Hydroxychloroquine for Outpatients With Confirmed COVID-19
Phase: PHASE2
Conditions: Coronavirus Infection, Coronavirus, Infectious Disease
Sponsor: University of Utah

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Protocol version 1.6 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
UTAH One (Understanding Treatment And Health in the Ongoing coroNa Epidemic): A 
Hydroxychloroquine Outpatient Study  
 
 
 
Principal Investigators 
 
Adam Spivak, MD 
Assistant Professor of Medicine 
Infectious Diseases 
University of Utah 
 
Rachel Hess, MD, MS 
Professor of Population Health Science and Internal Medicine 
University of Utah 
 
 
 
 
STATEMENT OF COMPLIANCE 
 
 
This study will be carried out in accordance with Good Clinical Practice (GCP) and information 
privacy/security as required by the following: 
 
• 
United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46 (The Common 
Rule) 
• 
International Council on Harmonization (ICH) E6 (R2) 
• 
45 CFR Part 160 and Part 164, Subparts A, C, and E  
 
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 
 
 
 

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KEY ROLES 
 
 
Individuals:  
 
 
 
Principal Investigators:  Adam Spivak, Rachel Hess 
 
Data Coordinating Center Principal Investigators:  Tom Greene, Rich 
Holubkov 
 
Medical Monitor:  Brandon Webb 
 
 
Committees:   
Trial Executive Committee:  Adam Spivak, Rachel Hess, Tom Greene, 
Rich Holubkov, J. Michael Dean, Emily Spivak, Brandon Webb, Samuel 
Brown, Raj Srivastava, Ithan Peltan 
 
Trial Advisory Committee: Willard Dere, Mark Briesacher, Angela Dunn 
 
 
 
 
 
 
 
 

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1.0 
Definitions 
 
Definitions 
 
Eligible patients: All patients who meet all inclusion criteria and no exclusion criterion.  
 
Consented participants: All eligible patients who have completed the consenting process.  
 
Enrolled participants:  All participants who have been randomized. 
 
Intention-to-treat (ITT) Population: All enrolled participants, regardless of whether they 
received study drug or completed study procedures. This is the primary analysis population. 
 
Study day: The calendar day of enrollment (randomization) is study day zero. The next day is 
study day one, and so on.  
 
Assessment day: This corresponds to the survey instrument (day one survey is given on 
assessment day one). 
 
Study Drug Discontinuation: Participant chooses to discontinue study drug, for any reason.  
Other study procedures may continue as decision of participant. 
 
Study withdrawal: Participant discontinues study drug and does not wish to provide further 
study samples or data.  Data recorded up to the time of withdrawal will be included in the study 
analysis. 
 
Serious unexpected suspected adverse event (SUSAR). A serious adverse event or drug 
reaction that is unexpected and believed related to participation in study. 
 
 
 

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2.0 
Study Summary 
 
2.1 
Study title: Hydroxychloroquine for Outpatients with Confirmed COVID-19 (HCQ Trial).  
 
2.2 
Study objectives: Assess the efficacy and safety of hydroxychloroquine (HCQ) for 
reduction of viral shedding and hospitalization in outpatients with confirmed COVID-19.  
 
2.3 
Study hypothesis: Hydroxychloroquine is effective in reducing viral shedding and need 
for hospitalization in outpatients with confirmed COVID-19. 
 
2.4 
Study design: Phase 2, prospective, open-label, parallel group, randomized controlled 
trial 
 
2.5 
Inclusion criteria 
Inclusion Criteria for Randomized Group: 
• 
Patient age ≥18 years, competent to provide consent 
• 
Within 72 hours of positive nucleic acid test for SARS-CoV-2 
 
Inclusion Criteria for Household Contact Group: 
• 
Individual age ≥18 living in the same house as someone diagnosed with COVID, 
competent to provide consent 
 
2.6 
Exclusion criteria 
• 
Patient already prescribed chloroquine or hydroxychloroquine 
• 
Allergy to hydroxychloroquine  
• 
History of bone marrow or solid organ transplant 
• 
Known G6PD deficiency 
• 
Chronic hemodialysis, peritoneal dialysis, continuous renal replacement therapy or 
Glomerular Filtration Rate < 20ml/min/1.73m2 
• 
Known liver disease (e.g. Child Pugh score ≥ B or AST>2 times upper limit) 
• 
Psoriasis 
• 
Porphyria 
• 
Known cardiac conduction delay (QTc > 500mSec) 
• 
Concomitant use of digitalis, flecainide, amiodarone, procainamide, propafenone, or any 
other prescription medication known to prolong the QT interval 
• 
Seizure disorder 
• 
Prisoner 
• 
Weight < 45kg 
• 
Inability to follow-up – no cell phone or no address or not Spanish or English speaking  
• 
Receipt of any experimental treatment for SARS-CoV-2 (off-label, compassionate use, or 
trial related) within the 30 days prior to the time of the screening evaluation 
• 
Patient or another member of patient’s household has been already enrolled in this study. 
• 
History of ventricular arrhythmia 
 
2.7 
Sample size: The study will enroll up to approximately 200 participants in each arm (total 
400 participants).  
 
2.8 
Primary Endpoint:  

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• 
Duration of viral shedding, as defined by time from randomization to the first of two 
consecutive negative swabs, measured on days 1 - 14. 
 
2.9  
Interim Monitoring: 
Formal safety review by Data Safety Monitoring Board (DSMB) after 100, 200, and 300 subjects 
enrolled.  No interim efficacy analyses or monitoring. 
3.0 STUDY DESCRIPTION 
 
3.1 
Background 
COVID-19 is a pandemic illness caused by the SARS-CoV-2 virus and has a high mortality 
among hospitalized patients despite a benign course in the large majority of patients infected. 
Limited data are available from small outpatient studies and have not shown efficacy in 
preventing hospitalization.  Hydroxychloroquine (HCQ) and chloroquine have antiviral and 
immune-modulating effects1, but there are no data concerning their efficacy in reducing viral 
load and shedding in outpatients.   
 
3.1.1 Evidence supporting possible efficacy for hydroxychloroquine.  
In cell models, chloroquine both interferes with terminal glycosylation of the ACE2 receptor (the 
cell surface receptor by which SARS-CoV-2 enters human cells) and increases endosomal pH, 
which interferes (at least in vitro) with a crucial step in viral replication.1,2 HCQ is 5x more potent 
than chloroquine in a Vero cell model of SARS-CoV-2 infection.3 In independent experiments, 
chloroquine has confirmed in vitro activity against SARS-CoV-2.4 Additionally, HCQ has in vitro 
efficacy against SARS-CoV-1.5  According to news releases, an as-yet-unpublished set of case 
series in China (N reportedly 120) suggests the possibility of rapid viral clearance and low rates 
of progression to critical illness. In addition to in vitro anti-viral effects chloroquine and HCQ 
appear to have immune-modulatory effects, especially via suppression of release of TNF and 
IL6, especially in macrophages.1,7-10 
 
3.1.2 Evidence against efficacy for hydroxychloroquine. 
Chloroquine and HCQ have been promoted as extremely broad anti-infective agents for 
decades. The reported effects include suppression of fungi, atypical bacteria, and viruses. Other 
than the effects on ACE2 glycosylation, the mechanisms invoked as evidence for efficacy 
against SARS-CoV-2 have also been invoked for a wide range of viruses. However, when 
chloroquine and HCQ have been studied in humans, neither agent has demonstrated consistent 
efficacy in clinical trials, including in HIV, influenza, hepatitis, and Dengue.11 In one trial, 
chloroquine resulted in increased viral replication in Chikungunya virus [Roques et al, Viruses 
2018 May 17;10(5)] while in another hydroxychloroquine was associated with increased HIV 
viral load [Paton et al, JAMA 2012 Jul 25;308(4):353]. Expert opinion advises against HCQ for 
MERS, another serious coronavirus.12 An underpowered (n=30) study of HCQ in COVID-19 
recently published in China did not demonstrate any clinical benefit [Chen et al, J Zhejiang 
University, 2020 March 9]. The long history of clinical failure despite in vitro anti-viral activity 
suggests a low probability of efficacy. 
 
3.1.3. Rationale for Trial 
There is significant publicity concerning the potential use of HCQ in this pandemic, and many 
patients are seeking access to this unproven therapy. The ANZICS guidelines emphasize that 
novel treatments should be administered within clinical trials; the Surviving Sepsis Campaign 
guidelines (http://bit.ly/SSCCOVID-19) also affirm the lack of evidence to support the clinical use 

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of (hydroxy)chloroquine. WHO guidance 
(https://apps.who.int/iris/bitstream/handle/10665/331446/WHO-2019-nCoV-clinical-2020.4-
eng.pdf) also strongly affirms that “investigational anti-COVID-19 therapeutics should be done 
under ethically approved, randomized, controlled trials.” The evidence thus strongly favors 
equipoise.13  
 
3.2  
Study Design 
Phase 2, prospective, placebo-controlled, parallel group, randomized trial 
 
3.3  
Study Objective 
A novel coronavirus, SARS-CoV-2, is responsible for a rapidly spreading pandemic that has 
reached 160 countries, infecting over 500,000 individuals and killing more than 24,000 people. 
SARS-CoV-2 causes an acute and potentially lethal respiratory illness, known as COVID-19, 
that is threatening to overwhelm health care systems due to a dramatic surge in hospitalized 
and critically ill patients. Patients hospitalized with COVID-19 typically have been symptomatic 
for 5-7 days prior to admission, indicating that there is a window during which an effective 
intervention could significantly alter the course of illness, lessen disease spread, and alleviate 
the stress on hospital resources. 
 
There is no known treatment for COVID-19, though in vitro and one poorly controlled study have 
identified a potential antiviral activity for HCQ. The rationale for this clinical trial is to measure 
the efficacy and safety of hydroxychloroquine for reducing viral load and shedding in adult 
outpatients with confirmed COVID-19. 
 
3.4 
Study Hypothesis 
HCQ is effective in reducing viral shedding in outpatients with confirmed COVID-19.   
 
3.5  Primary endpoint 
• 
Duration of viral shedding, as defined by time from randomization to the first of two 
consecutive negative swabs, measured on days 1 - 14. 
 
3.6 Secondary endpoints 
• 
Average level of select COVID-19-attributable symptoms 
• 
Hospitalization within 14 days of enrollment. 
• 
Persistence of viral shedding on day 28. 
• 
Adult household contact viral acquisition 
 
4.0  
Study population 
Ambulatory patients for whom SARS-CoV-2 testing is obtained at University of Utah testing 
sites after evaluation via telehealth services or  by providers in University affiliated clinical 
facilities.  
 
4.1  
Screening 
Patients undergoing testing for SARS-CoV-2 will be informed of this actively enrolling 
interventional trial and provided with informed consent documentation (hard copy or electronic) 
at the time of testing. Patients will be asked if they would be interested in considering trial 
participation if their test is positive. Investigators will monitor test results of individuals who 
indicate interest in the trial and contact those with positive tests to verify eligibility and provide 
remote informed consent by telephone, electronic consent, or videoconference.  The consenting 

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process will be performed via a consenting mechanism that confirms the identity of the patient, 
provides access to the consent form, and obtains a signature to complete documentation, 
without requiring physical proximity of research staff and the study subject.  The informed 
consent documentation will include HIPAA authorization for access to the medical record. 
 
4.2  
Inclusion and Exclusion Criteria 
See sections 2.5 and 2.6. 
5.0 Study Procedures 
 
5.1 Intake medication review. 
 Prior to randomization, study personnel and/or clinical pharmacists will review medications 
being prescribed for patients on study to confirm eligibility. Study personnel will advise patients 
to contact the study team if any new medications are prescribed during the 5 day treatment 
course so that the medication may be reviewed for risk of prolonging QTc. 
 
5.2 Cardiac review.  
Prior to randomization, study personnel will review if patient has electrocardiograms (ECG) and 
will verify that prolongation of QTc has not been diagnosed clinically or on ECG. 
 
5.3 Randomization.  
After obtaining informed consent, participants will be randomized using variable block sizes 
stratified by patient age group (age ≤ 44, 45-59, 60-74, 75+ years).  The randomization system 
at the Data Coordinating Center will require entry of patient initials, date of birth and sex.  This 
will assure that patients do not attempt to enroll multiple times in order to secure active drug.   
 
5.4 Study drug.  
This is an open label, variable block randomized placebo controlled trial.  If a participant is 
admitted to the hospital at any time during the active treatment period, the clinical team will 
decide whether or not to continue study drug treatment during hospitalization. 
 
Participants randomized to the HCQ arm will receive HCQ 400mg po BID x 1 day, then 200mg 
po BID x 4 days3. The drug dose (2.4 gm over 5 days) falls at the lower end of doses proposed 
in various international trials, but it has proven in vitro efficacy, with a ratio of lung tissue trough 
concentrations to the EC50 (effective concentration to suppress 50% of viral activity) of >20.3   
 
Those randomized to placebo will receive a placebo to be taken on the same schedule. 
 
5.5 Study Assessments.  
Coordinators will obtain baseline information at the time of randomization.  This will include 
review of all medications being prescribed for patients on study. Study personnel will advise 
patients to contact the study team if any new medications are prescribed during the 5 day 
treatment course so that the medication may be reviewed for risk of prolonging QTc, or having a 
drug interaction with HCQ (see Appendix 3). 
 
Daily assessments (assessment days 1 through 15) will include review for hospitalization and 
current symptoms.  Daily assessments will also explicitly solicit occurrence of rash, symptomatic 
hypoglycemia, seizure, oxygen supplementation, nausea, vomiting, and impaired vision. Quality 
of life assessments will be made at baseline, day 28 - 2 days/+2 weeks, and six months - 1 

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week/+2 months, using the EQ-5D-5L, PHQ-9, GAD 7, and PLC 5. If the six-month survey is 
missed during the above outlined window, the study team may attempt to collect it for up to a 
year following the six-month timepoint.  
 
Participants will be taught how to perform self-collection of oral swabs for SARS-CoV-2 on 
assessment days 1 – 14 and 28 +/- 2 (considering day 1 as day of study drug delivery).  Oral 
swabs will not be required during hospitalizations, but patients will be asked to provide a swab 
on the day following discharge from the hospital, even if this occurs after day 28. These will be 
refrigerated after collection and collected by a courier associated with the study for transport to 
the central laboratory (ARUP) for testing. Training will be provided with written instructions, 
video, and discussion with the research coordinators. 
 
Phlebotomy will be performed at day 1, day 7 (+/-2 day),day 28 (+/-2 day) and 6 months- 1 
week/+2 months.  This will require personal protective equipment (PPE) for the phlebotomy-
certified research staff. Note that the 6 months blood draw is being added mid-study, after 
subjects have been enrolled, Therefore, already enrolled participants will be notified of the 6 
months blood draw, provided with a new copy of the consent form, and told that they do not 
have to participate in the 6 month blood draw. If the six-month blood draw is missed during the 
above outlined window, the study team may attempt to collect it for up to a year following the 
six-month timepoint.  
Blood samples will be used to assess the immune response to SARS-CoV-2, drug screening, 
investigation of viral biology, cardiac biomarkers, and development of diagnostic assays.  
Plasma and peripheral blood mononuclear cells (PBMCs) will be stored in the University of Utah 
Center for Clinical and Translational Science (CCTS) biospecimen repository.  If there is 
remaining sample after these analyses, they may be used to study other diseases. 
 
Six months after enrollment, study staff will verify subsequent hospitalizations and vital status of 
the participant.   
 
5.6 Household Contacts  
Household contacts 18 years or older will be asked to self-collect oral swabs in the same 
manner and same daily schedule as the study participant.  Provision of the oral swabs will be 
considered implied consent, waiving the need for consent documentation. 
 
5.7 Data collection.  
Research coordinators and/or investigators will collect data and record them on paper and/or 
electronic CRF provided by the Data Coordinating Center (DCC). Data quality will be monitored 
by clinical data managers at the DCC. Note that given concerns for contagion during the 
pandemic, coordinators will practice “no-touch” practices for data collection and entry.  
 
6.0 Analysis and interpretation of data.  
A formal statistical analysis plan (SAP) will be written and finalized before the conclusion of 
enrollment and prior to the beginning of data analysis. The principles of this SAP are outlined 
here. 
 
We note that in the unique circumstances of this trial setting, it is possible that information may 
become available that would lead to modifications of prespecified analysis.  A hypothetical 
example would be evidence from multiple global studies that a particular underlying condition is 
strongly associated with outcomes such as shedding or hospitalization rates in response to 
hydroxychloroquine.  In such circumstances, a modification to this study’s analysis plan could 

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be considered, if possible with the investigators blinded to the effect of the modification on the 
analysis, and in consultation with the DSMB.  If the statistical analysis plan were to be modified, 
the analytic plan would be updated, with the previous version retained, and the modification 
explicitly noted in the presentation of the trial results. 
 
The primary prespecified analysis for efficacy is a comparison of duration of viral shedding 
during the first 14 days after randomization between the two treatment arms. For each 
participant, this outcome will be defined as the number of days until an oral swab sample shows 
no shedding, as confirmed by a sample from the subsequent day. Thus, for example, a 
participant with their first negative samples on days 7 and 8 would be treated as having stopped 
shedding on Day 7. The requirement for confirmation will be waived for patients who are 
negative for shedding on Day 14.  
 
Due to the nature of the data collected over a 14-day interval, and uncertainty about the 
distribution of shedding duration and the resulting hazard function, our primary analysis will 
apply the stratified log-rank test to compare the distribution of shedding duration between the 
hydroxychloroquine and control groups, with administrative right censoring at day 14. The 
primary analysis will be conducted using a 2-sided α=0.05. The log-rank test will be stratified by 
the age group randomization stratum. The Efron approach will be used to account for tied 
shedding duration times. Kaplan-Meier curves will summarize the shedding time distributions in 
the two randomized groups.  
 
Special handling will be required in our primary analysis of shedding duration for periods in 
which patients are hospitalized because swabs will not be obtained during hospitalizations. In 
our primary analysis, we will apply a last value carried forward imputation approach during 
hospitalization, and assume continued viral shedding during hospitalizations for patients whose 
last pre-hospitalization assessment is positive. A sensitivity analysis will right censor follow-up 
on the day of hospital admission. These two analyses represent the range of plausible 
scenarios for shedding during hospitalization under the assumption that any association 
between hospitalization and shedding must be positive; i.e., conditional on past history, the risk 
of viral shedding on any given day is at least as large for hospitalized as for non-hospitalized 
patients. We expect a relatively small proportion of subjects to be hospitalized, limiting the 
impact of assumptions concerning shedding during hospitalizations on the primary analysis. 
Additional sensitivity analyses, including analyses in which the end date of shedding is modeled 
as a latent variable will be considered.  
 
Quantification of the magnitude of “treatment effect”, and indeed the interpretation of the trial 
results, will depend on the specific patterns of the shedding distribution.  For example, in the 
unexpected scenario where the cumulative incidence curves for the ending of shedding actually 
cross during the 14-day evaluation period, the treatment arm with lower 14-day shedding rate 
would likely be preferred regardless of any shorter-term benefit observed in the other arm.  
Assuming, however, that the assumption of proportional hazards is found to be consistent with 
the data, the effect of the treatment will be expressed as a hazard ratio with 95% confidence 
interval. We will also report the differences between the randomized groups in truncated mean 
shedding duration to 14 days and in median shedding duration with 95% confidence intervals 
based on estimates derived from Kaplan-Meier curves.  
 
The comparison of proportion of patients hospitalized by day 14 between the randomized 
hydroxychloroquine and placebo groups will be performed with a two-sided Mantel-Cochran-
Haenszel test stratifying by the age categories as used for randomization, with 2-sided 

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alpha=0.05.  In the unlikely event that some patients die within 14 days after randomization 
without being hospitalized, these patients will be assigned to the hospitalization category in the 
analysis. Results will be presented as relative risks with 95% confidence intervals within each 
age stratum, and then pooled across strata. 
 
The average symptom level for assessment days 1 through 15 will be compared between 
treatment groups, as described in the Statistical Analysis Plan. The duration of COVID-19 
attributable symptoms through assessment day 15 will be summarized graphically across 
evaluation time points using Kaplan-Meier curves, and compared between randomized groups 
by applying the log rank test with stratification by the age randomization strata.  Participants 
who are hospitalized by assessment day 15 will be treated as having symptoms each day they 
are in the hospital. Follow-up time will be right censored at assessment day 15  
 
 
Our main analysis of adult household contact viral acquisition will be restricted to households 
with at least 2 adults for which no other adult besides the index study subject tests positive for 
COVID-19 at baseline. We will evaluate the effect of the hydroxychloroquine intervention on the 
risk of adult household viral acquisition by applying a Mantel-Cochran-Haenszel test stratifying 
by the randomization age categories and total number of adults within the household. Results 
will be presented as relative risks with 95% confidence intervals within each stratum, and then 
pooled across strata. A secondary analysis will assess the effect of treatment arm on rate of 
household viral acquisition rates averaged across all adults within the household by using a 
modified Poisson regression model incorporating correlation between participants in the same 
household, and controlling for age category and number of household members. 
 
The Statistical Analysis plan will detail additional analyses to be performed, including additional 
exploratory analysis as well as reporting of six-month outcomes among participants.   
 
Safety—already well established in studies of thousands of patients and in post-marketing 
surveillance—will be assessed through counts (proportions) of adverse events, with special 
attention to those listed in the package insert for hydroxychloroquine and careful investigation of 
any SUSARs.  As noted elsewhere in this protocol, safety data will be reported to the trial DSMB 
after every (approximately) 100 subjects have been enrolled in the trial. 
 
We do not anticipate applying formal stopping rules for either efficacy or futility in this trial. It is 
expected that the trial will remain open for up to 12 months, as the cyclic nature of the illness is 
not well understood.  Thus, if enrollment is not accomplished in this first wave of infection, the 
trial will not be suspended for futility, anticipating that subsequent waves may occur and enable 
full enrollment. 
 
6.1 Power and sample size analysis 
 
For a survival analysis, statistical power is readily expressed as a function of the number of 
events or event rate.  Table 2 below shows minimum increases in the hazard rate due to 
hydroxychloroquine detectable with 80% power, under different overall event rates by 14 days in 
the trial (calculations done in PASS assuming a conventional proportional hazards model with 
treatment arm as a single predictor, using a two-sided test with alpha=0.05).  With 400 enrolled 
participants, within our expected range of observed shedding rates, we expect the trial to have 
substantial power to detect a treatment effect if hydroxychloroquine increases the “successful 

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outcome” rate (at each timepoint) 1.4-fold or greater compared to the rates observed with 
placebo. 
 
 
Table 2. Minimum Increase in Hazard Rate Yielding 80% Power with 2-sided α=0.05, with 
N=400 randomized and evaluable subjects  
Assumed Overall 
Rate of No Shedding 
by 14 Days 
Minimum Hazard Ratio for “No Shedding” Outcome due to 
Hydroxychloroquine for which Power is 80%  
 
50% 
1.49 
55% 
1.46 
60% 
1.44 
65% 
1.42 
70% 
1.40 
75% 
1.38 
80% 
1.37 
 
  
 
 
7.0 Human Subjects Considerations. 
 
If a person without insurance is hospitalized for illness related to COVID-19, he or she is eligible 
for emergency Medicaid. This is beyond usual Medicaid eligibility and related to special rules 
related to COVID-19 illness. In 2019, the United States government issued new rules in the form 
of an executive order restricting the ability for immigrants who use public benefits, including 
Medicaid, from obtaining permanent residency. For many individuals who are not citizens or 
permanent residents of the United States—whether they are documented or not—this has made 
them reluctant to use public programs for which they are eligible, including Medicaid and 
COVID-19 related health benefits.  
 
In order to uphold principle of justice for all research participants, and to ensure that everyone 
who participates in this study will be appropriately respected for volunteering, we have 
partnered with U Health to offer participants who are uninsured and for whom completing 
paperwork regarding financial assistance would put them at risk in their judgement, the ability to 
receive the same level of care for COVID-19 as other people, should this be needed during their 
participation.  
 
All participants will be provided with information during their first visit by the study nurse that if 
they require hospitalization, are uninsured, and if in their judgement completing paperwork 
regarding financial assistance would put them at risk, they should, upon presenting to a U 
Health emergency department, identify themselves to the registrar and financial counselor. The 
financial counselor will identify their participation in the electronic health record and note this in 
the hospital billing system. 
 
Participants will be provided with a card identifying them as study participants and with 
instructions on it so as to remind them of what to do if they need to be hospitalized. They will 
also be provided with a handout to keep at home in case they are unable to speak to the 
financial counselor and hospital rules restrict visitors so the person contacted regarding the 
patient at home has the same information. 

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7.1 Institutional Review Board oversight.  
Institutional Review Board (IRB) approval is required and will be secured before any subject is 
enrolled at the study site. The DCC will not enable access to the electronic data capture or 
randomization systems until IRB documentation is received. 
 
7.2 Informed consent.  
Informed consent will be obtained from participants prior to randomization.  Proxy consent will 
not be used.  Informed consent will be obtained without an original paper signature because of 
the contagious nature of the virus.  Adult household contacts who agree to provide daily swabs 
are presumed to be consenting, and documentation of consent will be waived for them. 
 
7.3 Potential risks 
Risks associated with participation in this study include risks associated with HCQ 
administration and potential loss of confidentiality. 
 
The package insert for HCQ lists visual impairment, cardiac impairment, QTc prolongation, 
worsening of psoriasis or porphyria, proximal myoneuropathy, suicidality, and hypoglycemia. All 
of these risks are quite rare and where observed are seen after prolonged administration, 
generally in the range of years. While ocular examinations are recommended after a year (and 
for acute symptoms), routine ocular examinations have never been recommended for brief 
duration of therapy. While QTc prolongation has been described with HCQ, it is generally 
modest, and routine EKG monitoring is not normally practiced even during long-term 
administration of hydroxychloroquine. HCQ may be associated with prolongation of QTc.  We 
chose a conservative threshold of 500msec as an exclusion criterion after consultation with 
electrophysiology cardiologists. 
 
7.4 Mitigation of risks 
In order to mitigate the risk of prolongation of QTc, we have chosen a conservative exclusion 
threshold of 500 msec after consultation with electrophysiology cardiologists.  Daily 
assessments will specifically ask about the adverse events listed above on a daily basis.  Our 
eligibility criteria exclude patients with elevated risk of HCQ toxicity, and we have selected 
dosages in the lower end of the therapeutic range.  Further, treatment is restricted to 5 days.   
 
Risk of loss of confidentiality is mitigated by securing all paper materials used by coordinators 
for data collection, and IT security maintained at the DCC. Direct patient identifiers (names, 
contact information, medical record numbers) will not be recorded at the DCC, but will be 
secured at the study sites.  The study sites will maintain lists that correlate medical record 
numbers with study ID numbers recorded in the DCC electronic data capture system. 
 
7.5 Discontinuance of HCQ 
Patients may choose to discontinue HCQ for any reason, and HCQ will be discontinued if a 
known contraindication arises.  Study procedures should otherwise continue. This is not the 
same as withdrawal from the study.  
 
7.6 Withdrawal from study.  
Patients may withdraw from the study at any time. Data recorded up to the time of withdrawal 
will be included in the study analysis.   
 

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7.7 Protocol deviations and violations.  
The investigator will not implement any deviation from, or changes of the protocol without prior 
review and documented approval/favorable opinion from the IRB of an amendment, except 
where necessary to eliminate immediate hazard(s) to study subjects or research personnel,, or 
when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of 
telephone number(s)). Protocol deviations will be reported to the DCC within 24 hours of the site 
becoming aware of the deviation. The study team will provide explanation of the deviation to the 
DCC.  The DCC will notify the IRB of protocol deviations that have potential impact on human 
subjects safety or trial integrity.  The investigator may implement a deviation from, or a change 
of, the protocol to eliminate immediate hazard(s) to trial subjects without prior IRB 
approval/favorable opinion. As soon as possible, the implemented deviation must be reported to 
the DCC, which will notify the medical monitor and the IRB.   
8.0 Adverse Events 
Patient safety is central to this study protocol. 
 
8.1 Adverse event reporting. Adverse events will be recorded from randomization through day 
14 or hospitalization, whichever occurs first. The following adverse events will be collected in 
the adverse event case report forms and entered into the DCC electronic data capture system:  
 
• 
Serious adverse events  
• 
Non-serious adverse events that are considered by the investigator to be related to 
study drug or study procedures or of uncertain relationship 
• 
Adverse events that lead to permanent discontinuation of the study drug. 
 
The following adverse events will be collected prospectively as part of the study-specific 
outcomes and do not require additional adverse event reporting with the DCC unless they meet 
criteria for being serious (defined below): 
 
• Rash 
• 
Symptomatic hypoglycemia 
• 
Seizure 
• 
Cardiac arrhythmias 
• 
Worsening requirement for oxygen supplementation and support  
• 
Nausea/vomiting 
• 
Impaired vision 
 
8.2 Serious Adverse Events  
All serious adverse events (SAE) will be reported to the DCC.  As per federal definitions 
(primarily in 21 CFR 312.32(a)), a serious adverse event is any adverse event that results in 
one of the following outcomes:  
 
• 
Death 
• 
A life-threatening event, one that places the subject at immediate risk of death (this does 
not include an event that, had it been more serious, would have placed the subject at 
immediate risk of death) 
• 
Prolonged inpatient hospitalization or rehospitalization  

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• 
Persistent or significant disability/incapacity, indicating a substantial disruption of a 
person's ability to conduct normal life functions (i.e., the adverse event resulted in a 
significant, persistent or permanent change, impairment, damage or disruption in the 
patient's body function/structure, physical activities and/or quality of life).  
 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition.  
 
SAEs must be reported to the DCC within 24 hours of becoming aware of the SAE.  This may 
be accomplished by telephone call or email and can be succinct notification. 
 
Investigators must assess serious adverse events for expectedness and relatedness.   
Expected SAE include known side effects of study drug as well as clinical events consistent with 
worsening of COVID, or consistent with pre-existing co-morbidities of individual patients.  
Relatedness must be assessed by an investigator, and is based on clinical judgment that the 
event is related to having participated in this study.  This is assessed as not related, possibly 
related, and related.  This information must be provided to the DCC within 48 hours of becoming 
aware of the SAE.  
 
Deaths from worsening of viral infection or underlying co-morbidities are expected, and do not 
automatically require expedited reporting.  Sudden deaths or deaths believed related to cardiac 
arrhythmias must be reported to the DCC within 24 hours of becoming aware of the death.  The 
DCC or medical monitor will report these deaths to the DSMB chair within 24 hours of 
notification.  As these are expected complications of study drug, these do not require expedited 
reporting to the FDA or IRB as described in the next paragraph. 
 
Serious adverse events that are unexpected and related to study participation must be reported 
to the FDA and the IRB within 7 days of the DCC becoming aware of the classification of the 
SAE.  The DSMB chair will also be notified.  All other SAE do not need to reported to the IRB or 
FDA.  All SAE will be tabulated by study arm and presented to the DSMB at its regular 
meetings. 
 
 
 
8.3 Unanticipated Problems  
Investigators must also report Unanticipated Problems associated with the study drug or study 
procedures to the DCC within 24 hours. An unanticipated problem is any incident, experience, 
or outcome that meets all of the following criteria:  
• 
Unexpected, in terms of nature, severity, or frequency, given the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and the characteristics of the subject 
population being studied;  
• 
Related or possibly related to participation in the research. Possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research; it is not intended to identify the event 
as possibly related imply because it cannot be proven to be unrelated.  

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• 
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
 
9.0 Miscellaneous Topics 
 
9.1 Reporting and Regulatory Compliance. 
 All relevant information will be reported in compliance with relevant regulations and Good 
Clinical Practice. This is not a registrational trial but will be performed under an IND exemption. 
 
9.2 ClinicalTrials.gov registration. 
This trial is registered with ClinicalTrials.gov (NCT04342169).  Updates to the Clinicaltrials.gov 
entry will be made in compliance with relevant regulations.  
 
9.3 Records retention. Study sites will arrange for the retention of raw data as per institutional 
protocol but for a minimum of 3 years after publication of the primary paper. All data and 
documents will be made available when requested by appropriate authorities. Records will be 
maintained to verify the existence of each patient in the study, as per standard protocol. 
 
 

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APPENDICES 
 
Appendix 1. Visit schedule 
 
 
 
Visit 
Procedure 
Baseline 
Daily 
through 
15 days 
14 
days 
Hospitalization  
28 
days 
6 
months 
Screening procedures 
X 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
Data collection 
X 
X 
X 
X 
X 
X 
Active Adverse Event review 
 
X 
 
 
 
 
Passive Adverse Event review 
 
 
 
X 
 
 
EQ-5D-5L, PHQ-9, GAD 7, PLC 5 
X 
 
 
 
X 
X 
EQ-5D-5L: EuroQol-5 dimensions-5 level; PHQ-9: Patient Health Questionnaire-9, GAD 7: Generalized 
Anxiety Disorder 7-item scale, PLC 5: PTSD Checklist for DSMB-5 scale 
 
 
 

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Appendix    2: Biospecimen collection schedule:  
 
 
 
 
Day 
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
28
6 months
COVID-19 PCR swab positive
1
Inclusion / Exclusion criteria
1
Informed consent discussion / signatures
1
1
Adverse event review
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Surveys (EQ-5D-5L / PHQ-9 / GAD7 / PLC5)
1
1
1
HCQ or Placebo administration
1
1
1
1
1
Research Specimen Collection
Oropharyngeal self-swab for SARS-CoV-2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Household contact over age 18 oropharyngeal 
self-swab for SARS-CoV-2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Peripheral blood (PBMC / plasma biobank)
1
1
1
1
Study Events
40 mL (five yellow top 
ACD tubes)
HCQ or Placebo

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Appendix 3. Potential medication interactions with hydroxychloroquine 
 
A. Medications considered contraindicated, which if ordered on a subject during the 5-day 
study period will prompt study personnel or clinical pharmacists to discuss with treating 
clinicians whether stopping the study drug is appropriate or whether this medication 
could be stopped or substituted: amiodarone; cimetidine; dofetilide; phenobarbital; 
phenytoin; sotalol. 
 
B. Medications considered to present a potential interaction with hydroxychloroquine, which 
if ordered on an inpatient during the 5-day study period, will prompt study personnel or 
clinical pharmacists to discuss with treating clinicians the risk-benefit assessment of this 
medication and potential need for additional monitoring: ampicillin, antacids, 
cyclosporine, digoxin, flecainide, mefloquine, methotrexate, mexilitine, rifampicin, 
rifapentine. 
 
 

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