Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease
Phase: PHASE3
Conditions: Coronavirus, Acute Respiratory Infection, SARS-CoV Infection
Sponsor: Massachusetts General Hospital

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The PETAL Investigators 
 
Title:  
Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients 
with symptomatic Disease 
Acronym:  
ORCHID  
 
Funder:  
The National Heart, Lung, and Blood Institute (NHLBI) 
Network:  
The Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials 
Network 
Protocol:  
Version 4.0 
Date: 
 
June 4, 2020 
NCT:   
NCT04332991 
 
 
 
 
 
 
 
 
 
 
Contacts: 
Protocol Committee Contact: Wesley H. Self, MD, MPH  
Coordinating Center Contact: B. Taylor Thompson, MD  
 
 
Outcomes Related to COVID-19 Treated with Hydroxychloroquine 
among In-patients with Symptomatic Disease 

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ORCHID Trial Leadership 
 
 
Protocol Committee Chair 
Wesley H. Self, MD, MPH 
Vanderbilt University Medical Center 
Email: wesley.self@vumc.org 
 
Protocol Committee Co-Chair 
Samuel M. Brown, MD, MS 
Intermountain Medical Center 
Email: samuel.brown@imail.org 
 
Protocol Committee Members 
Samuel M. Brown 
Jonathan D. Casey 
Steven Y. Chang 
Sean P. Collins 
John Eppensteiner 
Kevin Gibbs  
Adit A. Ginde 
Michelle N. Gong 
Terri Hough 
Nicholas Johnson 
Lindsay Leither 
Christopher J. Lindsell 
Michael Matthay  
Marc Moss 
Pauline Park 
Todd W. Rice 
Bryce Robinson 
David Schoenfeld 
Wesley H. Self 
Matthew W. Semler 
Nathan I. Shapiro 
Jay Steingrub 
B. Taylor Thompson 
      Alexandra Weissman 
      Donald M. Yealy 
 
Coordinating Center at Massachusetts General Hospital 
B. Taylor Thompson 
David Schoenfeld 
Douglas L. Hayden 
Nancy Ringwood 
Cathryn Oldmixon 
 
PETAL Steering Committee Chair 
Roy G. Brower 
 
NHLBI Officers 
Lora Reineck 
Neil Aggarwal 
 
Consultants to the Protocol 
Frank Harrell  
Dan M. Roden 
 
Donna Torr 
Timothy Uyeki 
 

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Table of Contents 
 
REVISIONS TO THE PROTOCOL............................................................................................................. 6 
ABBREVIATIONS ...................................................................................................................................... 8 
1. STUDY SUMMARY ................................................................................................................................ 9 
2. TRIAL DESCRIPTION .......................................................................................................................... 12 
2.1 Background ................................................................................................................................. 12 
2.1.1 COVID-19 Infection ....................................................................................................................... 12 
2.1.2 Hydroxychloroquine as a Therapeutic for COVID-19 ................................................................... 12 
2.1.3 Rationale for a Randomized Trial among Hospitalized Patients .................................................... 13 
2.1.4. Rationale for Evaluating Hydroxychloroquine Monotherapy ....................................................... 14 
2.2 Study Aims.................................................................................................................................. 14 
2.2.1 Study aim ........................................................................................................................................ 14 
2.2.2 Study hypothesis ............................................................................................................................. 14 
2.3 Study Design ............................................................................................................................... 14 
3. STUDY POPULATION AND ENROLLMENT ................................................................................... 14 
3.1 Inclusion Criteria ........................................................................................................................ 14 
3.2 Exclusion Criteria ....................................................................................................................... 15 
3.3 Justification of Exclusion Criteria............................................................................................... 15 
3.4 Screening..................................................................................................................................... 15 
3.5 Assessment of Eligibility and Exclusion Tracking ..................................................................... 16 
3.6 Process of Obtaining Informed Consent ..................................................................................... 16 
3.6.1 Paper-based approach ..................................................................................................................... 16 
3.6.2 Electronic/e-consent approach ........................................................................................................ 17 
3.6.3 Attestation of informed consent ...................................................................................................... 18 
3.7 Randomization and Blinding ...................................................................................................... 18 
3.8 Minorities and Women ............................................................................................................... 19 
4. STUDY INTERVENTIONS................................................................................................................... 19 
4.1 Treatment of Study Participants .................................................................................................. 19 
4.2 Hydroxychloroquine Group ........................................................................................................ 19 
4.3 Control Group ............................................................................................................................. 20 
4.4 Co-Interventions ......................................................................................................................... 20 
4.5 On-Study Monitoring .................................................................................................................. 20 

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4.6 Criteria for Stopping Study Drug ................................................................................................ 21 
5. OUTCOMES........................................................................................................................................... 22 
5.1 Primary Outcome ........................................................................................................................ 22 
5.2 Secondary Outcomes .................................................................................................................. 22 
5.3 Safety outcomes .......................................................................................................................... 22 
5.4 Rationale for Primary Outcome .................................................................................................. 23 
6. DATA COLLECTION ........................................................................................................................... 23 
6.1 Baseline Variable Collection ...................................................................................................... 23 
6.2 Assessments between Hospital Presentation and Hospital Discharge ........................................ 24 
6.3 Assessments following Hospital Discharge ................................................................................ 25 
7. STATISTICAL CONSIDERATIONS .................................................................................................... 26 
7.1 Statistical Approach .................................................................................................................... 26 
7.2 Planned deviations from this design ........................................................................................... 29 
8. DATA QUALITY MONITORING AND STORAGE ........................................................................... 29 
8.1 Data Quality Monitoring ............................................................................................................. 29 
8.2 Data Storage ................................................................................................................................ 29 
9. RISK ASSESSMENT ............................................................................................................................. 29 
9.1 Potential Risk to Participants ...................................................................................................... 29 
9.1.1 Potential risks of receiving hydroxychloroquine ............................................................................ 30 
9.1.2 Potential risks of receiving placebo with COVID-19 ..................................................................... 31 
9.1.3 Potential risks of receiving an EKG. .............................................................................................. 31 
9.2 Minimization of Risk .................................................................................................................. 31 
9.3 Potential Benefit .......................................................................................................................... 32 
9.4 Risk in Relation to Anticipated Benefit ...................................................................................... 32 
10. HUMAN SUBJECTS PROTECTIONS ............................................................................................... 32 
10.1 Selection of Subjects ................................................................................................................. 32 
10.2 Justification of Including Vulnerable Subjects ......................................................................... 32 
10.3 Informed Consent ...................................................................................................................... 33 
10.4 Continuing Consent .................................................................................................................. 33 
10.5 Withdrawal of Consent ............................................................................................................. 33 
10.6 Identification of Legally Authorized Representatives .............................................................. 33 
10.7 Justification of Surrogate Consent ............................................................................................ 34 
10.8 Additional Safeguards for Vulnerable Participants................................................................... 34 

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10.9 Confidentiality .......................................................................................................................... 35 
11. ADVERSE EVENTS ............................................................................................................................ 35 
11.1 Adverse Event Definitions ........................................................................................................ 35 
11.2 Safety Monitoring ..................................................................................................................... 36 
11.3 Serious Adverse Events ............................................................................................................ 36 
12. Data and Safety Monitoring Board (DSMB) ........................................................................................ 37 
13. REFERENCES ..................................................................................................................................... 39 
14. APPENDICES ...................................................................................................................................... 43 
Appendix A. Schedule of Events ...................................................................................................... 43 
Appendix B. Potential medication interactions with hydroxychloroquine ....................................... 44 
Appendix C:  Adverse Event Reporting and Unanticipated Events ................................................. 45 
C.1. Unanticipated Problems (UP) .......................................................................................................... 45 
C.2. Determining Relationship of Adverse Events to Study Drug or Study Procedures ......................... 45 
C.3. Clinical Outcomes that may be Exempt from Adverse Event Reporting......................................... 46 
C.4. Decision tree for determining if an adverse event is reportable ....................................................... 47 
Appendix D. Public Readiness and Emergency Preparedness Act ................................................... 48 
Appendix E: ORCHID-BUD Ancillary Study Protocol .......................................................................... 49 
 
 
 
 

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REVISIONS TO THE PROTOCOL 
 
Protocol Version 1 
Date: March 27, 2020 
Initial protocol 
 
Protocol Version 1.1 
Date: March 29, 2020 
Substantive protocol changes in Version 1.1: 
1. Based on recommendations from FDA, the dose of hydroxychloroquine in the trial was changed 
from hydroxychloroquine 400 mg every 12 hours for 10 doses (version 1) to hydroxychloroquine 
400 mg every 12 hours for 2 doses followed by 200 mg every 12 hours for 8 doses (version 1.1). 
This change was made before any patients were enrolled and before the trial was posted on 
clinicaltrials.gov.   
  
Protocol Version 2.0 
Date: April 14, 2020 
Substantive protocol changes in Version 2.0: 
1. Inclusion criterion #4 changed so that only patients with laboratory-confirmed SARS-CoV-2 
infection are eligible. Patients with pending SARS-CoV-2 test results with a high clinical 
suspicion of COVID-19 are no longer eligible. This change was made because SARS-CoV-2 
laboratory results are now routinely available within hours of initial hospital presentation at 
participating hospitals (which was not true early in the COVID-19 pandemic). 
2. Exclusion criterion #16 was added.  This exclusion criterion states that a patient is excluded if the 
treating clinical team does not believe equipoise exists regarding the use of hydroxychloroquine 
for treatment of this patient. 
3. Discussion of potential drug shortages was removed because study drug for all sites will be 
supplied by the PETAL Network and will not rely on local drug supplies. 
4. Language describing consent processes was revised to increase precision. 
5. Revised the statistical considerations section (Section 7). 
6. Corrected the definition of serious adverse event in section 11.1 to harmonize with section 11.3 
7. Added the following statement to Appendix C: “The Medical Monitor will provide to Sandoz 
Pharmacovigilance any significant safety findings (without disclosing protected health 
information) during the conduct of the trial.”     
8. Added Appendix D: Public Readiness and Emergency Preparedness Act 
9. Additional data collection added:  Clinically diagnosed deep vein thrombosis (DVT) or 
pulmonary embolism (PE) 
10. Clarification of patient co-morbidities added 
 
 

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Protocol Version 3.0 
Date: May 4, 2020 
Substantive Changes in Version 3.0: 
1. Operationalized the definition of shortness of breath in inclusion criteria #3. 
2. Added option for attestation of signature for confirmation of informed consent (section 3.6). 
3. Clarified recommendations for stopping guidelines in statistical considerations section, using an 
odds ratio to suggest futility of 1.1 (section 7.1). 
 
Protocol Version 4.0 
Date: June 4, 2020 
Substantive Changes in Version 4.0 
1. Added language for the DMSB to consider stopping the trial for harm (section 7.1): “If we 
determine there is >70% probability that the odds ratio is <0.70, the DSMB should consider 
stopping the trial for harm.”  
2. Added language that enrollment will be paused after 510 participants until the DSMB reviews 
primary outcome data from all 510 participants.  
3. Added Appendix E: The ORCHID-BUD Outcomes Related to COVID-19 treated with 
Hydroxychloroquine among In-patients with symptomatic Disease – Brain Outcomes and 
Psychological Distress Ancillary study procedures. 
 
 

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ABBREVIATIONS 
 
ACE-I 
Angiotensin-converting-enzyme inhibitor 
ARB 
Angiotensin II receptor blocker 
ADR 
Adverse drug reaction 
AE 
Adverse event 
DSMB 
Data safety monitoring board 
eCRF 
Electronic case report forms 
GFR 
Glomerular filtration rate 
ICU 
Intensive care unit 
IV 
Intravenous 
LAR 
Legally authorized representative 
LFT 
Liver function test 
MIC 
Minimum inhibitory concentration 
NSAIDs 
Nonsteroidal anti-inflammatory drug 
PI 
Principal investigator (a clinician responsible for one site) 
RCT 
Randomized control trial 
SAE 
Serious adverse events 
S/F 
SpO2/FiO2 ratio 
SOFA 
Sequential Organ Failure Assessment 
SOP 
Standard operating Procedure 
 
 
 
 
 
 
 

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1. STUDY SUMMARY 
 
Title 
Hydroxychloroquine for the Early Treatment of COVID-19 in Hospitalized 
Adults: A Multicenter Randomized Clinical Trial 
Acronym  
ORCHID 
Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-
patients with symptomatic Disease 
Background 
Effective therapies for COVID-19 are urgently needed. Hydroxychloroquine is 
an antimicrobial agent with immunomodulatory and antiviral properties that has 
demonstrated in vitro activity against SARS-CoV-2, the virus that causes 
COVID-19.  Preliminary reports suggest potential efficacy in small human 
studies.  Clinical trial data are needed to determine whether hydroxychloroquine 
is effective in treating COVID-19.   
Study Design 
Blinded, multicenter, placebo-controlled randomized clinical trial 
Intervention group 
 
Hydroxychloroquine 400 mg twice daily for two doses, then 200 mg twice daily 
for the subsequent eight doses (10 total doses) 
Control group                       Matched placebo twice daily for 10 total doses 
Sample Size 
Up to 510 patients 
Inclusion Criteria 
1. Age ≥18 years 
2. Currently hospitalized or in an emergency department with anticipated 
hospitalization. 
3. Symptoms of acute respiratory infection, defined as one or more of the 
following: 
a. cough 
b. fever (> 37.5° C / 99.5° F) 
c. shortness of breath (operationalized as any of the following: subjective 
shortness of breath reported by patient or surrogate; tachypnea with 
respiratory rate ≥22 /minute; hypoxemia, defined as SpO2 <92% on 
room air, new receipt of supplemental oxygen to maintain SpO2 ≥92%, 
or increased supplemental oxygen to maintain SpO2 ≥92% for a patient 
on chronic oxygen therapy).  
d. sore throat  
4.   Laboratory-confirmed SARS-CoV-2 infection within the past 10 days prior 
to randomization.  
Exclusion Criteria 
1. Prisoner 
2. Pregnancy  
3. Breast feeding 
4. Unable to randomize within 10 days after onset of acute respiratory infection 
symptoms  
5. Unable to randomize within 48 hours after hospital arrival 
6. Seizure disorder 
7. Porphyria cutanea tarda 
8. QTc >500 ms on electrocardiogram within 72 hours prior to enrollment 
9. Diagnosis of Long QT syndrome 
10. Known allergy to hydroxychloroquine, chloroquine, or amodiaquine 

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11. Receipt in the 12 hours prior to enrollment, or planned administration during 
the 5-day study period that treating clinicians feel cannot be substituted for 
another medication, of any of the following: amiodarone; cimetidine; 
dofetilide; phenobarbital; phenytoin; sotalol 
12. Receipt of >1 dose of hydroxychloroquine or chloroquine in the 10 days prior 
to enrollment 
13. Inability to receive enteral medications 
14. Refusal or inability to be contacted on Day 15 for clinical outcome 
assessment if discharged prior to Day 15 
15. Previous enrollment in this trial 
16. The treating clinical team does not believe equipoise exists regarding the use 
of hydroxychloroquine for the treatment of this patient 
Randomization 
Eligible participants will be randomized 1:1 to hydroxychloroquine versus 
placebo. Randomization will be completed in permuted blocks of variable size 
and stratified by site. 
Blinding 
Patients, treating clinicians, trial personnel, and outcome assessors will be 
blinded to group assignment. 
Primary Outcome 
COVID Ordinal Outcomes Scale on Study Day 15:  
1. Death 
2. Hospitalized on invasive mechanical ventilation or ECMO 
3. Hospitalized on non-invasive ventilation or high flow nasal cannula 
4. Hospitalized on supplemental oxygen 
5. Hospitalized not on supplemental oxygen 
6. Not hospitalized with limitation in activity  
7. Not hospitalized without limitation in activity  
Secondary Outcomes 
• Time to recovery, defined as time to reaching level 5, 6, or 7 on the COVID 
Outcomes Scale, which is the time to the earlier of final liberation from 
supplemental oxygen or hospital discharge 
• All-location, all-cause 14-day mortality (assessed on Study Day 15) 
• All-location, all-cause 28-day mortality (assessed on Study Day 29) 
• COVID Ordinal Outcomes Scale on Study Day 3 
• COVID Ordinal Outcomes Scale on Study Day 8 
• COVID Ordinal Outcomes Scale on Study Day 29 
• Composite of death or receipt of ECMO through Day 28 
• Oxygen-free days through Day 28 
• Ventilator-free days through Day 28 
• Vasopressor-free days through Day 28 
• ICU-free days through Day 28 
• Hospital-free days through Day 28 
Safety Outcomes 
• Seizure 
• Atrial or ventricular arrhythmia 
• Cardiac arrest 
• Elevation in aspartate aminotransferase or alanine aminotransferase to twice 
the local upper limit of normal 
• Acute pancreatitis 
• Acute kidney injury 
• Receipt of renal replacement therapy 

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• Symptomatic hypoglycemia 
• Neutropenia, lymphopenia, anemia, or thrombocytopenia 
• Severe dermatologic reaction 
Analysis 
The primary analysis will be an intention-to-treat comparison of the primary 
outcome between patients randomized to hydroxychloroquine versus placebo 
using a proportional odds model. An odds ratio (OR) >1.0 indicates more 
favorable outcomes with hydroxychloroquine on the COVID Ordinal Outcome 
scale, while an OR <1.0 indicates more favorable outcomes with placebo. The 
trial is designed with a Bayesian monitoring plan and has an anticipated sample 
size around 510 patients. The suggested stopping boundaries for the DSMB to 
consider include: >95% probability that the OR is >1.0 with a skeptical prior 
distribution (stop for efficacy); >90% probability that the OR is <1.1 with a flat 
prior (stop for futility); or >70% probability that the OR is <0.7 with a flat prior 
(stop for harm). With 5 interim analyses, a simulation showed that over 90% of 
trials would show efficacy on or before the fifth interim analysis (510 patients) if 
the true odds ratio were 1.8. Meanwhile, 6% of trials would show efficacy, and 
77% would stop for futility if the odds ratio were 1.0.  If the trial enrolls 510 
participants, further enrollment will be paused until the DSMB reviews data on 
the primary outcome from all enrolled participants; a decision to continue 
enrollment will be made by NHLBI after reviewing DSMB recommendations 
while the investigators remain blinded.   
 
 
 

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2. TRIAL DESCRIPTION 
2.1 Background 
Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious illness caused by severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2  Although the epidemiology has not been fully 
elucidated, most adults with COVID-19 appear to experience fever, cough, and fatigue and then recover 
within 1-3 weeks.  However, a portion of adults with COVID-19 develop severe illness, typically 
manifesting as pneumonia and hypoxemic respiratory failure, with continued progression to acute 
respiratory distress syndrome (ARDS) and death in some cases.1–3  Currently, no therapies have been 
demonstrated to prevent progression of COVID-19 to severe illness.  Based on mechanism of action and 
early clinical experiences, several agents currently available in the United States (US) have been proposed 
as potential therapies to prevent progression.4–6  Among these potential therapies, hydroxychloroquine has 
generated substantial interest due to its antiviral and immunomodulatory activity and established safety 
profile.  In fact, many US hospitals are currently recommending hydroxychloroquine as first-line therapy 
for hospitalized patients with COVID-19 despite extremely limited clinical data supporting its 
effectiveness. Thus, data on the safety and effectiveness of hydroxychloroquine for the treatment of 
COVID-19 are urgently needed to inform clinical practice.  In this trial, we will evaluate the safety and 
effectiveness of hydroxychloroquine for the treatment of adults hospitalized with COVID-19.  
2.1.1 COVID-19 Infection 
COVID-19 was first identified as a cluster of cases of pneumonia among a group of workers from a 
seafood wholesale market in Wuhan, China in December 2019.7  This observation, along with subsequent 
viral genotyping showing significant genetic similarities to the bat coronaviruses8 suggest a zoonotic 
origin, although the specific reservoir and  intermediary species remain unclear.9  The COVID-19 
infection represents the seventh coronavirus known to cause disease in humans.10  Four of the 
coronaviruses viruses are known to cause symptoms of the common cold in immunocompetent 
individuals while two others (SARS-CoV and MERS-CoV) have caused recent outbreaks of severe and 
sometimes fatal respiratory diseases.11 SARS-CoV-2 appears to exploit the same cellular receptor as 
SARS-CoV and MERS-CoV,12 and its severity may similarly result from a predilection for 
intrapulmonary epithelial cells over cells of the upper airways.13,14  
Since the first documented human case, COVID-19 has spread exponentially with 216,846 confirmed 
cases and 8,908 deaths as of March 18, 2020.  While most patients recover after a mild, brief illness with 
fever and cough, the disease has a clinical spectrum ranging from asymptomatic infection15 to ARDS and 
death.16  The most common reasons for ICU care are respiratory failure and ARDS, with a minority 
developing shock and possibly cardiomyopathy.17 The case fatality rate is estimated to be 0.25% to 
3.0%.18   
2.1.2 Hydroxychloroquine as a Therapeutic for COVID-19 
Hydroxychloroquine is a medication approved by the US Food and Drug Administration and accounts for 
millions of US prescriptions annually.  It is used both as an antiparasitic agent for malaria and an 
immunomodulatory agent for rheumatologic diseases.  When used for short periods, hydroxychloroquine 
is generally well-tolerated, with the most common side effects including nausea, vomiting, diarrhea, rash, 
and headache.  Mechanisms of action include: 1) immunomodulation: decreased inflammatory response 

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via inhibition of IL1, IL6, and tumor necrosis factor and impairment of complement-dependent antigen-
antibody reactions; 2) antimalarial: increasing pH of the vacuole within malaria parasites preventing 
normal growth and replication; and 3) antiviral: increasing endosomal pH, which limits virus-cell fusion 
and interferes with glycosylation of cell receptors targeted by coronaviruses.4,5,19,20  Recent laboratory 
studies demonstrate that hydroxychloroquine is a potent inhibitor of SARS-CoV-2 in vitro.4,5,21 Based on 
these laboratory data and case series of clinical experiences, hydroxychloroquine has been proposed as a 
potential therapeutic for treatment of COVID-19.22 
2.1.3 Rationale for a Randomized Trial among Hospitalized Patients 
The initial symptoms of COVID-19 develop approximately 2-10 days after infection with the SARS-
CoV-2 virus,23 with the progression to respiratory failure and ARDS occurring approximately 7-10 days 
after the onset of symptoms.24  While most adults with COVID-19 recover without complications, 
patients who require hospitalization experience high rates of complications. In case series of hospitalized 
patients with COVID-19, up to 26% require ICU admission and up to 17% die in the hospital.24,25  The 
period between onset of symptoms and development of severe respiratory failure represents a potential 
window for treatment of hospitalized patients to prevent disease progression.  
 
Given the unprecedented public health crisis caused by COVID-19, there is significant interest in finding 
effective therapies and, specifically, in repurposing approved medications with widespread availability 
and known safety profiles.3,26  Potential therapies that are being considered include hydroxychloroquine, 
chloroquine, lopinavir/ritonavir, interferon β, and corticosteroids. Despite extremely limited clinical data, 
hydroxychloroquine has been adopted into treatment guidelines in China27 and has been proposed as first-
line therapy for hospitalized patients in institutional protocols for COVID-19 at some hospitals in the US.   
Data on the safety and efficacy of hydroxychloroquine from randomized trials is urgently needed.  A 
randomized clinical trial demonstrating that hydroxychloroquine prevents disease progression in 
hospitalized patients with COVID-19 would provide evidence-based therapy for an ongoing pandemic.  A 
randomized clinical trial demonstrating that hydroxychloroquine is ineffective against COVID-19 would 
also have important public health impacts.  Hydroxychloroquine is known to be associated with a risk of 
QT prolongation, seizure, bone marrow suppression, and neuromyopathy. Risks of hydroxychloroquine 
may increase in patients with decreased renal function and critical illness, as may occur in COVID-19.  It 
also interacts with many medications commonly administered to hospitalized and critically ill patients.  If 
hydroxychloroquine is not effective at treating COVID-19, patients should not be exposed to these 
potential toxicities.  Additionally, prior trials have suggested that hydroxychloroquine may worsen 
outcomes for some viral infections.  In a placebo-controlled trial of hydroxychloroquine for HIV 
treatment, it caused significantly higher HIV viral loads and lower CD4 counts.28  A related drug, 
chloroquine, was shown to delay the immune response to Chikungunya infection and lead to higher viral 
loads and more lymphopenia in a non-human primate model.29 
Given the need for effective treatments of COVID-19, the unclear efficacy and safety of 
hydroxychloroquine as a treatment of COVID-19, and the widespread clinical use of hydroxychloroquine 
during the current pandemic, a randomized clinical trial is urgently needed. 
 

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2.1.4. Rationale for Evaluating Hydroxychloroquine Monotherapy 
In addition to hydroxychloroquine, several other medications have been proposed as potential therapies 
for COVID-19, including remdesivir and azithromycin.  Remdesivir treatment for COVID-19 is being 
studied in a clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) 
[NCT04280705]. Azithromycin is a macrolide antibiotic that is commonly used in the US for treatment of 
respiratory infections. During the design of this protocol, the investigators considered studying 
combination therapy of hydroxychloroquine plus remdesivir and hydroxychloroquine plus azithromycin. 
The investigators noted that combination therapy would likely increase the risk of toxicities. With no 
preliminary data suggesting combination therapy is likely to be more effective than hydroxychloroquine 
monotherapy, the investigators believe the risks of studying combination therapy likely outweigh the 
benefits at this time. Additionally, results of a trial evaluating combination therapy may be difficult to 
interpret.  Trial results suggesting effectiveness would probably not be attributable to a single agent and 
would leave uncertainty about whether treatment with combination therapy is preferable to monotherapy. 
Furthermore, null results of a trial evaluating combination therapy could occur if neither agent is 
effective, if one is effective and one is detrimental, or if both are effective but there are unfavorable drug-
drug interactions.  Interpretation of a trial of one agent will be straightforward and may provide the basis 
for subsequent trials of combination therapy. The investigators note that two distinct, simultaneously 
conducted placebo-controlled randomized trials evaluating remdesivir and hydroxychloroquine separately 
will provide high quality data on the effectiveness and safety of each agent versus placebo.             
 
2.2 Study Aims  
2.2.1 Study aim 
To compare the effect of hydroxychloroquine versus placebo on clinical outcomes, measured using the 
COVID Ordinal Outcomes Scale at Day 15, among adults with COVID-19 requiring hospitalization.  
2.2.2 Study hypothesis 
Among adults hospitalized with COVID-19, administration of hydroxychloroquine will improve clinical 
outcomes at Day 15.  
2.3 Study Design 
We will conduct an investigator-initiated, multicenter, blinded, placebo-controlled, randomized clinical 
trial evaluating hydroxychloroquine for the treatment of adults hospitalized with COVID-19. Patients, 
treating clinicians, and study personnel will all be blinded to study group assignment.     
 
3. STUDY POPULATION AND ENROLLMENT 
3.1 Inclusion Criteria 
1. Age ≥18 years 
2. Currently hospitalized or in an emergency department with anticipated hospitalization. 

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3. Symptoms of acute respiratory infection, defined as one or more of the following: 
a. Cough 
b. fever (> 37.5° C / 99.5° F) 
c. shortness of breath (operationalized as any of the following: subjective shortness of breath 
reported by patient or surrogate; tachypnea with respiratory rate ≥22 /minute; hypoxemia, 
defined as SpO2 <92% on room air, new receipt of supplemental oxygen to maintain 
SpO2 ≥92%, or increased supplemental oxygen to maintain SpO2 ≥92% for a patient on 
chronic oxygen therapy). 
d. sore throat 
4. Laboratory-confirmed SARS-CoV-2 infection within the past 10 days prior to randomization  
 
3.2 Exclusion Criteria 
1. Prisoner 
2. Pregnancy  
3. Breast feeding 
4. Unable to randomize within 10 days after onset of acute respiratory infection symptoms  
5. Unable to randomize within 48 hours after hospital arrival 
6. Seizure disorder 
7. Porphyria cutanea tarda 
8. QTc >500 ms on electrocardiogram within 72 hours prior to enrollment 
9. Diagnosis of Long QT syndrome 
10. Known allergy to hydroxychloroquine, chloroquine, or amodiaquine 
11. Receipt in the 12 hours prior to enrollment, or planned administration during the 5-day study 
period that treating clinicians feel cannot be substituted for another medication, of any of the 
following: amiodarone; cimetidine; dofetilide; phenobarbital; phenytoin; sotalol 
12. Receipt of >1 dose of hydroxychloroquine or chloroquine in the 10 days prior to enrollment 
13. Inability to receive enteral medications 
14. Refusal or inability to be contacted on Day 15 for clinical outcome assessment if discharged prior 
to Day 15 
15. Previous enrollment in this trial 
16. The treating clinical team does not believe equipoise exists regarding the use of 
hydroxychloroquine for the treatment of this patient 
3.3 Justification of Exclusion Criteria 
The exclusion criteria are primarily designed for patient safety.  In addition to excluding specific 
vulnerable populations (e.g., prisoners), these criteria are designed to exclude patients for whom receipt of 
hydroxychloroquine might increase the risk of serious adverse events.  For example, patients who have a 
prolonged QTc or are taking medications that would increase the risk of experiencing a prolonged QTc 
when combined with hydroxychloroquine are excluded to minimize the risk of Torsades de Pointes. 
3.4 Screening 
The site investigator or delegate will screen for hospitalized patients with laboratory confirmed COVID-
19 (that is, a positive laboratory test for SARS-CoV-2) or a pending SARS-CoV-2 test.  Treating 
clinicians will also be instructed to contact the site investigator or delegate for patients with a high clinical 
suspicion of COVID-19.   

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3.5 Assessment of Eligibility and Exclusion Tracking 
For patients who appear to meet inclusion criteria during screening, an electronic case report form will be 
completed to determine eligibility and track exclusions.  The electronic case report form will be accessed 
and stored in the electronic database.  At the time of entry into the screening database, the patient will be 
assigned a screening number.  
If a patient appears to meet all eligibility criteria, the site investigator or delegate will approach the 
treating clinician to ask permission to approach the patient or Legally Authorized Representative (LAR) 
to confirm eligibility, discuss potential study recruitment, and proceed with informed consent.   
For all excluded patients, including refusal by the treating clinician or patient/surrogate, a small number 
of de-identified variables will be collected including month and year the patient met screening criteria, 
age, sex, ethnicity, patient location, and reason(s) patient was excluded.  For the safety of research 
personnel and conservation of personal protective equipment, these encounters may occur via telephone 
or videophone.  
3.6 Process of Obtaining Informed Consent 
Informed consent will be obtained from the patient or from a surrogate decision maker if the patient lacks 
decision-making capacity.    
In some instances, bringing a paper consent form and pen to the bedside of a patient with known or 
suspected COVID-19 and then taking these out of the room would violate infection control principles and 
policies.  Given the infectious risk from COVID-19 and potential shortages of personal protective 
equipment (PPE), there is a moral and practical imperative to minimize face-to-face contact between 
patients and non-clinical personnel.  The current epidemic also presents unique challenges to obtaining 
consent from participant’s legally authorized representative (LAR).  To minimize infectious risk, many 
institutions are not allowing visitors to enter the hospital. Furthermore, the LAR is likely to have been 
exposed to the patient and may therefore be under self-quarantine at the time of the informed consent 
discussion. 
Therefore, in addition to the traditional approach of an in-person consent discussion and signed paper 
informed consent document, we will allow use of “no-touch” consent procedures for this trial.  Below, we 
outline three examples of no-touch consent procedures that may be used: (a)  a paper-based approach; (b) 
an electronic/e-consent approach; and (c) attestation of informed consent.   
 
3.6.1 Paper-based approach 
1. The informed consent document is delivered to the patient or LAR. 
a. If the patient or LAR is on-site, the informed consent document many be delivered to the 
patient or LAR either by research staff or by clinical staff 
b. If the LAR is off-site, the informed consent document may be emailed, faxed, or 
otherwise electronically transferred to the LAR (method dictated by institutional policy) 
2. Research staff discuss the informed consent document with the patient or LAR either in-person or 
by telephone or videophone.  This step confirms subject/LAR identity. 

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3. If the patient or LAR decides to consent to participate, the patient or LAR signs the paper copy of 
the informed consent document. 
4. A photograph is taken of the signature page of the informed consent document and uploaded into 
the electronic database (e.g. REDCap).  
a. If using the patient’s device (such as a patient’s personal cellular phone), a survey link 
can be sent to their device to allow direct upload of the image into the electronic database 
(e.g. REDCap). 
b. If using a staff device, it must be approved to store PHI by the local institution. In that 
case, research personnel can take a photograph of the signature page of the informed 
consent document either directly or through the window or glass door leading into the 
patient’s room.  The photograph can then be uploaded into the electronic database.  If a 
staff device is taken into the patient’s room to take a photograph it must be able to be 
disinfected according to local institutional practices.  
5. Research staff and witness provide signatures within the electronic database (e.g. REDCap) 
confirming their participation in the informed consent process. 
6. The patient or LAR retains the paper consent document. The image of the signature page may be 
printed and bundled with a copy of the blank informed consent document for research records. 
 
3.6.2 Electronic/e-consent approach 
1. The electronic informed consent document is opened on a research device or a link for the 
electronic informed consent document is sent to the patient’s or LAR’s device. 
2. Research staff discuss the informed consent document with the patient or LAR either in person or 
by telephone or videophone.  This step confirms subject/LAR identity. 
3. If the patient or LAR decides to consent to participate the patient or LAR signs the electronic 
informed consent document.  This signature may be either: 
a. an actual signature (often tracing a finger on the screen) OR 
b. a username and password specific to the individual signing 
4. Research staff and witness provide signatures within the electronic database (e.g., REDCap) 
confirming their participation in the informed consent process. 
5. The image of the signature page may be printed and bundled with a copy of the blank informed 
consent document for research records. 
 
If a hospital device is provided to facilitate electronic or paper-based consent, that device will be 
disinfected according to institutional protocols and removed by research staff or clinical staff during the 
next entry into the patient’s room. 
This approach complies with relevant regulations and sub-regulator guidance at 45 CFR 46.117, 45 CFR 
164.512, 21 CFR 11 Subpart C (11.100–11.300), https://www.hhs.gov/ohrp/regulations-and-
policy/guidance/use-electronic-informed-consent-questions-and-answers/index.html, 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent 
The information for the informed consent discussion will be provided in a formal document (or electronic 
equivalent) that has been approved by the IRB and in a language comprehensible to the potential 
participant, using an interpreter if necessary. The information presented in the consent form and by the 
research staff will detail the nature of the trial and what is expected of participants, including any 

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potential risks or benefits of taking part. It will be clearly stated that the participant is free to withdraw 
from the trial at any time for any reason without prejudice to future care, and with no obligation to give 
the reason for withdrawal. Where a patient does not speak English, a short-form consent and qualified 
interpreter will be employed, using similar “no-touch” principles.  Use of an interpreter and the 
interpreter’s identity will be documented on the electronic consent. 
3.6.3 Attestation of informed consent 
If none of the options outlined above (traditional signature and storage of a paper consent form, electronic 
photographs of a signed consent page, or e-consent) are available, study personnel may attest to 
completion of the informed consent process using the procedures outlined below.  Importantly, the 
process of informed consent using this attestation option should not change compared with the traditional 
method of obtaining informed consent for trial participation except for the method of documenting the 
consent process in the research record.  Rather than storing a paper document with the participant’s 
signature, a member of the research team and an impartial witness will attest to completion of the 
informed consent process and that the participant signed the informed consent document. This option of 
attestation of informed consent is not available when obtaining consent through an LAR.   
Procedures for attestation of informed consent: 
1. An unsigned paper consent form is provided to the patient by a heath care worker or study 
member. 
2. The study member obtaining consent arranges an in-person meeting or three-way call or video 
conference with himself/herself, the patient, and an impartial witness. If desired and feasible, 
additional people requested by the patient (e.g., next of kin) may also join this discussion. 
3. Study member reviews consent and answers questions in the presence of the impartial witness. 
4. Patient signs the paper informed consent document while the witness is listening on the phone or 
directly observing. 
5. Patient provides verbal confirmation that he/she would like to participate in the trial and he/she 
has signed and dated the informed consent document. This signed informed consent document 
stays with the patient due to the risk of spreading the virus.   
6. Study member and witness attest that other techniques for documenting informed consent were 
not available for this participant and that the participant provided written informed consent for 
trial participation by signing a paper informed consent document.  An attestation form is available 
in the ORCHID REDCap toolkit for documenting this attestation.  This attestation page with 
signatures from the study member and witness will be save as evidence of the informed consent 
process.  A signature from the participant will not be saved in the research record.   
   
3.7 Randomization and Blinding  
Participants confirmed to meet all eligibility criteria who have provided informed consent will be 
randomized 1:1 to hydroxychloroquine versus placebo.  A randomization code  will be provided to the 
site investigator or delegate from a centralized, web-based platform.  Randomization will require 
provision of the screening number and confirmation of patient eligibility. 
Randomization will be completed in permuted blocks of varying size and stratified by site. The 
randomized sequence allocation will be stored on a secure server and will not be available to site study 
personnel. Site research personnel will have a unique Personal Identification Number (PIN) to access the 

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randomization system. Each subject will receive a computer-generated randomization ID number.  The 
computer-generated randomization ID number will be provided to the pharmacy who will provide a dose 
pack containing hydroxychloroquine or placebo.  The participant, treating clinicians, study personnel, and 
outcome assessors will all remain blinded to group assignment until after the database is locked and 
blinded analysis is completed. 
3.8 Minorities and Women 
No patients will be excluded on the basis of race, ethnicity, or sex. The clinical coordinating center will 
monitor recruitment of minorities and women. If necessary, additional recruitment efforts will be made to 
ensure that the aggregate patient sample contains representative race/ethnicity and sex subsets. 
 
4. STUDY INTERVENTIONS 
4.1 Treatment of Study Participants 
A summary of the trial’s schedule of events is included in Appendix A.  
Timing of study procedures is based on the time of randomization, which is defined as “Time 0”.    The 
primary outcome will be assessed on Study Day 15, which corresponds to 14 days (2 weeks) after 
randomization.  
Study medications will be administered by clinical or research personnel while the patient is hospitalized. 
The first dose of study medications will be administered within 4 hours of randomization. In the hospital, 
medication delivery after the first dose will correspond to the timing of morning and evening medication 
delivery for the hospital/unit.  If the patient is discharged prior to completion of the study medication, the 
patient will be discharged with the study medication packet to complete the course after discharge. At 
home, the patient will be instructed to take the morning dose upon awakening and the evening dose 
approximately 12 hours later.  
On Study Days 1-5, study personnel will review patient records to confirm administration of study drug 
and document the number and reason for any missed doses.  For patients who are discharged prior to Day 
5, study personnel will obtain data on study drug adherence and safety outcomes from the patient or 
surrogate at via telephone follow-up scheduled at Day 8. Research personnel will also assess patients at 
Day 15 and Day 29; these assessments will be completed by phone if the patient has been discharged 
from the hospital.  
4.2 Hydroxychloroquine Group 
Participants assigned to the hydroxychloroquine arm will receive hydroxychloroquine sulfate 400 mg 
enterally twice daily for the first two doses and then 200 mg twice daily for the subsequent eight doses 
(“Days 2 – 5”).  This dosing regimen is a total of 10 doses over 5 days with an 800 mg load in the first 24 
hours divided into two doses followed by 400 mg daily divided into two doses over the following 4 days.  
Medication dose packs containing all 10 doses will be provided at randomization by the investigational 
pharmacy. 

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Hydroxychloroquine is available in 200 mg oral tablets of hydroxychloroquine sulfate. Common 
hydroxychloroquine dosing for treatment of uncomplicated malaria is 800 mg followed by 400 mg at 6 
hours, 24 hours, and 48 hours. Common initial dosing for rheumatoid arthritis is 400 mg to 600 mg daily. 
For this COVID-19 trial, we selected a dose of hydroxychloroquine (400 mg twice daily for the first two 
doses followed by 200 mg twice daily for next 8 doses) based on similar doses being well tolerated in the 
treatment of other conditions and in vitro studies suggesting that SARS-CoV-2 inhibition is achieved by a 
dose of 800 mg on the first day followed by 400 mg for the following 4 days.5  This dose and duration is 
comparable to the dose and duration being administered empirically to patients with COVID-19 as a part 
of clinical care during the current epidemic.          
4.3 Control Group 
Participants randomized to the control group will receive matching placebo enterally twice daily matching 
the dosing regimen described above for hydroxychloroquine.  Medication dose packs containing all 10 
doses will be provided at randomization by the Investigational Pharmacy.  The placebo pills will be as 
similar as possible to the hydroxychloroquine pills to ensure blinding. 
4.4 Co-Interventions 
This trial will control the use of hydroxychloroquine vs placebo during the 5-day intervention period.  
Enrolled participants will not receive open-label hydroxychloroquine or chloroquine during the 5-day 
intervention period. All other treatment decisions will be made by treating clinicians without influence 
from the protocol.  Administration of other antiviral medications (“rescue therapy”) will be allowed.  The 
decision to administer other antiviral medications will be made by treating clinicians and will be recorded 
in the case report form.   The decision to administer immunomodulating medications, including 
corticosteroids, will be made by treating clinicians and will be recorded in the case report from.   
4.5 On-Study Monitoring 
All patients enrolled in the study will be initially hospitalized and will therefore receive monitoring as a 
part of routine clinical care, including monitoring by their physicians, nurses, respiratory therapists, and 
ancillary staff. 
In addition to routine clinical monitoring, enrolled patients will have an assessment of the QTc with an 
electrocardiogram (EKG) or rhythm strip performed 24-48 hours after administration of the first study 
medication.  If an EKG or rhythm strip has been performed as a part of clinical care during this window, 
study personnel will assess the QTc on these clinically performed tracings.  If an EKG or rhythm strip has 
not been performed as a part of clinical care during this window, an EKG or rhythm strip will be ordered 
and performed as a part of study procedures. This QTc will be used to monitor patient safety and inform 
stopping of the study drug as described below. If a patient is discharged from the hospital before the QTc 
is evaluated at 24-48 hours, the study drug may be continued after discharge without this assessment. 
Between randomization and Day 5, study personnel will review the electronic health record daily for 
potential medication interactions with hydroxychloroquine (see Appendix B).  If a medication that is 
considered to be contraindicated with hydroxychloroquine is discovered, treating clinicians will be 
contacted to discuss if stopping study drug is appropriate or if the medication in question can be stopped 
or substituted.  If a medication with a potential interaction with hydroxychloroquine is identified, study 

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personnel will contact treating clinicians to ensure they are aware of the potential interaction.  Treating 
clinicians will determine whether an alternative medication would be appropriate or whether the risk-
benefit ratio favors continuing the medication with the known potential interaction.  If a patient is started 
on a medication listed in Appendix B that potentially prolongs the QTc, study personnel will recommend 
to treating clinicians use of continuous cardiac monitoring when available during the study drug treatment 
period.    
In addition to manual monitoring by study personnel for medication interactions, many electronic health 
records contain tools within the electronic order entry system to automatically screen for medication 
interactions with hydroxychloroquine and notify ordering providers of the potential interaction at the time 
of order entry. 
4.6 Criteria for Stopping Study Drug 
Administration of the blinded study drug may be stopped temporarily or permanently for (a) adverse 
events, (b) results of on-study monitoring, (c) clinical deterioration, or (d) evidence of an alternative cause 
to the patient’s symptoms.   
If a patient experiences an adverse event that the patient (or legally authorized representative), treating 
clinicians, or investigators feel merits temporarily or permanently stopping the study drug, the study drug 
will be stopped. The explanation for stopping the study drug will be recorded in the case report form, and 
the adverse event will be recorded and reported according to the adverse event guidelines below.  If the 
adverse event resolves to the extent that the patient (or legally authorized representative), treating 
clinicians, and investigators feel that resuming the study drug is appropriate, the study drug will be 
resumed, and this information will be recorded in the case report form.   
If a QTc assessed after randomization is >500 ms, the study drug will be discontinued for 24 hours and a 
repeat EKG will be performed daily until either the QTc is less than 500 ms, at which time study drug is 
resumed until 5 days after randomization with daily QTc assessments, or until 5 days after randomization 
is reached without resumption of study drug.  Both the value for the QTc and the decision to continue or 
stop the study drug will be recorded in the case report form. If the QTc in hospitalized patients cannot be 
assessed at 24-48 hours, study drug will be discontinued until the QTc can be assessed.  If the daily on-
study monitoring by study personnel for medication interactions indicates a potential interaction with a 
medication that treating clinicians feel is required for the optimal treatment of the patient and with which 
treating clinicians and the investigator feel it would be unsafe to administer hydroxychloroquine  
(including but not limited to: amiodarone; cimetidine; chloroquine; dofetilide; phenobarbital; phenytoin; 
sotalol), the study drug will be stopped and the reason will be recorded in the case report form. 
Patients on study may experience clinical deterioration due to their illness.  Clinical deterioration will be 
defined as a decrease of 1 point or more on the ordinal scale for the primary outcome (e.g., patient 
transitions from “hospitalized on supplemental oxygen” to “hospitalized on non-invasive ventilation or 
high flow nasal cannula”).  Patients who experience clinical deterioration in either group may be 
administered other antivirals or immunomodulators as “rescue therapy”.  For patients who experience 
clinical deterioration for which treating clinicians feel optimal care would be to stop the study drug, 
unblind group assignment, and administer hydroxychloroquine to patients in the placebo group, the study 
drug will be stopped, the site investigator will contact the coordinating center to receive the unblinded 

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study group assignment, and any additional treatment will be deferred to treating clinicians.  In this 
situation, the following data will be recorded in the case report form: the criteria met for clinical 
deterioration; the reason for stopping study drug and unblinding; use of hydroxychloroquine, other 
antivirals, and immunomodulators; and study outcomes. Crossovers from placebo to open-label 
hydroxychloroquine will be recorded and reported to the DSMB at DSMB reviews and interim analyses.  
Before implementation of protocol version 2.0, patients could be enrolled with a pending SARS-CoV-2 
test result if clinical criterial were present suggesting a high likelihood of COVID-19. In these patients, if 
SARS-CoV-2 results returned negative and the clinical team identified a likely alternative cause of the 
patient’s clinical syndrome, the clinical team could elect to stop administration of the study drug. If the 
study drug was stopped for this reason, the timing and reason for study drug discontinuation was 
recorded.  After implementation of protocol version 2.0, only patients with laboratory-confirmed SARS-
CoV-2 infection are eligible.  
5. OUTCOMES 
5.1 Primary Outcome  
COVID Ordinal Outcomes Scale on Study Day 15:  
1. Death 
2. Hospitalized on invasive mechanical ventilation or ECMO 
3. Hospitalized on non-invasive ventilation or high flow nasal cannula 
4. Hospitalized on supplemental oxygen 
5. Hospitalized not on supplemental oxygen  
6. Not hospitalized with limitation in activity 
7. Not hospitalized without limitation in activity  
5.2 Secondary Outcomes 
• Time to recovery, defined as time to reaching level 5, 6, or 7 on the COVID Outcomes Scale, 
which is the time to the earlier of final liberation from supplemental oxygen or hospital discharge 
• All-location, all-cause 14-day mortality (assessed on Study Day 15) 
• All-location, all-cause 28-day mortality (assessed on Study Day 29) 
• COVID Ordinal Outcomes Scale on Study Day 3 
• COVID Ordinal Outcomes Scale on Study Day 8 
• COVID Ordinal Outcomes Scale on Study Day 29 
• Composite of death or receipt of ECMO through Day 28 
• Oxygen-free days through Day 28 
• Ventilator-free days through Day 28 
• Vasopressor-free days through Day 28 
• ICU-free days through Day 28 
• Hospital-free days through Day 28 
5.3 Safety outcomes 
• Seizure 
• Atrial or ventricular arrhythmia 
• Cardiac arrest 

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• Elevation in aspartate aminotransferase or alanine aminotransferase to twice the local upper limit 
of normal 
• Acute pancreatitis 
• Acute kidney injury 
• Receipt of renal replacement therapy 
• Symptomatic hypoglycemia 
• Neutropenia, lymphopenia, anemia, or thrombocytopenia 
• Severe dermatologic reaction 
5.4 Rationale for Primary Outcome 
COVID-19 has a broad spectrum of clinical severity.   Even among hospitalized patients, most recover 
without experiencing critical illness.30  Designing a trial with statistical power to detect a meaningful 
difference in ICU-free days or mortality might require an unfeasibly large sample size and could miss 
significant morbidity experienced by the majority of hospitalized patients.  Since the majority of 
morbidity from COVID-19 relates to hypoxemia, the fact that this outcome is tied to degree of hypoxemic 
respiratory failure increases its face validity and relevance.  For similar reasons, previous trials of severe 
influenza have employed a similar ordinal outcome.31  This ordinal scale has been selected as an outcome 
in multiple ongoing COVID-19 trials and is a preferred outcome by the World Health Organization 
Research and Development Blueprint for COVID-19.32 Use of this standardized outcome will increase the 
potential to compare the results of this trial with other trials and perform meta-analyses. 
 
6. DATA COLLECTION 
Given the infectious risk from COVID-19 and potential shortages of personal protective equipment 
(PPE), we will minimize face-to-face contact between patients and non-clinical staff.  Additionally, 
minimizing research activities and conducting the trial in a pragmatic manner will increase the ability to 
complete the trial in the face of strained clinical and research resources during the COVID-19 pandemic. 
We will emphasize data that can be collected from the electronic health record, radiographs obtained as 
part of routine clinical care, and assessments that can be completed over the telephone as needed.   
Biological specimens will not be collected as part of this trial.  To further elucidate the pathophysiology 
of COVID-19 and the effects of hydroxychloroquine, we encourage ancillary studies and co-enrollment in 
observational studies that collect biological specimens and more detailed data. 
6.1 Baseline Variable Collection 
• Presence or absence of inclusion and exclusion criteria 
• Date and time of randomization 
• Date of symptom onset 
• Admission data: date and time of presentation, origin (home, skilled nursing facility, 
rehabilitation/LTACH, nursing home, outside hospital, outside ICU), location at enrollment (ED, 
hospital ward, ICU) 
• Demographics (age, sex, race, ethnicity, height, weight) 

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• Comorbidities: AIDS, Leukemia, Malignant Lymphoma, Hemiplegia, Cerebrovascular Disease, A 
prior myocardial infarction, Congestive Heart Failure, Peripheral vascular disease, Dementia, 
COPD, Connective tissue disease, Peptic ulcer disease, History of hypertension, HIV positive 
(without AIDS), Alcoholism, Coronary artery disease, Rapidly fatal disease, Solid tumor, Liver 
disease, Diabetes mellitus, Moderate to severe kidney disease 
• Acute signs and symptoms: altered mental status, acute hypoxemic respiratory failure, liver 
function tests, renal function, coagulation studies, chest imaging results 
• Sequential Organ Failure Assessment (SOFA)33 at enrollment 
• Chronic use of medication: corticosteroids, ACE inhibitors, angiotensin receptor blockers, non-
steroids anti-inflammatory drugs, other  
• Receipt of open label antivirals between hospital presentation and enrollment: chloroquine, 
hydroxychloroquine, remdesivir, lopinavir/ritonavir, other  
• Receipt of open label immunomodulators between hospital presentation and enrollment: 
corticosteroids, tocilizumab, sarilumab, interferon β, other  
• Receipt of convalescent plasma between hospital presentation and enrollment 
• Receipt of azithromycin between hospital presentation and enrollment 
• Receipt of invasive mechanical ventilation, non-invasive ventilation, high-flow nasal cannula, 
vasopressors, and oxygen therapy at enrollment 
• Highest fraction of inspired oxygen, lowest arterial oxygen saturation, highest respiratory rate, 
lowest systolic blood pressure, highest heart rate in the 12 hours prior to enrollment 
• Diagnosis of Acute Respiratory Distress Syndrome (ARDS) by Berlin Criteria33 at enrollment 
• COVID Ordinal Outcomes Scale at enrollment 
6.2 Assessments between Hospital Presentation and Hospital Discharge 
• Specimen type, date, and result of SARS-CoV-2 testing conducted clinically  
• Specimen type, date, and result of viral testing conducted clinically 
• Specimen type, date, and result of bacterial testing conducted clinically 
• Date and time of study drug administration and reason for missed doses 
• COVID Ordinal Outcomes Scale on Days 2, 3, 4, 5, 8, 15, and 29 
• SOFA on Day 3 
• S/F ratio on Day 3 
• Receipt of open label antivirals between randomization and hospital discharge: chloroquine, 
hydroxychloroquine, remdesivir, lopinavir/ritonavir, other  
• Receipt of open label immunomodulators between randomization and hospital discharge: 
corticosteroids, tocilizumab, sarilumab, interferon β, other  
• Receipt of convalescent plasma between hospital presentation and enrollment 
• Receipt of azithromycin and other antibiotics between randomization and Day 8 
• Clinically diagnosed deep vein thrombosis (DVT) or pulmonary embolism (PE) between hospital 
presentation and hospital discharge. 
• Date and time of first receipt of supplemental oxygen (if applicable)  
• Date and time of final receipt of supplemental oxygen (if applicable) 
• Date and time of first receipt of high flow nasal cannula (if applicable)  

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• Date and time of final receipt of high flow nasal cannula (if applicable) 
• Date and time of first receipt of non-invasive ventilation (if applicable)  
• Date and time of final receipt of non-invasive ventilation (if applicable) 
• Date and time of first receipt of invasive mechanical ventilation (if applicable)  
• Date and time of final receipt of invasive mechanical ventilation (if applicable) 
• Date and time of first receipt of extracorporeal membrane oxygenation (if applicable)  
• Date and time of final receipt of extracorporeal membrane oxygenation (if applicable) 
• Date and time of first receipt of vasopressors (if applicable)  
• Date and time of final receipt of vasopressor (if applicable) 
• Date and time of first meeting the Berlin Diagnostic Criteria for ARDS33 (if applicable) 
• Date and time of first ICU admission (if applicable)  
• Date and time of final ICU discharge (if applicable) 
• Date and time of hospital discharge (if applicable) 
• Date of death (if applicable) 
• Safety Outcomes: seizure, atrial or ventricular arrhythmia, cardiomyopathy, cardiac arrest, aspartate 
aminotransferase or alanine aminotransferase levels that are greater than twice the local upper limit 
of normal, acute pancreatitis (defined by a clinically obtained lipase level above the local upper 
limit of normal), stage II or greater acute kidney injury according to KDIGO criteria34, receipt of 
new renal replacement therapy, symptomatic hypoglycemia, neutropenia, lymphopenia, anemia, 
thrombocytopenia, or severe dermatologic reaction (e.g., Steven’s Johnson Syndrome) 
• Patient destination at discharge 
6.3 Assessments following Hospital Discharge 
6.3.1 Acute Care Follow-up 
For participants discharged from the study hospital prior to the Day 8, Day 15 or Day 29 assessment, we 
will perform these assessments via telephone follow-up.  The Day 8 call window will be Day 8 through 
14. The Day 15 call window will be Day 15 through 22.  The Day 29 call window will be Day 29 through 
36.  During these telephone calls, we will interview the patient, LAR, or facility staff to assess: 
• Number and reason for missed doses of study drug (only for those discharged prior to completing 
study drug) 
• Date of death (if applicable) 
• ED visits, hospital readmissions, and use of supplemental oxygen after hospital discharge 
• Non-laboratory safety outcomes after hospital discharge and adverse events 
• Symptoms of acute respiratory infection 
• COVID Ordinal Outcomes Scale 
6.3.2 Long-term Follow-up 
We will follow-up selected patients at 3, 6, and 12 months to assess vital status, cognition, basic and 
instrumental activities of daily living, quality of life, employment status, physical disability, and 
psychological distress (i.e., depression, post-traumatic stress disorder, etc.), place of residence, and 
rehospitalizations. These assessments may occur by phone, in-person, or videoconferencing. 

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Follow-up procedures in ORCHID are further specified by the Outcomes Related to COVID-19 treated 
with Hydroxychloroquine among In-patients with symptomatic Disease – Brain Outcomes and 
Psychological Distress (ORCHID-BUD) ancillary study.  In summary, ORCHID-BUD will perform a 
phone battery at 12-months to determine cognition, post-traumatic stress disorder, and depression.  In 
order to determine incident cases of cognitive impairment, post-traumatic stress disorder, and depression, 
baseline data will be collected from the subject’s family member or friend or the subject him/herself. 
Details of ORCHID-BUD study procedures are described in Appendix E. 
 
7. STATISTICAL CONSIDERATIONS 
 
7.1 Statistical Approach 
The primary analysis will be an intention-to-treat comparison of the Day 15 COVID Ordinal Outcome 
score between patients randomized to hydroxychloroquine versus placebo.  This analysis will be 
conducted with a proportional odds model using the Day 15 COVID Ordinal Outcome score as the 
dependent variable, randomized group assignment as the primary independent variable, and the following 
co-variables: age, sex, baseline COVID Ordinal Outcome score, baseline SOFA score, and duration of 
acute respiratory infection symptoms prior to randomization.  An odds ratio >1.0 indicates more favorable 
outcomes with hydroxychloroquine on the COVID Ordinal Outcome scale, while an odds ratio <1.0 
indicates more favorable outcomes with placebo.  
Patients enrolled prior to implementation of protocol version 2.0 who did not have laboratory confirmed 
SARS-CoV-2 infection will be included in the primary intention to treat analysis. In additional to 
reporting data for the full trial population we will also report data separately for patients randomized in 
the ICU (who tend to be more severely ill) and those randomized outside the ICU (who tend to be less 
severely ill) as well as those with duration of symptoms ≤5 days prior to randomization and those with >5 
days of symptoms prior to randomization.  
The anticipated study size is about 510 patients. We calculated the sample size under the assumption that 
we would have an interim analysis after approximately each 102 patients. We calculated the standard 
error of the log(odds-ratio) statistic with 51 patients per arm based on data from a recently completed trial 
within the PETAL Network that enrolled patients early in the course of critical illness, the Vitamin D to 
Improve Outcomes by Leveraging Early Treatment (VIOLET) trial.35 In the VIOLET trial at Day 15, 
11.5% of patients had died, 5.8% were on invasive mechanical ventilation, 22.9% remained in the 
hospital, and the remaining had been discharged from the hospital (Table 1). We used these outcomes in 
VIOLET to approximate Day 15 outcomes on the COVID Ordinal Outcome scale that we may observe in 
this trial.   
Table 1. Patient status 14 days (“Day 15”) after randomization in the VIOLET trial.35 
Patient Status 
Percentage of patients 
Dead 
11.5% 
Invasive mechanical ventilation 
5.8% 
Hospitalized, not on invasive mechanical ventilation 
21.9% 
Discharged from the hospital 
60.8% 

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We plan to use a Bayesian analysis of the evolving data which allows flexibility in the number and timing 
of the interim analyses.  If we determine there is >95% probability of the odds ratio being >1.0, the 
DSMB should consider stopping the trial for efficacy. If we determine there is >90% probability that the 
odds ratio is <1.1, the DSMB should consider stopping the trial for futility. If we determine there is >70% 
probability that the odds ratio is <0.70, the DSMB should consider stopping the trial for harm. We will 
use a prior odds ratio of 1.0 (equal chance of harm and benefit; mean log OR of 0.0) and a prior 
distribution of the standard error for its log set at 0.352 for tests of efficacy and a non-informative prior 
for tests of futility and harm. The results will be reported in a similar manner to those published by 
Goligher et al.36    One advantage of Bayesian analysis is that stopping guidelines are not binding and the 
DSMB is charged with using judgement and data both internal and external to the trial to make any 
irrevocable decision. 
 
If the trial enrolls 510 participants, further enrollment will be paused until the DSMB reviews data on the 
primary outcome from all enrolled participants; a decision to continue enrollment will be made by 
NHLBI after reviewing DSMB recommendations while the investigators remain blinded.   
 
We calculated probabilities that this trial would stop for efficacy or futility based on several fixed 
scenarios assuming we had an interim analysis after each 102 patients.  The probabilities for continuing, 
stopping for efficacy, and stopping for futility based on a true odds ratio of 1.0 (no difference between the 
hydroxychloroquine and placebo groups) and 1.8 (substantially better outcomes in the 
hydroxychloroquine group) are show in Table 2 and Table 3.   
 
Table 2.  Probabilities of continuing or stopping the trial before or at the time 510 patients analysed 
based on a true odds ratio of 1.0 and 1.8.   
 
Odds Ratio = 1.0 
Probability 
Odd Ratio = 1.8 
Probability 
Continue 
0.556 
0.057 
Stop for Efficacy 
0.061 
0.937 
Stop for Futility 
0.383 
0.007 
 
 
Table 3. Probabilities of continuing or stopping the trial on or before the nth interim analysis based on a 
true odds ratio of 1.0 and 1.8.   
 
Odds Ratio = 1.0 
 
Odds Ratio = 1.8 
Interim 
Analysis 
Continue 
Stop for 
Efficacy  
Stop for 
Futility 
 
Continue 
Stop for 
Efficacy  
Stop for 
Futility 
1 
0.844 
0.006 
0.150 
 
0.840 
0.154 
0.006 
2 
0.744 
0.021 
0.235 
 
0.494 
0.500 
0.007 
3 
0.667 
0.036 
0.297 
 
0.254 
0.740 
0.007 
4 
0.606 
0.0509 
0.344 
 
0.122 
0.871 
0.007 
5 
0.556 
0.061 
0.383 
 
0.056 
0.937 
0.007 
 
To illustrate frequentist properties of these tests, we plotted the p-values at each interim analysis where 
the interim stopped for futility or efficacy or continued based on an odds ratio of 1.0 (Figure 1) and 1.8 
(Figure 2) 

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FIGURE 1 
 
 
 
FIGURE 2 
 
 

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7.2 Planned deviations from this design 
This trial is being conducted in a rapidly evolving pandemic of a novel disease.  Thus, we have developed 
a statistical plan with flexibility to be modified based on results from other concurrently conducted trials 
and emerging data on the clinical epidemiology of COVID-19.  The primary advantage of a Bayesian 
monitoring plan is that whenever the trial is stopped the inference only depends on the data and not the 
original statistical plan that was developed at a time when less was known about COVID-19 and 
potentially effective treatments.  
We suspect multiple trials of hydroxychloroquine for COVID-19 will be conducted simultaneously.  We 
will be receiving reports of completed studies and may be receiving interim reports of ongoing ones as 
well. We will incorporate this information using Bayesian methods, which allows us to calculate posterior 
probabilities that use this information.37 This method weights the external data based on their relevance to 
the trial we are conducting.  In addition, there may be reasons to continue this trial past the 510 patients 
initially planned. For instance, if the trial reaches the 510 patient interim analysis, the posterior 
probabilities indicate a reasonable chance of efficacy, and the question of hydroxychloroquine’s efficacy 
is still relevant, the current design can be continued with the same stopping rules. 
 
8. DATA QUALITY MONITORING AND STORAGE 
8.1 Data Quality Monitoring 
Data quality will be reviewed remotely using front-end range and logic checks at the time of data entry 
and back-end monitoring of data using application programming interface tools connecting the online 
database to statistical software to generate data reports. Patient records and case report forms will also be 
examined by site personnel for a randomly selected 5-10% sample to evaluate the accuracy and 
completeness of the data entered into the database and monitor for protocol compliance.  The 
coordinating center will perform remote monitoring of each study site to examine the completeness and 
accuracy of informed consent documents for study participants, documentation of eligibility criteria, and 
the completeness of study outcome collection. 
8.2 Data Storage  
Data will be entered into a secure online database.  All data will be maintained in the secure online 
database until the time of study publication.  At the time of publication, a de-identified version of the 
database will be generated. 
 
9. RISK ASSESSMENT 
9.1 Potential Risk to Participants 
Although hydroxychloroquine is an FDA approved medication with an established safety profile 
(described as “among the safest medications used for the treatment of systematic rheumatic disease”),38 

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potential risks exist to participating in this study of hydroxychloroquine versus placebo for the treatment 
of COVID-19.   
9.1.1 Potential risks of receiving hydroxychloroquine   
Potential risks of receiving hydroxychloroquine can be classified based on their severity as Major or 
Minor.  Major potential risks of receiving hydroxychloroquine include: 
1) Neurological System 
a) Seizure – Hydroxychloroquine can lower the seizure threshold and co-administration of 
hydroxychloroquine with other medications known to lower the seizure threshold has been 
reported to increase the risk of seizures.  This trial protocol excludes patients with a seizure 
disorder. 
b) Psychosis – A small number of case reports describe psychosis in patients on long-term treatment 
with hydroxychloroquine,39 but has not been described with short-term treatment. 
c) Suicidal behavior - Suicidal behavior has been rarely reported in patients on long-term treatment 
with hydroxychloroquine for rheumatologic disorders,40 but not with short-term therapy. 
2) Circulatory system 
a) Cardiac arrhythmias 
i) Ventricular arrhythmias and torsades de pointes – Hydroxychloroquine can prolong the QT 
interval and ventricular arrhythmias and torsades de points have been reported in patients 
taking hydroxychloroquine.  This trial protocol excludes patients with a prolonged QTc on 
baseline EKG and history of prolonged QTc syndromes, assesses the QTc after receipt of 
study drug, monitors daily for co-administration of medications that prolong the QTc and 
specifies criteria for stopping the study drug based on prolonged QTc. 
ii) Cardiomyopathy, sick sinus syndrome, atrioventricular block, or bundle branch block – 
Cardiomyopathy and conduction system disease have rarely been reported among patients on 
long-term hydroxychloroquine,41 but have not been reported among patients receiving less 
than 3 months of therapy. 
3) Digestive system 
a) Liver injury – Fulminant hepatic failure has been reported in at least two cases from long-term 
administration of hydroxychloroquine.42  Porphyria cutanea tarda appears to be a risk factor for 
liver injury from hydroxychloroquine.  This trial protocol excludes patients with porphyria 
cutanea tarda. 
b) Increased cyclosporine or digoxin levels – hydroxychloroquine can increase levels of 
cyclosporine or digoxin for patients being co-administered these medications.  This trial protocol 
monitors daily for receipt of medications that interact with hydroxychloroquine and notifies 
treating clinicians about potential medication interactions. 
4) Endocrine system 
a) Symptomatic hypoglycemia – hydroxychloroquine can increase risk of hypoglycemia, especially 
when co-administered with antidiabetic agents, although this is rarely observed in clinical 
practice.43 
5) Integumentary system 
a) Severe dermatologic reactions – A mild dermatologic reaction occurs in approximately 10 percent 
of patients treated with hydroxychloroquine, but severe dermatologic reactions such as Steven’s 

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Johnson Syndrome or Toxic Epidermal Necrolysis are rare.  For example, in one recent case 
series of patients on hydroxychloroquine with dermatologic reactions, none of the reported 
reactions were severe.44 
6) Hematological system 
a) Neutropenic, leukopenia, anemia, thrombocytopenia – Rare toxicities of hydroxychloroquine 
include agranulocytosis45 and aplastic anemia, but there has never been a report of this occurring 
with hydroxychloroquine in doses less than 7 mg/kg/day or during short-term use. 
Minor potential risks of receiving hydroxychloroquine include: retinopathy or corneal deposits (with 
months-to-years of therapy); vertigo, tinnitus, or deafness; headache; light-headedness; insomnia; tremor 
or dyskinesia; peripheral neuropathy (with months-to-years of therapy); nausea, vomiting, or diarrhea; 
mild dermatologic reaction; and muscle weakness (with months-to-years of therapy). 
9.1.2 Potential risks of receiving placebo with COVID-19 
One potential risk to participating in this study is receiving placebo rather than hydroxychloroquine.  This 
risk is only relevant if hydroxychloroquine is ultimately found to be an effective therapy for COVID-19 
and is not relevant if hydroxychloroquine is ultimately found to be an ineffective therapy for COVID-19.  
This trial protocol minimizes this risk through rigorous design to minimize the number of patients who 
must be enrolled to determine whether hydroxychloroquine is an effective therapy for COVID-19, 
excluding patients who decline to participate because they feel their optimal care requires 
hydroxychloroquine, excluding patients whose treating clinicians declines to allow enrollment because 
they feel the patient’s optimal care requires treatment with hydroxychloroquine, and specifying 
procedures for stopping the study drug, unblinding, and allowing open-label administration of 
hydroxychloroquine for patients who experience clinical deterioration during the study period. 
9.1.3 Potential risks of receiving an EKG. 
EKGs are a safe, noninvasive, painless test and have no major risks. Patients may develop a mild rash or 
skin irritation where the electrodes were attached. If any paste or gel was used to attach the electrodes, 
patients may have an allergic reaction to it. This irritation usually goes away once the patches are 
removed, without requiring treatment. 
9.2 Minimization of Risk 
Federal regulations at 45 CFR 46.111(a)(1) require that risks to participants are minimized by using 
procedures which are consistent with sound research design.  This trial protocol incorporates numerous 
design elements to minimize risk to patients that meet this human subject protection requirement.  
Hydroxychloroquine has been approved by the Food and Drug Administration and has been used in 
clinical practice for decades in a number of patient populations with an established safety profile.  The 
dose and route of administration of hydroxychloroquine in this trial are comparable to the dose and route 
of administration approved for the treatment of other acute infections, such as malaria.  The duration of 
treatment in this trial of 5 days is significantly shorter than for treatment of rheumatologic conditions, for 
which the drug is frequently administered for multiple years.  To further mitigate risk, we will exclude 
patients with specific risk factors for adverse events from hydroxychloroquine including patients with 
prolonged QTc, patients receiving medications that may interact with hydroxychloroquine to prolong the 
QTc, patients with seizure disorder, and patients with porphyria cutanea tarda.  The trial protocol includes 

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on-study monitoring to minimize the risk to patients during therapy.  This monitoring includes assessment 
of QTc after receipt of study drug with specific criteria at which the study drug would be stopped.  This 
monitoring also includes both automated electronic health record and manual study personnel review for 
medications with potential interactions with hydroxychloroquine during the 5-day study period.  The trial 
protocol includes monitoring of adverse events, clinical outcomes, and interim analyses by an 
independent data and safety monitoring board empowered to stop or modify the trial at any time.   
9.3 Potential Benefit 
Study participants may or may not receive any direct benefits from their participation in this study. 
Administration of hydroxychloroquine may improve clinical outcomes among adults hospitalized for 
COVID-19 infection. 
9.4 Risk in Relation to Anticipated Benefit 
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable in relation to 
anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be 
expected to result.” Based on the preceding assessment of risks and potential benefits, the risks to subjects 
are reasonable in relation to anticipated benefits.  Hydroxychloroquine has been used in clinical practice 
for decades and previously evaluated for the treatment of patients acutely ill from infection with 
substantial data to support its safety and potential efficacy. 
 
10. HUMAN SUBJECTS PROTECTIONS 
Each study participant or a LAR must sign and date an informed consent form. Approval of the central 
institutional review board will be required before any participant is entered into the study.  
10.1 Selection of Subjects 
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of subjects. The emergency 
departments, hospital wards, and ICUs of participating sites will be screened to determine if any patient 
meets inclusion and exclusion criteria. Data that have been collected as part of the routine clinical care of 
the patient will be reviewed to determine eligibility. If any patient meets criteria for study enrollment, 
then the attending physician responsible for his or her care will be asked for permission to approach the 
patient or his or her LAR for informed consent. Study exclusion criteria neither unjustly exclude classes 
of individuals from participation in the research nor unjustly include classes of individuals for 
participation in the research. Hence, the recruitment of participants conforms to the principle of 
distributive justice. 
10.2 Justification of Including Vulnerable Subjects 
The present research aims to investigate the safety and efficacy of hydroxychloroquine for the treatment 
of patients with COVID-19 who are at high risk for respiratory failure and mortality. Due to the nature of 
this patient population, many of these patients will have impaired decision-making capabilities. 
Moreover, those with intact decision-making capacities probably have milder disease than those with 
impaired capacity. Therefore, the validity of the study and its generalizability to severely ill patients 
would be compromised by enrolling only those participants with retained decision-making capacity. 

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Hence, participants recruited for this trial are not being unfairly burdened with involvement in this 
research. 
10.3 Informed Consent 
Federal regulations 45 CFR 46.111(a)(5) require that informed consent will be sought from each patient 
or the patient’s LAR. Study personnel obtaining informed consent are responsible for ensuring that the 
patient or LAR understands the risks and benefits of participating in the study, answering any questions 
the patient or LAR may have throughout the study and sharing any new information in a timely manner 
that may be relevant to the patient’s or LAR’s willingness to permit the patient’s continued participation 
in the trial. The study personnel obtaining informed consent will make every effort to minimize coercion. 
All patients or their LARs will be informed of the objectives of the study and the potential risks. The 
informed consent document will be used to explain the risks and benefits of study participation to the 
patient or LAR in simple terms before the patient is entered into the study, and to confirm that the patient 
or LAR is satisfied with his or her understanding of the risks and benefits of participating in the study and 
desires to participate in the study. The investigator is responsible for ensuring that informed consent is 
given by each patient or LAR. This includes obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures including administration 
of study agent. 
For additional details, see Section 3. 
10.4 Continuing Consent 
Patients for whom consent was initially obtained from a LAR, but who subsequently regain decision-
making capacity while in hospital will be approached for consent for continuing participation, including 
continuance of data acquisition. The consent form signed by the LAR should reflect that such consent 
should be obtained.  The process for obtaining consent from these patients will be the same as that 
outlined in section 3. 
10.5 Withdrawal of Consent 
Participating patients may withdraw or be withdrawn (by the LAR, treating physician, or investigator) 
from the trial at any time without prejudice. Data recorded up to the point of withdrawal will be included 
in the trial analysis, unless consent to use data has also been withdrawn. Withdrawal of consent prior to 
receipt of study drug will constitute a screen-failure and will be recorded.  Withdrawal of consent after 
randomization and administration of one or more doses of study drug will lead to discontinuation of study 
interventions but site staff will request access to medical records for data related to the trial.   
10.6 Identification of Legally Authorized Representatives 
Many of the patients approached for participation in this research protocol will have impaired decision-
making capacity due to critical illness and will not be able to provide informed consent. Accordingly, 
informed consent will be sought from the patient’s LAR.   
Regarding consent from the LAR, the existing federal research regulations (‘the Common Rule’) states at 
45 CFR 46.116 that “no investigator may involve a human being as a subject in research…unless the 
investigator has obtained the legally effective informed consent of the subject or the subject’s legally 

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authorized representative”; and defines at 45 CFR 46 102 (c) a LAR as “an individual or judicial or other 
body authorized under applicable law to consent on behalf of a prospective subject to the subject’s 
participation in the procedures(s) involved in the research.” The Office of Human Research Protections 
(OHRP) defined examples of “applicable law” as being state statutes, regulations, case law, or formal 
opinion of a State Attorney General that addresses the issue of surrogate consent to medical procedures. 
Such “applicable law” could then be considered as empowering the LAR to provide consent for 
participant participation in the research. Interpretation of “applicable law” may be state specific and will 
be addressed by the central IRB.  
According to a previous President’s Bioethics Committee (National Bioethics Advisory Committee 
(NBAC)), an investigator should accept a relative or friend of the potential participant who is recognized 
as an LAR for purposes of clinical decision making under the law of the state where the research takes 
place.46 Finally, OHRP has stated in their determination letters that a surrogate could serve as a LAR for 
research decision making if such an individual is authorized under applicable state law to provide consent 
for the “procedures” involved in the research study 
10.7 Justification of Surrogate Consent 
According to the Belmont Report, respect for persons incorporates at least two ethical convictions; first, 
that individuals should be treated as autonomous agents, and second, that persons with diminished 
autonomy are entitled to protection. One method that serves to protect patients is restrictions on the 
participation of patients in research that presents greater than minimal risk. Commentators and research 
ethics commissions have held the view that it is permissible to include incapable participants in greater 
than minimal risk research as long as there is the potential for beneficial effects and that the research 
presents a balance of risks and expected direct benefits similar to that available in the clinical setting.47 
Several U.S. task forces have deemed it permissible to include incapable participants in research. For 
example, the American College of Physicians’ document allows surrogates to consent to research 
involving incapable participants only “if the net additional risks of participation are not substantially 
greater than the risks of standard treatment”.48 Finally, NBAC stated that an IRB may approve a protocol 
that presents greater than minimal risk but offers the prospect of direct medical benefits to the participant, 
provided that “the potential subject’s LAR gives permission…”.46 
Consistent with the above ethical sensibilities regarding the participation of decisionally incapable 
participant in research and the previous assessment of risks and benefits in the previous section, the 
present trial presents a balance of risks and potential direct benefits that is similar to that available in the 
clinical setting. 
10.8 Additional Safeguards for Vulnerable Participants 
The present research will involve participants who might be vulnerable to coercion or undue influence. As 
required in 45CFR46.111(b), we recommend that sites utilize additional safeguards to protect the rights 
and welfare of these participants. Such safeguards might include but are not limited to: a) assessment of 
the potential participant’s capacity to provide informed consent, and b) the availability of the LAR to 
monitor the participant’s subsequent participation and withdrawal from the study. The specific nature of 
the additional safeguards will be left to the discretion of the central IRB, in conjunction with the sites. 

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10.9 Confidentiality 
Federal regulations at 45 CFR 46 111 (a) (7) requires that when appropriate, there are adequate provisions 
to protect the privacy of participants and to maintain the confidentiality of data. At no time during the 
course of this study, its analysis, or its publication will patient identities be revealed in any manner.  The 
minimum necessary data containing patient or provider identities will be collected.  All patients will be 
assigned a unique study ID number for tracking.  All data collected for this study will be entered directly 
into a secure online database.  All data will be maintained in the secure online database until the time of 
study publication.  At the time of publication, a de-identified version of the database will be generated. 
Further, tools within the secure online database will be used so that only the coordinating center and 
investigators from the enrolling site will have access to data from participants enrolled at that site. 
 
11. ADVERSE EVENTS 
 
Assuring patient safety is an essential component of this protocol.  Hydroxychloroquine has been 
approved by the Food and Drug Administration and used in clinical practice for decades with an 
established safety profile.  Use of hydroxychloroquine for the treatment of acute respiratory infection due 
to COVID-19, however, raises unique safety considerations.  This protocol addresses these considerations 
through: 
1. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse events with 
receipt of hydroxychloroquine; 
2. Proactive education of treating clinicians regarding medication interactions relevant to use of 
hydroxychloroquine in the inpatient setting; 
3. On-study monitoring of co-interventions (e.g., medications) and patient characteristics (e.g., EKG) to 
intervene before adverse events occur; 
4. Systematic collection of safety outcomes relevant to use of hydroxychloroquine in this setting; 
5. Structured reporting of adverse events 
11.1 Adverse Event Definitions 
Adverse Event: Any untoward medical occurrence associated with the use of a drug or a study 
procedure, whether or not considered drug related. 
Serious Adverse Event: A serious adverse event is any adverse event that results in one of the outcomes 
listed in section 11.3 below.  
Adverse Reaction: An adverse reaction means any adverse event caused by a study intervention. An 
adverse reaction is a subset of all suspected adverse events where there is a reason to conclude that the 
study intervention caused the event.  
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the 
study procedures caused the adverse event. Reasonable possibility means there is evidence to suggest a 

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causal relationship between the study procedures and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction.  
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is both 
unexpected (not consistent with risks outlined in the study protocol or investigator brochure), serious, and 
meets the definition of a suspected adverse reaction. 
11.2 Safety Monitoring 
Assuring patient safety is an essential component of this protocol. Each participating investigator has 
primary responsibility for the safety of the individual participants under his or her care. The Investigators 
will determine daily if any adverse events occur during the period from enrollment through study day 7 
(48 hours after completion of the study drug) or hospital discharge, whichever occurs first and will 
determine if such adverse events are reportable.  Thereafter, adverse events are not required to be reported 
unless the investigator feels the adverse event was related to study drug or study procedures.   
The following adverse events will be considered reportable and thus collected in the adverse event case 
report forms: 
 
 Serious adverse events 
 Non-serious adverse events that are considered by the investigator to be related to study 
procedures or of uncertain relationship (Appendix C) 
 Events leading to permanent discontinuation of study drug 
Study-specific clinical outcomes (Primary, Secondary and Safety Outcomes and Assessments 
During the Study), including serious outcomes such as organ failures and death, are 
systematically recorded in the case report forms and are exempt from adverse event reporting 
unless the investigator deems the event to be related to the administration of study drug or the 
conduct of study procedures (or of uncertain relationship) as outlined in Appendix C.  
After randomization, adverse events must be evaluated by the investigator. If the adverse event is judged 
to be reportable, as outlined above, then the investigator will report to the CCC their assessment of the 
potential relatedness of each adverse event to the study drug or protocol procedure via electronic data 
entry. Investigators will assess if there is a reasonable possibility that the study procedure caused the 
event, based on the criteria outlined in Appendix C. Investigators will also consider if the event is 
unexpected.  Unexpected adverse events are events not listed in the study protocol and the investigator 
brochure for Hydroxychloroquine. Investigators will also determine if adverse events are unanticipated 
given the patient’s clinical course, previous medical conditions, and concomitant medications.   
If a patient's treatment is discontinued as a result of an adverse event, study site personnel must also 
report the circumstances and data leading to discontinuation of treatment in the adverse event case report 
forms.   
11.3 Serious Adverse Events 
Serious adverse event collection begins after randomization and study procedures have been initiated.  If a 
patient experiences a serious adverse event after consent, but prior to randomization or starting study 
procedures, the event will NOT be collected. Study site personnel must alert the CCC of any serious and 

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study procedure related adverse event within 24 hours of investigator awareness of the event.  Alerts 
issued via telephone are to be immediately followed with official notification on the adverse event case 
report form. See Appendix C for reporting timelines for serious, unexpected, study related events (SAEs) 
and serious, unexpected suspected adverse reactions (SUSARs) 
As per the FDA and NIH definitions, a serious adverse event is any adverse event that results in one of 
the following outcomes: 
 Death 
 A life-threatening experience (that is, immediate risk of dying) 
 Prolonged inpatient hospitalization or re-hospitalization 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if admission 
to the hospital or prolongation of hospitalization was a result of the adverse event. Emergency room 
visits that do not result in admission to the hospital should be evaluated for one of the other serious 
outcomes (e.g., life-threatening; required intervention to prevent permanent impairment or damage; 
other serious medically important event). 
 Persistent or significant disability/incapacity 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if the adverse 
event resulted in 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. 
Reportable serious adverse 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. 
Serious adverse events will be collected during the first 7 study days or until hospital discharge, 
whichever occurs first, regardless of the investigator's opinion of causation.  
 
12. Data and Safety Monitoring Board (DSMB) 
The principal role of the DSMB is to assure the safety of participants in the trial. They will regularly 
monitor data from this trial, review and assess the performance of its operations, and make 
recommendations to the steering committee and NHLBI with respect to:  
• 
Review of adverse events 
• 
Interim results of the study for evidence of efficacy or adverse events 
• 
Possible early termination of the trial because of new external information, early attainment of 
study objectives, safety concerns, or inadequate performance 
• 
Possible modifications in the clinical trial protocol  
• 
Performance of individual centers  
The NHLBI PETAL Network DSMB is appointed by the Director of the NHLBI and makes 
recommendations to the Director. The DSMB reviews all protocols for safety following review by an 

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independent NHLBI Protocol Review Committee. The DSMB will consist of members with expertise in 
acute lung injury, emergency medicine, biostatistics, ethics, and clinical trials. An NHLBI staff member 
not associated with PETAL will serve as Executive Secretary. Appointment of all members is contingent 
upon the absence of any conflicts of interest. All the members of the DSMB are voting members. The 
Principal Investigator and the Medical Monitor of the CCC will be responsible for the preparation of all 
DSMB and adverse event reports and may review unblinded data. The DSMB will develop a charter and 
review the protocol and sample consent form during its first meeting. Subsequent DSMB meetings will be 
scheduled in accordance with the DSMB Charter with the assistance of the CCC. When appropriate, 
conference calls may be held in place of face-to-face meetings. Recommendations to end, modify, or 
continue the trial will be prepared by the DSMB executive secretary for review by the NHLBI Director. 
Recommendations for major changes, such as stopping the trial, will be reviewed by the NHLBI Director 
and communicated immediately. Other recommendations will be reviewed by the NHLBI director and 
distributed in writing to the CCC, which will distribute to the PETAL steering committee with 
instructions for reporting to local IRBs when appropriate.   
Details of the NHLBI policies regarding DSMBs can be found at the following URL: 
https://www.nhlbi.nih.gov/grants-and-training/policies-and-guidelines/nhlbi-policy-data-and-safety-
monitoring-extramural-clinical-studies 
 
 
 

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Coronaviruses. Trends Microbiol 2016;24(6):490–502.  
11.  Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 
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and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern 
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COVID-19 in Washington State. JAMA [Internet] 2020 [cited 2020 Mar 19];(Publised Online). 
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20.  Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy 
for the treatment of emerging viral diseases. Pharmacol Res Perspect 2017;5(1):e00293.  
21.  Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in 
inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6(1):1–4.  
22.  Colson P, Rolain J-M, Lagier J-C, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as 
available weapons to fight COVID-19. Int J Antimicrob Agents 2020;105932.  
23.  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. Ann Intern Med [Internet] 
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Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020;323(11):1061–9.  
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27.  Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in 
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28.  Paton NI, Goodall RL, Dunn DT, et al. Effects of hydroxychloroquine on immune activation and 
disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized 
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29.  Roques P, Thiberville S-D, Dupuis-Maguiraga L, et al. Paradoxical Effect of Chloroquine 
Treatment in Enhancing Chikungunya Virus Infection. Viruses 2018;10(5).  

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30.  Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J 
Med 2020;0(0):null.  
31.  Wang Y, Fan G, Salam A, et al. Comparative effectiveness of combined favipiravir and oseltamivir 
therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection. J 
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33.  ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress 
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35.  National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Ginde AA, Brower RG, 
et al. Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients. N Engl J Med 
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36.  Goligher EC, Tomlinson G, Hajage D, et al. Extracorporeal Membrane Oxygenation for Severe 
Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a Post Hoc 
Bayesian Analysis of a Randomized Clinical Trial. JAMA 2018;320(21):2251–9.  
37.  Schoenfeld DA, Hui Zheng, Finkelstein DM. Bayesian design using adult data to augment pediatric 
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38.  Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in 
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39.  Manzo C, Gareri P, Castagna A. Psychomotor Agitation Following Treatment with 
Hydroxychloroquine. Drug Saf - Case Rep 2017;4(1):6.  
40.  Gonzalez-Nieto JA, Costa-Juan E. Psychiatric symptoms induced by hydroxychloroquine. Lupus 
2015;24(3):339–40.  
41.  Joyce E, Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving 
biventricular cardiomyopathy: key diagnostic features and literature review. Eur Heart J Acute 
Cardiovasc Care 2013;2(1):77–83.  
42.  Hydroxychloroquine [Internet]. In: LiverTox: Clinical and Research Information on Drug-Induced 
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43.  Cansu DU, Korkmaz C. Hypoglycaemia induced by hydroxychloroquine in a non-diabetic patient 
treated for RA. Rheumatol Oxf Engl 2008;47(3):378–9.  
44.  Pelle MT, Callen JP. Adverse cutaneous reactions to hydroxychloroquine are more common in 
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2002;138(9):1231–3; discussion 1233.  

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45.  Sames E, Paterson H, Li C. Hydroxychloroquine-induced agranulocytosis in a patient with long-
term rheumatoid arthritis. Eur J Rheumatol 2016;3(2):91–2.  
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1989;111(10):843–8.  
 
 
 
 

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14. APPENDICES  
Appendix A. Schedule of Events 
Study Activity  
Pre-
Enrollment 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15  
Day 
29  
3 
Months 
6 
Months 
12 
Months 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
Xa 
 
 
 
 
 
 
 
 
 
Pregnancy test (if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic and 
baseline variable 
collection 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug delivery 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Assessment for study 
drug adherence 
 
X 
Xa 
Xa 
Xa 
Xa 
Xb 
 
 
 
 
 
Safety monitoring for 
adverse events 
 
X 
Xa 
Xa 
Xa 
Xa 
Xb 
Xb 
Xb 
 
 
 
Assessment of COVID 
ordinal outcome score 
X 
 
Xa 
Xa 
Xa 
Xa 
Xb 
Xb 
Xb 
 
 
 
Mortality assessment 
 
 
 
 
 
 
 
Xb 
Xb 
 
 
 
28-day in-hospital 
outcomes  
(chart review) 
 
 
 
 
 
 
 
 
X 
 
 
 
Long-term outcomes 
 
 
 
 
 
 
 
 
 
Xc 
Xc 
Xc 
 
a. Assessed only if patient remains hospitalized. 
b. Assessed by telephone follow-up if the patient has been discharged. 
c. Assessed in selected patients in-person, or by telephone or videophone.    
 
 

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Appendix B. Potential medication interactions with hydroxychloroquine 
A. Medications considered contraindicated, which if ordered on an inpatient during the 5-day study 
period will prompt study personnel to discuss with treating clinicians whether stopping the study 
drug is appropriate or if this medication cannot be stopped or substituted: amiodarone; 
chloroquine; 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 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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Appendix C:  Adverse Event Reporting and Unanticipated Events 
As noted in section 11, investigators will report all “serious adverse events,” defined as adverse events 
that are serious and have a reasonable possibility that the event was due to a study drug or procedure (or 
of uncertain relatedness), to the CCC within 24 hours. The CCC will then notify the NHLBI and Central 
Institutional Review Board (cIRB).  
The Medical Monitor at the CCC will work collaboratively with the reporting investigator to determine if 
a serious adverse event has a reasonable possibility of having been caused by the study drug or study 
procedure, as outlined in 21 CFR 312.32(a)(1), and below. The Medical Monitor will be unblinded and 
will also determine if the event is unexpected for hydroxychloroquine.  An adverse is considered 
“unexpected” if it is not listed in the investigator brochure or the study protocol (21 CFR 312.32(a)). If a 
determination is made that a serious adverse event has a reasonable possibility of having been caused by a 
study procedure or the study drug, it will be classified as a suspected adverse reaction. If the suspected 
adverse reaction is unexpected, it will be classified as a serious unexpected suspected adverse reaction 
(SUSAR).  
The CCC will report all unexpected deaths, serious and treatment related adverse events, and SUSARs to 
the DSMB, NHLBI, and cIRB within 7 days after receipt of the report from a clinical site. A written 
report will be sent to the NHLBI, DSMB, FDA, and the cIRB within 15 calendar days. The DSMB will 
also review all reported adverse events and clinical outcomes during scheduled interim analyses. The 
CCC will distribute the written summary of the DSMB’s periodic review of reported adverse events to the 
cIRB in accordance with NIH guidelines (http://grants.nih.gov/grants/guide/notice-files/not99-107.html). 
The Medical Monitor will provide to Sandoz Pharmacovigilance any significant safety findings (without 
disclosing protected health information) during the conduct of the trial.  
 
C.1. Unanticipated Problems (UP) 
Investigators must also report Unanticipated Problems, regardless of severity, associated with study 
procedures within 24 hours. An unanticipated problem is defined as follows: 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, in this guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research;  
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
C.2. Determining Relationship of Adverse Events to Study Drug or Study Procedures 
Investigators will be asked to grade the strength of the relationship of an adverse event to study drug or 
study procedures as follows:  

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• 
Definitely Related: The event follows: a) A reasonable, temporal sequence from a study 
procedure; and b) Cannot be explained by the known characteristics of the patient’s clinical state 
or other therapies; and c) Evaluation of the patient’s clinical state indicates to the investigator that 
the experience is definitely related to study procedures.  
• 
Probably or Possibly Related: The event should be assessed following the same criteria for 
“Definitely Associated”. If in the investigator’s opinion at least one or more of the criteria are not 
present, then “probably” or “possibly” associated should be selected.  
• 
Probably Not Related: The event occurred while the patient was on the study but can reasonably 
be explained by the known characteristics of the patient’s clinical state or other therapies.  
• 
Definitely Not Related: The event is definitely produced by the patient’s clinical state or by other 
modes of therapy administered to the patient.  
• 
Uncertain Relationship: The event does not meet any of the criteria previously outlined.  
C.3. Clinical Outcomes that may be Exempt from Adverse Event Reporting 
Study-specific outcomes of acute respiratory infection, COVID-19, and critical illness will be 
systematically collected for all patients in both study group and are exempt from adverse event 
reporting unless the investigator considers the event to be Definitely or Possibly Related (or of an 
Uncertain Relationship) to the study drug or study procedures.  Examples of study-specific clinical 
outcomes include: 
• 
Death not related to the study procedures  
• 
Neurological events 
o Seizure 
• 
Cardiovascular events 
o Receipt of vasopressors 
o Atrial or ventricular arrhythmia 
o Cardiac arrest 
• 
Respiratory events 
o Hypoxemia requiring supplemental oxygen 
o Acute respiratory distress syndrome 
o Receipt of mechanical ventilation 
o Receipt of extra-corporeal membrane oxygenation 
• 
Gastrointestinal events 
o Elevation of aspartate aminotransferase or alanine aminotransferase 
o Acute pancreatitis 
• 
Renal events 
o Acute kidney injury 
o Receipt of renal replacement therapy 
• 
Endocrine events 
o Symptomatic hypoglycemia 
• 
Hematologic or coagulation events 
o Neutropenia, lymphopenia, anemia, or thrombocytopenia 
• 
Dermatologic events 
o Severe dermatologic reaction (e.g., Steven’s Johnson Syndrome) 

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Note: A study-specific clinical outcome may also qualify as a reportable adverse event.  For example, a 
ventricular arrhythmia that the investigator considers Definitely or Possibly Related to the study drug 
would be both recorded as a study-specific clinical outcome and reported as a Serious and Definitely or 
Possibly Related Adverse Event. 
 
C.4. Decision tree for determining if an adverse event is reportable 
Figure 1. Decision tree for determining if an adverse event is reportable 
 
 
 
Figure adapted from Ranieri VM, Thompson BT, Barie PS et al. Drotrecogin alfa (activated) in 
adults with septic shock. N Engl J Med. 2012 May 31;366 (22):2055-64. PMID: 22616830. 
 
 
 
 

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Appendix D. Public Readiness and Emergency Preparedness Act 
This study is being conducted to determine whether hydroxychloroquine can safely and effectively be 
used to mitigate, treat, or cure COVID-19 or limit the harm of the COVID-19 pandemic in accordance 
with the Secretary of the Department of Health and Human Services’ (HHS’s) Declaration under the 
Public Readiness and Emergency Preparedness Act for medical countermeasures against COVID-19 
(COVID-19 Declaration)  effective February 4, 2020.  The purpose of this study is to test if 
hydroxychloroquine results in clinical benefit in patients hospitalized with COVID- 19.   
Hydroxychloroquine has been approved by the FDA for other uses and its investigational use for COVID-
19 in this study has been exempted by the FDA from investigational new drug application requirements 
pursuant to 21 CFR 312.2(b)(1).  This study is conducted under a Research Project Cooperative 
Agreement with the National Heart, Lung, and Blood Institute. 
 
 

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Appendix E: ORCHID-BUD Ancillary Study Protocol  
1. Title: Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with 
symptomatic Disease – Brain Outcomes and Psychological Distress (ORCHID-BUD) 
2. Objective: 
• 
Aim 1: To determine (a) the epidemiology (i.e., prevalence) of cognitive impairment (i.e., 
acquired-Alzheimer’s Disease and Related Dementia [ADRD]) characterized by impairments in 
memory, attention, language, reasoning, and executive function at 12-months in adults 
hospitalized with COVID-19 infection, and (b) if hydroxychloroquine administration is 
associated with improvement in these same outcomes. 
• 
Aim 2: To determine (a) the epidemiology of post-traumatic stress disorder (PTSD) and 
depression at 12-months in adults who are hospitalized with COVID-19 infection, and (b) if 
hydroxychloroquine administration is associated with improvement in these same outcomes.  
• 
Aim 3: To identify modifiable risk factors (e.g., sedatives, isolation, intravenous fluids, 
antibiotics, pressor, angiotensin-converting enzyme [ACE]-inhibitor or angiotensin II receptor 
blocker [ARB] use, etc.) associated with worse long-term cognitive impairment, PTSD, and 
depression at 12 months in adults hospitalized with COVID-19 infection. 
3. Hypothesis: The primary hypothesis of this proposal is that (a) COVID-19 survivors will have a high 
burden of ADRD, PTSD, and depression. The secondary hypothesis is that hydroxychloroquine will 
lower the burden of these three outcomes as compared to placebo. 
4. Study Design: ORCHID-BUD will assess 12-month cognition, PTSD, and depression using a 
comprehensive phone battery in all patients enrolled in ORCHID since the beginning of the study 
(March 2020).  ORCHID-BUD essentially expands and better defines the ORCHID’s follow-up study 
procedures that are already described its study protocol (ORCHID protocol Version 1.1, Section 
6.3.2, and page 22):“We will follow-up selected patients at 3, 6, and 12 months to assess vital status, 
cognition, basic and instrumental activities of daily living, quality of life, employment status, physical 
disability, and psychological distress (i.e., depression, post-traumatic stress disorder, etc.), place of 
residence, and rehospitalizations. These assessments may occur by phone, in-person, or 
videoconferencing.”   In anticipation of ORCHID-BUD, the ORCHID parent study has already added 
language to the informed consent document to conduct the proposed study procedures, including the 
baseline phone interview with the patient and family member:  
 
 
 
 
 
 
 
 
 
 
 
 
 

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Therefore, the ORCHID-BUD study activities will be considered part of the ORCHID parent study 
activities, and separate informed consent will not be performed.   
5. Study procedures:  
5.1 Baseline data collection study procedures 
For ORCHID-BUD, we will contact the surrogate approximately 3-months (+/- 2 months) 
after hospital discharge in order to establish baseline cognition, PTSD, and depression. We 
will contact the surrogate listed on ORCHID by their preferred method of contact (phone, 
text message, or e-mail).  
For the family member, we will administer the short form Informant Questionnaire on 
Cognitive Decline in the Elderly (IQCODE) establish the subject’s baseline cognition; this 
16-item questionnaire takes less than 5 minutes to complete. We will also ask the surrogate if 
they thought the patient was more confused than usual during hospitalization. We will also 
conduct the FAM-CAM and SQiD, which are informant-based delirium assessments, to 
further characterize delirium during hospitalization. We will ask them to estimate the number 
of days they felt the patient was confused.  We will also ask if they (or any family members) 
were able to visit the patient in person, by phone, or by mobile device. We will also ask them 
to estimate the number of days the subject was hospitalized for and if applicable, duration of 
ICU length of stay and mechanical ventilation.  We will also ask if the surrogate whether or 
not the subject has baseline dementia, PTSD, or depression. We will also ask about the 
subject’s race, ethnicity, age, level of education, highest occupation, and region of residence.  
These data will be obtained over the phone, but the family member will have the option to 
complete the surveys via an online REDCap survey if preferred.   
If no surrogate is listed for ORCHID, we will contact the patient by their preferred method of 
contact (phone, text message, or e-mail).  If the surrogate is available, we obtain the 
surrogate’s contact information.   For the patient, we will administer the IQCODE and ask if 
they have baseline dementia, PTSD, or depression.  We will also ask if they were on 
cholinesterase inhibitors before they were hospitalized for COVID-19. We will also ask their 
race, ethnicity, age, level of education, highest occupation, and region of residence.  We will 
ask patients some questions about their hospitalization.  We will also ask how long they were 
hospitalized, how long were they in the ICU, and how long they were mechanically 
ventilated. These questions may be answered by their family member or caregiver if 
requested. We will also ask patients if they felt confused, disoriented, or had hallucinations 
during hospitalization. We will ask them to estimate the number of days during the 
hospitalization they felt they had these symptoms. We will also ask how much contact family 
and friends had with the patient during hospitalization and if the contact was in person, by 
video conferencing, or by phone.  We will also ask about the subject’s race, ethnicity, age, 
level of education, highest occupation, and region of residence. These data will be obtained 
over the phone, but the subject will have the option to complete the surveys via an online 
REDCap survey if preferred.   

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After the conversation has concluded, we will let them know that we will contact them 
approximately 12-months (+/- 3 months) after randomization to assess their cognition and 
psychological well-being using a phone battery. We will also let them know that we will give 
them a gift card after they complete the 12-month phone call.  
5.2 Twelve-month study procedures 
The CIBS Center will then contact enroll subjects at approximately 12-months (+/- 3 months).  We 
will perform the phone battery as described in the Primary Endpoints (Section 10) and Secondary 
Endpoints (Section 11) section.  Any data not obtained during the baseline phone call will be 
obtained during the 12-month phone call to minimize missing data.  After the 12-month follow-up is 
completed, patients will be given a gift card. 
It is possible that ORCHID-BUD patients will be co-enrolled with other PETAL network COVID-19 
trials (e.g., BLUE CORAL) who are conducting long-term follow-ups. We may coordinate with the 
University of Washington and University of Michigan study teams to streamline data collection and 
minimize overburdening the patient.  
5.3 Medical Record Review 
We will use electronic medical records, in whatever institutions make this this available, to obtain 
detailed data regarding these potentially modifiable risk factors. Specifically, we will evaluate how 
modifiable risk factors such as the use of sedative medications and oxygen therapy, mechanical 
ventilation settings, social isolation, ventilator weaning protocols, intravenous fluid administration, 
antibiotics, medications such as ACE-inhibitors, ARBs, antacids, and pressors affect the 12-month 
outcomes.   
6. Risks: Because ORCHID-BUD is only adding a comprehensive phone battery at 12-months, its risks 
are minimal: 
6.1 Fatigue or distress: For ORCHID-BUD specifically, subjects will undergo a comprehensive phone 
battery at 12-months that can take up to 45 to 60 minutes to perform. There is a small risk that the 
patient may become fatigued or distressed during the study’s cognitive assessments. 
6.2 Confidentiality: Because patient identifiers are accessed throughout all phases of the study, there is a 
small risk of loss of patient confidentiality. 
7. Inclusion Criteria: : All patients enrolled in ORCHID will be included. 
8. Exclusion Criteria: ORCHID-BUD will exclude patients who are:  
(1) non-English or non-Spanish speaking,  
(2) deaf, or  
(3) non-verbal or unable to follow simple commands prior to the COVID-19 illness.   
We will exclude non-English and Non-Spanish speaking patients because our neuropsychological 
raters can only provide their assessments in these languages.  We will also exclude patients who are 
non-verbal or unable to follow simple commands prior to the COVID-19 illness to exclude patients 
with end-stage dementia. 

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9. Randomization and Study Initiation Time Window: The ORCHID-BUD ancillary study will enroll 
patients from ORCHID parent study.  ORCHID-BUD study activities will the subject and/or 
surrogates approximately one to three months after ORCHID randomization.  At approximately 12-
months (+/- 3 months) after randomization, we will call the patients and conduct the phone battery to 
assess cognition, PTSD, and depression. 
10. Primary Endpoint  
 
Assessment 
Domain 
Description 
Cognition 
Telephone Montreal 
Cognitive Assessment 
Global Cognition 
Measure of global cognition and assesses 
attention concentration, memory, language, 
conceptual thinking, calculations, and 
orientation. 
WAIS-IV Digit Span3 
Attention 
Subject repeats a string of numbers forwards, 
backwards, and ascending order 
Hayling test4 
Executive 
Function 
It consists of two sets of 15 sentences; the 
examiner reads the questions aloud and 
subject completes the sentences 
DKEFS Verbal 
Fluency5 
Language 
Subject is asked to name as many animals 
they can think of 60 seconds and as many 
words that begin with the letter “F”, “A”, and 
“S” over 60 seconds 
Paragraph Recall - 
Immediate6 
Immediate 
Memory 
Subject is read a paragraph and then recalls 
the paragraph immediately 
Paragraph Recall - 
Delayed6 
Delayed Memory 
Subject recalls the paragraph memorized from 
the immediate memory task 15 to 20 minutes 
later 
WAIS-IV Similarities3 
Reasoning/Verbal 
Abstraction 
Subject is given two words and then is asked 
how they are alike 
DKEFS Proverbs5 
Reasoning/Verbal 
Abstraction 
Subject is asked to interpret 5 proverbs 
Psychological 
Hospital Anxiety and 
Depression Scale 7 
Depression 
Multiple-choice inventory that is used for 
measuring the severity of depression 
PTSD Checklist for the 
DSM-V (PCL-5)8 
PTSD 
Multiple-choice questions reflecting DSM-IV 
symptoms of PTSD. Subjects with a score of 
> 35 will receive a formal assessment 
performed over the phone by a clinical 
psychologist using the CAPS-5 
Table 1. Telephone Battery to assess cognitive, psychological, and functional outcomes. WAIS-IV, 
Wechsler Adult Intelligence Scale-IV; DKEFS, Delis–Kaplan Executive Function System; PTSD, 
Post-Traumatic Stress Disorder; Clinician Administered PTSD Scale for the DSM-5 (CAPS-5). 
11. Secondary Endpoint: We will also record 12-month mortality and place of residence. We will 
also ask the number of times the patient was re-hospitalized since the index hospitalization.   
12. Sample Size / Interim Monitoring  
All patients enrolled in the ORCHID parent study will be screened for ORCHID-BUD.   ORCHID 
will enroll 460 patients who are hospitalized with COVID-19. We estimate that 70% will survive 
and of these, 93% will meet ORCHID-BUD’s eligibility criteria. We estimate that we will 

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successfully complete the phone battery in 90% of eligible patients providing 270 patients for 
ORCHID-BUD’s analysis. 
 
Appendix E: References 
1. 
Jorm AF. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly 
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