There are no laboratory evaluations in the protocol. There is an opportunity for participants to 
participate in an optional lab-based sub-study. Details in Appendix A.  
Clinical outcomes are by self-report.   
SARS-COV2 positivity is by self-report.  
Informed consent will request permission to contact local public health authorities or their 
medical provider in the event of loss to follow up or COVID-19 disease. Public health 
authorities or medical providers may verify confirmatory laboratory results.  
There is no incentive to be dishonest, and we believe healthcare workers in particular 
will take their responsibilities seriously.  
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
33 
 
8 
ASSESSMENT OF SAFETY 
8.1 
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.  
8.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
8.2.1 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 as COVID19-related disease events which may include the need for hospitalization, 
pneumonia, respiratory failure, sepsis, and death.  
8.2.2 Reactogenicity (for Vaccine Studies and Some Therapeutic Trials) 
Not applicable  
8.2.3 Serious Adverse Events 
Hospitalization or death are protocol-defined endpoints. 
8.2.4 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
Not applicable 
8.3 
Reporting Procedures 
8.3.1 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:  


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
34 
 
● Death, 
● a life-threatening adverse event (as below),  
● hospitalization, 
● a 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, be life-threatening or require 
hospitalizations may be considered serious when based upon appropriate medical 
judgment they may jeopardize the participant 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 event. An AE is considered “life-threatening” if, in the view of either the 
site principal investigator or sponsor, its occurrence places the 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.  COVID-19 disease may indeed be 
teratogenic. For women who are pregnant, we will ask to follow them through the end of 
their pregnancy.  
 
Thus the hospitalization or death secondary endpoint will capture relevant SAEs. 
 
8.3.2 Regulatory Reporting  
As hydroxychloroquine is an FDA-approved medicine being used at standard dosing for 
malaria prophylaxis, reporting to regulatory authorities will occur in summary format after 
each DSMB reports and at a frequency of at least annually.  
Serious unexpected suspected adverse reactions (SUSARs) which are not expected 
with COVID19 nor listed in the FDA package insert will be reported to the IRB.  


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
35 
 
Those SUSARS which are deemed by an independent medical monitor to be related to 
the study medication will be reported to the FDA and IRB. 
 
8.3.3 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 could represent 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 until the end of their 
pregnancy to assess the outcome of the pregnancy via a brief survey.  
8.4 
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 
after the common closing date, to assess their final outcome.  Management will be as 
per the participant’s local healthcare provider. 
8.5 
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.  
9 
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 the 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 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
36 
 
that any critical study procedures are completed following specific instructions. 
Monitoring will be the responsibility of the University of Minnesota. 
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
37 
 
10 
STATISTICAL CONSIDERATIONS 
10.1 Study Hypotheses 
We hypothesize that Hydroxychloroquine is superior to placebo for preventing COVID-19 
disease. We hypothesize, that if COVID-19 develops while a person is taking 
hydroxychloroquine prophylaxis, then the COVID-19 disease would be less severe.  
10.2 Sample Size Considerations 
The planned sample size is up to 3500 participants.  There will be two comparisons:  treatment 
once weekly compared to placebo, and treatment twice weekly compared to placebo.  With 
1165 participants in each of the two treatment groups and in one placebo group, a two-sided 
log-rank test achieves 80% power at alpha = 0.025 significance level to detect a hazard ratio of 
0.65 when COVID-19 free survival is 90% in the placebo group.   
The study is powered at alpha = 0.025 to account for the two treatment versus placebo 
comparisons.  The two treatment groups will be compared to the same placebo group.  
Assumed loss to follow-up is 5% in the treatment groups and 15% in the placebo group.  With 
3500 participants approximately 310 COVID-19 or death events are anticipated.  
Sample Size Re-estimation: 
At the time of the second DSMB review, a sample size re-estimation will occur based on the 
disease transmission rate in the control group.  The conservative a priori assumption (based on 
limited data) is 10% transmission risk.  The table below shows that if the transmission rate is 8% 
(lower than assumed) then the sample size would need to be increased to a total of 4353 
participants.  On the other hand, if the transmission rate is greater than the assumed 10% then 
the sample size can be decreased. 
 
 
 
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
38 
 
Sample size requirements to detect a hazard ratio of 0.65 based on COVID19 
transmission rates without treatment (assuming 80% power, alpha = 0.025, 15% loss to 
follow-up in the placebo group and 5% loss to follow-up in the treatment groups) 
COVID 19 Transmission 
Rate Without Treatment 
Number Per Group 
Total Sample Size 
(3 Groups) 
8% 
1451 
4353 
10% 
1163 
3489 
12% 
971 
2913 
15% 
778 
2334 
18% 
650 
1950 
20% 
580 
1740 
 
10.3 Planned Interim Analyses 
Interim analyses will focus on the statistical testing of the primary endpoint with 
descriptive reporting of the secondary endpoints as well. Interim analyses will be 
conducted after enrollment of approximately: 25%, 50%, 75%, and 100% of participants 
are enrolled. This interval may be modified by the DSMB.  
A Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be used 
for the outcome of COVID-19-free survival. The provided table assumes four interim 
analyses with the final analysis with an overall alpha=0.025. The boundaries are 
truncated at |Z| = 3.01. 
  
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
39 
 
Interim Analysis 
Sample Size 
| Z | 
P-value 
1 
~875 (25%) 
> 3.1 
.0019 
2 
~1750   (50%) 
> 3.1 
.0036 
3 
~2625   (75%) 
> 2.78 
.0179 
Final 
3500 (100%) 
> 2.30 
.025 
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. In the event of early halting due to efficacy, the study will immediately convert 
to an open-label observational cohort of hydroxychloroquine prescribed to all consented 
participants. 
Based on the public health situation, the DSMB has the prerogative to alter the stopping rules. 
Futility Analysis: 
If the conditional power is <20% at the time of the second interim analysis with approximately 
50% of participants enrolled, discontinuation should be considered as a possible 
recommendation by the DSMB. The sample size re-estimation will be considered here as well 
as the pace of enrollment.   
10.4 Final Analysis Plan 
We will assessCOVID-19-free survival in high-risk healthcare workers who receive 
hydroxychloroquine compared to those who receive placebo. 
We will compare survival in a time-to-event analysis for COVID-19-free survival using Log-rank 
test with survival displayed as a Kaplan-Meier curve. Analysis will be intention-to-treat. Persons 
who develop confirmed COVID-19 or die will be considered failures. Persons lost to follow up 
will be censored. 
Secondary endpoints for incidence will be assessed via Fisher’s Exact test for the proportions 
by study arm. The secondary endpoint on the ordinal scale will be assessed with a proportional 
odds model.  


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
40 
 
Among those with symptoms, severity of symptoms (recorded on a 0-10 visual analog scale) will 
be compared via Mann-Whitney U by study arm. 
A priori subgroup analyses will include assessment by: 
● 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, will be separately analyzed and reported.  
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
41 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
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 may cause delays, 
compliance issues, and public health concerns. The internet-based design allows us to rapidly 
enroll participants across the country, in the setting of a public health emergency.  
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.  
12 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study medications will be FDA-approved following Good Manufacturing Practice. 
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
42 
 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1 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. 
13.2 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.  
13.3 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.covid19prep@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 (2 different doses) or vitamin 
placebo 
○ Whether hydroxychloroquine is known to be effective in preventing disease 
○ Duration of the study? (90 days) 
○ Duration of taking the study medicine (12 weeks) 
○ When follow up surveys will be sent (Days 1, weekly) 
○ If hydroxychloroquine can be shared? (No) 
13.3.1 Informed Consent/Assent Process (in Case of a Minor) 
● Persons under 18 years of age are not eligible to participate. COVID19 has 0% 
mortality in children, and rate of progression to symptomatic disease may likely 
be different. Furthermore, pediatric dosing is weight-based, making remote 
administration more complicated.  


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
43 
 
13.4 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. 
13.5 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 
the 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 the 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. 
13.6 Future Use of Stored Specimens 
● No specimens are to be collected.  
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
44 
 
14 
DATA HANDLING AND RECORD-KEEPING 
14.1 Data Management Responsibilities 
Investigators will maintain a REDCAP database of study records.  
Survey forms will be self-completed by study participants.  
14.2 Data Capture Methods 
● Data will be obtained via internet-based REDCAP forms. 
14.3 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. 
14.4 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 450 
participants complete 90 days of follow-up. 
● De-identified data will be shared with the research team members for analysis. 
14.5 Study Records Retention 
● No paper documents will be retained or stored. 
● Digital records will be kept in a secure server setting. 
14.6 Protocol Deviations 
Protocol violations will be reported to the IRB of record.  
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
45 
 
15 
PUBLICATION POLICY 
Publication will be expeditiously made with a full, de-identified data made available. 
 
16 
LITERATURE REFERENCES 
1. 
Lauer SA, Grantz KH, Bi Q, et al. The Incubation Period of Coronavirus Disease 2019 
(COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Annals of 
internal medicine 2020. 
2. 
Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in 
China. The New England journal of medicine 2020. 
3. 
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the 
recently emerged novel coronavirus (2019-nCoV) in vitro. Cell research 2020; 30(3): 269-71. 
4. 
Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS 
coronavirus infection and spread. Virology journal 2005; 2: 69. 
5. 
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(3): 
e0194868. 
6. 
Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized 
Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2). Clinical infectious diseases : an official publication of the 
Infectious Diseases Society of America 2020. 
7. 
Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is 
effective in inhibiting SARS-CoV-2 infection in vitro. Cell discovery 2020; 6: 16. 
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. International 
journal of antimicrobial agents 2020: 105949. 
9. 
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 Morbidity 
and mortality weekly report 2020; 69(9): 245-6. 
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
46 
 
Appendix A: Sub study 
 Sub study 
Title 
Pre-exposure Prophylaxis for SARS-Coronavirus-2: A Pragmatic 
Randomized Clinical Trial: A sub-study of peripheral blood correlatives 
Objectives 
This is a sub study for correlative sample collection of blood to evaluate: 
1)    Circulating antibody (IgG or IgM) presence specific for COVID-19 
virus protein at baseline 
a.    This is determined by ELISA from serum or plasma using baseline 
samples 
2)    Seroconversion from IgG/IgM negative-to-positive during the 
treatment period 
a.    This is determined by ELISA from serum or plasma using baseline 
samples and end-of-study samples 
3)    Evaluation of HLA-types and germline factors associated with 
outcomes. 
a.    This is determined by Illumina MEGAEX 6 million SNP array or 
targeted next generation sequencing of HLA alleles, or other 
germline DNA testing.  
Blood 
Collection 
Schedule 
Baseline (within 3 days of starting hydroxychloroquine) 
Study termination or at positive test for SARS-CoV2 
Number of 
Participants 
300 
Duration of 
Study 
Up to ~ 100 days 
  
Background:  
Due to the nature of COVID-19 infection, which is often asymptomatic in many 
individuals, it is conceivable that some population of enrollees in the parent trial “Pre-
exposure Prophylaxis for SARS-Coronavirus-2: A Pragmatic Randomized Clinical Trial”, 
may have already been exposed and recovered.  Due to the pragmatic and emergent 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
47 
 
nature of the trial, participants for primary prophylaxis, the absolute nature of prior 
exposure cannot be determined in real time, or across all participants in the trial. 
The purpose of this sub study is to allow for optional enrollment for collection of 
peripheral blood in health care workers at academic institutions with capabilities to 
collect and process peripheral blood.  The peripheral blood will be used to accomplish 
several objectives. First, it will allow for post-hoc analyses that can determine which 
participants enrolled in the sub arm have had prior exposure through assessment of IgG 
and IgM antibodies specific to COVID-19 viral proteins. Emerging literature suggests that 
exposed and recovered patients or individuals develop persistent antibodies that can be 
detected in serum or plasma. Thus, participants with prior exposure (i.e. had presence of 
antibodies at baseline) can be excluded in secondary efficacy analyses. Secondly, end-
of-study collection will allow for definitive assessment of the percentage of healthcare 
workers who seroconvert (i.e. negative at baseline, and positive at end-of-study) during 
the trial period in both dosing arms and the comparable placebo arms. Finally, 
preservation of buffy coat (white blood cells) will serve as a source of DNA and RNA that 
can be used for subsequent host-derived factors that contribute to drug efficacy or 
exposure/seroconversion rates. 
OBJECTIVES 
In participants from the PREP COVID-19 parent protocol, who choose to participate in this sub 
study, we will evaluate: 
Objective 1: Circulating antibody (IgG or IgM) presence specific for COVID-19 virus protein at 
baseline 
Endpoint 1: ELISA from serum or plasma using baseline samples 
Objective 2: Seroconversion from IgG/IgM negative-to-positive during the treatment period 
       
Endpoint 2: ELISA from serum or plasma using baseline samples and end-of-study samples 
Objective 3: Evaluation of HLA-types and germline factors associated with outcomes 
Endpoint 3: llumina MEGAEX 6 million SNP array or targeted next generation sequencing of HLA 
alleles, or other germline DNA testing 
 
 
 
 
 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
48 
 
STUDY CALENDAR 
Parameter 
Pre-Treatment 
End of 
Treatment 
 
 
Demographics 
X 
  
 
Blood collection 
  
X 
 
 Note:  The sample collection schedules outlined above are based on an ideal subject. The 
sample schedule should be followed as closely as is realistically possible; however, the schedule 
may be modified (± 4 business days) due to problems such as scheduling delays or conflicts (e.g., 
clinic closure, poor weather conditions, vacations, etc.).  
1.    Within 4 days prior to starting study drug, unless otherwise noted. 
2.    At the end of 90 days of study drug as per parent protocol or at positive test for SARS-
CoV2 
3.    One 10 mL EDTA tube (lavender top) 
STORAGE AND SUPPLY 
EDTA tubes (lavender top): Institutional own supplies will be utilized, kits will not be shipped to 
participating sites 
Collected/ Processed/ Aliquoted Sample Storage 
For ALL peripheral blood specimens collected, processed, and aliquoted: 
Samples should be stored at -80C and shipped or transferred below on dry ice.  Samples should 
be removed from -80C storage and placed directly in a dry ice-containing shipper with suitable 
volume of dry ice for overnight transport, taking special care in summer/warm months. 
If shipment is not required (e.g. collected and processed at VUMC), samples can be batch 
couriered or transferred weekly to the Balko lab. 
  
Blood Samples 


PREP COVID-19 
Version 1.0 
 
27 March 2020 
 
 
49 
 
Tubes should be packed according to the Lab manual and sent immediately (within 24 h). 
Peripheral blood will be collected in participants prior to initiating hydroxychloroquine under the 
parent protocol guidelines, and at the end of treatment (90 days or at positive test for SARS-
CoV2.  The molecular correlates for each biological sample/time point are listed below. 
  
Tube 
Amount 
Baseline (within 3 
days of enrollment) 
End of study (end of 90 days or at 
positive test for SARS-CoV2) 
EDTA tube 
(lavender top) 
10mL 
(1x10mL) 
X 
X 
  
Sample Source 
Test 
Needs immediate 
specialized processing 
Needs immediate 
shipping 
Buffycoat 
RNA and DNA 
extraction 
YES 
NO 
Plasma 
ELISA for COVID-19 
IgG and IgM 
STATISTICAL CONSIDERATIONS 
Correlative analyses will be compared to clinical endpoints on the parent protocol, particularly the 
primary endpoint of seroconversion during the treatment period. These exploratory analyses will 
be performed using the baseline and end of treatment blood collections, and are primarily 
descriptive in nature. 
Correlative analyses endpoints will be categorized as dichotomous variables. In exploratory 
analyses, patients will be stratified by clinical response (i.e. lack of seroconversion) to determine 
if the change in endpoint is associated with patient-specific clinical benefit from treatment. 
 

ICF_001.pdf: 
Version Date: 1 April 2020 
Page 1 of 10 
Title of Research Study: Post-exposure Prophylaxis 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:  Radha Rajasingham, 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:  
FAQ.covid19prep@gmail.com  
Supported By: This research is supported by the University of Minnesota, 
Oregon Health & Science University, and Vanderbilt University. 
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 you are a healthcare worker 
at risk of being exposed to someone with SARS coronavirus 2 who has COVID-19 
disease.  
NCT04328467 


Version Date: 1 April 2020 
Page 2 of 10 
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.  
 
Why is this research being done? 
The primary purpose of this research is to determine whether a medication can be given to 
prevent COVID-19 disease in healthcare workers at high risk of being exposed to the virus.  
The concept is called “pre-exposure prophylaxis” — a method where medication is given to 
prevent an infectious disease before contact with another infected person.  This strategy 
has proven useful for diseases like HIV. 
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 the first 
proposed to try to prevent disease in healthcare workers at high risk for exposure to 
COVID-19. 
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 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 followed for at least 4 weeks after you enroll, and up to 12 
weeks. If you develop symptoms of COVID-19, 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 
priority mail to be received tomorrow.  You will need to take the drug as prescribed, for up 
to 12 weeks.  We will send you a brief weekly internet-based survey about any COVID-19 
symptoms or hospitalizations that you experienced. These weekly surveys will take 
approximately two minutes to complete. No blood sample collections or visits to the 
doctor’s office are required.   You will need to: 
● Take the study medicine for up to 12 weeks.  
o The first day you will take 2 tablets by mouth, then 6-8 hours later 
take 2 tablets, then  


Version Date: 1 April 2020 
Page 3 of 10 
o Take 2 tablets once or twice weekly depending on your treatment 
assignment for up to 12 weeks 
The hydroxychloroquine dose is similar to what is given for malaria treatment.  
● 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 Weekly (to ask if you have become ill or been hospitalized) 
 
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 50 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.  The short duration of 
hydroxychloroquine use in our study should also reduce the chance of an adverse event. 
Aside from possible medication side effects, there are no direct harms of this internet 
based study.  As there is no known way to prevent COVID-19 disease, there are no 
standard medicines that other people are receiving.  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.  However, after you complete the trial, the 
medication will be stopped, so any benefit it was providing will be lost.  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)” 
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 


Version Date: 1 April 2020 
Page 4 of 10 
treatment trial that was ongoing at a hospital.  
 
Detailed Information About This Research Study 
The following is more detailed information about this study in addition to the information 
listed above. 
How many people will be studied? 
We expect up to 3500 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 once or twice weekly.  Once assigned, the medication will be sent by 
priority mail overnight to you.  You are to start the medication as soon as you receive it.  
Then you will fill out a survey every week collecting any symptoms, diagnoses, or 
hospitalization events 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 a 67% chance (2/3) of being given either treatment, and 33% chance (1/3) of 
receiving placebo.  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.  We will send you a brief questionnaire on:  
● Tomorrow (Day 1) 
● Every week until the study ends 
● If you get sick or have side effects, you may complete the questionnaire additionally 
as needed 
 
If you do become ill with COVID-19 symptoms, you will go through routine health 
procedures (i.e., contact your doctor 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 doctor. 
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  
2. Take your medication as prescribed  
3. Fill out online questionnaires 
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. 
 


Version Date: 1 April 2020 
Page 5 of 10 
We will make sure that you stop the study safely.  We will also talk to you about follow-up 
care, if needed.    
 
If you stop participating in the research study, information about you that has already been 
collected may not be removed from the study database.  
 
 
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, and blurred vision.  All these symptoms 
should resolve once the drug is stopped.   
● 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.  These 
include vision damage, heart rhythm problems, low blood sugar, and muscle 
weakness.  Persons with psoriasis may experience temporary skin worsening while 
taking the medication.   
● Persons with a previous allergy to chloroquine or hydroxychloroquine should avoid 
the drug. 
● Persons with Glucose-6-phosphate deficiency (G6PD) may have increased risk of 
hemolytic anemia when taking hydroxychloroquine.   
● 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).   
● 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 include: 
● 
Flecainide (Tambocor) 
● 
Procainimide (Procan) 
● 
Propafenone (Rythmol) 
● 
Amiodarone (Cordarone, Pacerone) 
● 
Quinidine  
● 
Digoxin (Lanoxin) 
 
● Some persons will receive a vitamin instead of hydroxychloroquine.  Oral vitamins 
are considered safe, though can occasionally cause upset stomach.  
 
● There is a risk that you may have a bad outcome if you contract 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 security standards to secure your information and 
minimize risks.  


Version Date: 1 April 2020 
Page 6 of 10 
 
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.    
 
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 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 


Version Date: 1 April 2020 
Page 7 of 10 
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 90 days from 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 Human Research Protections, the Office of Research 
Integrity, or government agencies in other countries); and 
 
 
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 


Version Date: 1 April 2020 
Page 8 of 10 
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 
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 


Version Date: 1 April 2020 
Page 9 of 10 
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 https://clinicaltrials.gov/ct2/show/NCT04328467, 
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.   
 
Will I be compensated for my participation?  
 
There is no compensation for study participation. The study medication 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). To share feedback privately with the HRPP about your 
research experience, call the Research Participants’ Advocate Line at 612-625-1650  (Toll 
Free: 1-888-224-8636) or go to z.umn.edu/participants.  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. 
            The research team can be reached by email at: FAQ.covid19prep@gmail.com 
● 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 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 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. 


Version Date: 1 April 2020 
Page 10 of 10 
 
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 symptoms concerning for COVID-19 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