Hydroxychloroquine Post Exposure Prophylaxis (PEP) for Household Contacts of COVID-19 Patients: A NYC Community-Based Randomized Clinical Trial
Phase: PHASE2
Conditions: COVID-19, Corona Virus Infection
Sponsor: Columbia University

NCT04318444 
 
 
IRB Protocol 
AAAS 9676 
April 30, 2020 
Modification 7 
 
Hydroxychloroquine Post Exposure Prophylaxis (PEP) for High-Risk Contacts of COVID19 Patients: A 
NYC Community-Based Randomized Clinical Trial 
Investigators: 
Jon Giles, MD, MPH (PI) 
Elizabeth Oelsner, MD, MPH 
Ying Kuen K. Cheung, PhD (Statistician) 
Steven JC Shea, MD, MS 
Helen Kim, PharmD 
Magdalena Sobieszczyk, MD, MPH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1. Study Purpose and Rationale 
COVID-19 is a massive threat to public health worldwide. Current estimates suggest that  
the novel coronavirus (SARS-CoV-2) is both highly contagious (estimated reproductive  
rate, 2-3) and five to fifty-fold more lethal than seasonal influenza (estimated mortality  
rate, 0.5-5%). Interventions to decrease the incidence and severity of COVID-19 are  
emergently needed. 
 
Hydroxychloroquine (brand name, Plaquenil), an inexpensive anti-malarial medication  
with immunomodulatory effects (1-4), is a promising therapy for COVID-19. Chloroquine,  
a related compound with a less favorable toxicity profile, has shown benefit in clinical  
studies conducted in approximately one-hundred SARS-CoV-2 infected patients (1, 2).  
In vitro, hydroxychloroquine has been recently shown to have greater efficacy  
against SARS-CoV-2 versus chloroquine (5). Although the molecular mechanisms of  
action are incompletely understood, previous studies suggest that hydroxychloroquine  
may inhibit coronaviruses by changing cell surface pH, inhibiting the fusion of the virus to  
the cell membrane, and by inhibiting nucleic acid replication, glycosylation of viral  
proteins, virus assembly, new virus particle transport, and virus release (6). 
 
The safety profile of hydroxychloroquine has been well-established over decades of  
regular use by patients with autoimmune disease. Indeed, hydroxychloroqine is on  
the World Health Organization (WHO) list of essential medications, highlighting it  
as one of the safest and most effective medications on the market. The major  
toxicity with short term use is QT prolongation, which may increase risk of arrhythmia.  
Other known toxicities include retinopathy, which is mainly observed at high daily doses  
(>5mg/kg/day), and hematologic abnormalities (agranulocytosis, thrombocytopenia). 
 
Post-exposure prophylaxis (PEP) is a strategy that has been proved to reduce  
transmission and improve outcomes for both seasonal influenza and HIV. Although  
two trials of hydroxychloroquine for COVID-19 PEP have been recently initiated  
(NCT04304053 and NCT04308668), additional studies are urgently needed, particularly  
in urban US communities where community spread of COVID-19 is currently  
accelerating.  
 
We propose a phase 2/3, double-blinded, randomized clinical trial of  
hydroxychloroquine PEP among close contacts of COVID-19 patients in New York  
City (NYC). The trial will be initiated at NewYork-Presbyterian (NYP)/Columbia  
University Irving Medical Center (CUIMC)/Weill Cornell Medical Center (WCMC). It will  
recruit adults (≥18 years old) with moderate or high-risk COVID-19 exposure, including 
household contacts of index COVID-19 cases or Persons Under Investigation (PUI), as  
identified by NYP/CUIMC/WCMC providers via outpatient or inpatient clinical evaluation.  
Extra institution index cases will be considered with sufficient source verification (i.e. test  
report, provider’s note). Within 72 hours of diagnosis of the index case, participants will  
be randomized (1:1) at the individual level to a 5-day course of hydroxychloroquine  
versus an identical course of placebo. The primary outcome will be development of  
symptomatic COVID-19, with laboratory confirmation of infection, within 14 days of  
enrollment. Secondary outcomes will include duration of COVID-19 symptoms; need for  
hospitalization or mechanical ventilation; and COVID-19 mortality. The target  

enrollment is N=1600 adults (800/arm), which will have 80% power to detect a 30%  
improvement in the symptomatic secondary attack rate (from 10.5% to 7.3%). The  
anticipated trial duration is 12 months. 
 
This pragmatic, community-based, randomized clinical trial will rapidly and  
efficiently test the hypothesis that hPEP will reduce the symptomatic secondary  
attack rate among close contacts of known or suspected COVID-19 patients. If the  
study hypothesis is confirmed, this work could substantially improve COVID-19  
outcomes in both the NYC and the global community. 
 
2. Study Design and Statistical Procedures 
We propose a single-center, double-blinded, placebo-controlled, randomized, Phase 2-3 
clinical trial to test if hydroxychloroquine post exposure prophylaxis (hPEP) reduces the 
symptomatic secondary attack rate of COVID-19 among close contacts of known or  
suspected COVID-19 patients identified at the largest academic medical center in NYC and  
surrounding metropolitan area. 
 
Setting: The study will be conducted in NYC, where the COVID-19 epidemic is rapidly  
accelerating. In order to optimize efficiency, the study will be initiated at the NYP/CUIMC  
campus in Washington Heights, with plans to expand across other NYP campuses if/as  
conditions allow. As this is a community-based study, where interaction is facilitated  
remotely, we wish to include the tri-state area as our immediate scope due to the patient  
demographic majority residing in this area. 
Population: Currently asymptomatic adults (≥18 years old) meeting the following inclusion  
and exclusion criteria: 
 
a. Inclusion criteria: 
a. Household contact of index case: currently residing in the same household as an  
index case: 
i. Index case definition: individual evaluated at outpatient, emergency  
department (ED), or inpatient services who (1) tests positive for COVID19, or (2) are 
defined as suspected cases, or persons under investigations (PUI), by the treating 
physician. 
b. Willing to take study drug as directed for 5 days. 
b. Exclusion criteria: 
a. Age <18 years old 
b. Suspected or confirmed current COVID-19, defined as: (1) temperature > 38  
Celsius; (2) cough; (3) shortness of breath; (4) sore throat; or, if available (not  
required), (5) positive confirmatory testing for COVID-19 
c. Suspected or confirmed convalescent COVID-19, defined as any of the above  
symptoms within the prior 4 weeks. 
d. Inability to take medications orally 
e. Inability to provide written consent or eConsent 
f. Known sensitivity/allergy to hydroxychloroquine 

g. Current use of hydroxychloroquine for another indication 
h. Pregnancy 
i. Prior diagnosis of retinopathy 
j. Prior diagnosis of G6PD deficiency 
k. Major comorbidities increasing risk of study drug:  
i. Hematologic malignancy 
ii. Advanced (stage 4-5) chronic kidney disease or dialysis therapy 
iii. Known history of ventricular arrhythmias  
iv. Current use of drugs that prolong the QT interval (Table 1) 
 
Table 1. Drugs that prolong QT, and for which current use will be an exclusion criterion for participation 
Antiarrhythmics, Antimicrobials, Antidepressants, Antipsychotics and Others, including:  
Amiodarone Levofloxacin Amitryptiline Haloperidol Cisapride Sotalol Ciprofloxacin Desipramine 
Droperidol Sumpatriptan Quinidine Gatifloxacin Imipramine Quetiapine Zolmitriptan Procainamide 
Moxifloxacin Doxepin Thioridazine Arsenic Dofetilide Clarithromycin Fluoxetine Ziprasidone Dolasetron 
Ibutilide Erythromycin Sertraline Methadone Ketoconazole Venlafaxine Itrconazole 
 
Recruitment: Information regarding the study will be shared with directors of the outpatient,  
ED, and inpatient services at NYP. Among services that agree to participate, information will  
be shared with providers via e-mail, telephone, and/or video-conference. Recruitment will be  
conducted in individuals’ preferred languages, using a telephone interpreter if necessary. 
Written materials will be provided in both English and Spanish. Recruitment will be  
accomplished by active surveillance and provider referral. Some interested participants  
might be patients at NYP (i.e. existing MRNs), but testing of the index case accomplished  
outside of the institution. Some NYP/CUIMC/WCMC faculty, trainees, and staff may be  
eligible to participate; it will be explicit that participation will be completely voluntary and  
100% non-coercive. 
Provider referral: 
1. Identification of index case: as noted above, consistent with current clinical care, the  
providers will be asked to define the index case as individuals who (1) test positive  
for COVID-19, or (2) are defined as suspected cases, or persons under investigation 
(PUI), by the treating physician. 
2. Determination of household contacts: The provider will ask the index case if he/she  
lives alone or has any household contacts. If the index case is unable to be  
interviewed (e.g., mechanically ventilated), the provider will ask the surrogate, as  
identified by the treating physician.  
3. Invitation to be contacted by the study: For index cases with at least one household  
contact, providers will ask any household contact(s) present with the index case, if  
they would be interested in participating in a research study. The index case and any  
household contact(s) present may be provided with a copy of a printed flyer that  
explains the study in lay terms, in English and in Spanish. This flyer will include  
contact information for the study.  
 
Active surveillance: research personnel will contact designated clinical personnel in participating  
services at least twice daily to ask if there are any index cases whose household contacts might  
be suitable for recruitment into the study. Research personnel will then contact the eligible  

households. 
 
Contact by the study: Study-initiated telephone contact: if verbal consent is given to the treating  
provider, trained personnel will call the household to screen potential participants. Householdinitiated 
telephone contact: if any household contacts decide they are interested in participating  
subsequent to the index case diagnosis (e.g., after reviewing the flyer) and call the provided  
number, trained research personnel will proceed with screening by phone. Screening: A  
structured interview will be used to assess inclusion and exclusion criteria. Screening forms for  
those who are found to be ineligible (or for those who are pre-screened as eligible but do not,  
for any reason, sign written informed consent or informed remote eConsent) will be abstracted,  
reviewed by the PI, and then discarded in a secure fashion such that no PHI is retained. 
 
Informed consent: Trained research personnel will obtain informed consent after confirming  
eligibility and prior to randomization. Written informed consent will be obtained with electronic  
tablets. Immediately following participant use/contact, and prior to re-use or re-contact by any  
other participant, the tablet will be subjected to a standard cleansing with a Chlorox disinfection  
wipe.If in person contact is not possible, remote eConsent will be obtained. In the case of  
eConsent, trained research personnel will first discuss the content of the informed consent form  
with the participant via telephone or, preferably, video conference. In this manner, the research  
personnel will be available to answer any questions. The participant will immediately thereafter  
be asked to perform eConsent. The platform for eConsent will be an integrated data  
management system that is easy to navigate, allowing the user to proceed forward or backward  
within the system and to stop and continue at a later time. This system will be secure with  
restricted access, and will ensure confidentiality of the Subject’s identity, study participation and  
personal information. This system will comply with the Columbia University Information Security  
Charter and the other Information Security Policies referred to in such Charter to the extent  
applicable. 
 
After eConsent is provided, it will be automatically transmitted to the study via the integrated  
data management system. Randomization: Randomization to the study drug versus the placebo  
will be performed in a 1:1 fashion, stratified by age (<55 years old, 55+ years old) and  
chromosomal sex (male, female).  
 
Blinding: Randomization will be accomplished by the Research Pharmacy, which will provide  
the study drug and the placebo in identical pill bottles. This will ensure double-blinding to both  
participants and the study team. 
 
Dispensing of study drug and placebo: consenting participants must pick up the study drug from  
a designated hospital location within 72 hours of the diagnosis of the index case. Or, if the  
consenting participants are unable to travel to the hospital, the study drug will be delivered to  
the participant’s home (e.g., by FedEx or courier). 
 
Study drug: the intervention will be a 5-day course of hydroxychloroquine sulfate (brand name,  
Plaquenil). Each participant will receive 12 tablets of hydroxychloroquine sulfate 200mg. They  
will be instructed to take two tablets (400mg) twice daily on day 1; for days 2-5, they will be  
instructed to take one table (200mg) twice daily. The rationale for this dosing regimen is as  
follows. A loading dose is important to efficacy, but loading doses >800mg/24 hours are  
expected to have a disadvantageous risk/benefit profile. The dose on the subsequent 4 days  

(400mg/day) is within the standard long-term daily dosing range for autoimmune diseases. For  
comparison, other current trials of hPEP propose the following regimens:  
• NCT04304053: 800mg on day 1, and 400mg on days 2, 3, 4. We believe that an  
additional day of therapy will be associated with minimal excess risk and the median  
incubation of CoV-SARS-2 is 5 days, suggesting that 5 days of prophylaxis may be  
superior to 4 days.  
• NCT04308668: 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg  
once a day for 6 consecutive days. We believe that the loading dose and the follow-up  
doses are excessively high. Together with an extended (7-day) course of treatment, we  
believe that this regimen carries higher risk of adverse effects without clear benefit and  
with lower likelihood of regimen adherence. 
 
Participants randomized to the placebo will receive an identical container of 12 placebo pills,  
with the same instructions for administration. 
 
Follow up 
 
Participant self-monitoring: participants will be asked to check and record their temperatures at  
home in the morning and in the evening. They will be instructed to contact the study if they  
develop a temperature >38 C, and/or if they develop cough or shortness of breath. 
Daily telephone or email follow-up: research personnel will contact participants by phone on a  
daily basis for 7 days post-randomization, and at 14 (+/- 3) and 30 days (+/- 3). They will  
conduct a structured interview to ascertain potential symptoms of COVID-19 (the primary  
outcome), adherence to and potential adverse effects of the study drug, and extent of ongoing  
exposure to the index case. Alternatively, if preferred by the participant, the participant will be  
able to submit answers to the daily symptomatic questionnaire via secure web-based  
questionnaire to support remote administration and immediate data capture. Participants with  
symptoms or signs of COVID-19 will be referred to the study physician, who will contact  
the participant and determine if he/she meets PUI criteria. The study physician will refer  
PUIs for confirmatory COVID-19 testing at NYP/CUIMC/WCMC. 
 
Psychosocial Questionnaire at Day7: Resources for mental health and wellness are provided at  
the end of the psychosocial questionnaire for all participants, as well as instructions for seeking  
medical attention if participants experience significant distress or feel unsafe.  
 
Participants who score in the severe or extremely severe range on the depression subscale,  
express passive or active suicidal ideation, or express thoughts of self-harm will be informed of  
mental health support hotlines, advised to seek care from a mental health professional, and  
encouraged to contact emergency services if they feel unsafe. For such participants who  
respond to the questionnaire online or by paper, an attempt will be made to contact them at the  
time the questionnaire is viewed to provide the information above.  
 
Active surveillance of healthcare utilization: the research personnel will monitor study  
participants to determine if any participants present to the outpatient clinic or to the ED, and/or if  
they require hospitalization. 
 
Extended follow-up of symptomatic participants: participants who develop COVID-19 symptoms  
will continue to be followed-up by daily telephone calls until 3 days following resolution of  

symptoms in order to measure the duration of symptom (secondary endpoint). 
 
Statistics 
 
We plan a phase 2 study at NYP/CUIMC/WCMC, with the phase 2 as an internal pilot for a  
potential phase 3 study, which would be conducted across all NYP sites.  
 
Population: Household contacts of COVID-19 cases with high-risk COVID-19 exposures 
 
Endpoint: Symptomatic, lab-confirmed COVID-19 over two-week follow-up, defined by: 
1. COVID-19 infection confirmed within 14 days of enrollment, following self-report of  
COVID-19 symptoms to the research study.  
2. COVID-19 infection confirmed within 14 days of enrollment, with self-report of COVID-19  
symptoms to a treating physician.  
 
Control outcome: The CDC has estimated symptomatic secondary attack rate of 10.5% (95%  
CI = 2.9%–31.4%) among household members of COVID-19 patients over 14 days (7) 
(https://www.cdc.gov/mmwr/volumes/69/wr/mm6909e1.htm). 
 
Effect size: a 30% risk reduction from a 10.5% to 7.4% symptomatic secondary attack rate 
 
Design:  
• Placebo-controlled 1:1 randomized at NYP/CUIMC/WCMC 
• Phase 2/3 internal pilot, with interim monitoring for futility and safety during the pilot  
phase 
• Pilot phase: one-sided test at 10% significance; data obtained in pilot phase will be used  
to size the phase 3 trial, and the pilot data will be used in the final analysis at the end of  
phase 3 
• Sample size for pilot phase: n = 800 per arm, i.e., total N = 1600 
Secondary endpoints:  
• Determination of symptoms consistent with PUI without confirmatory COVID-19 testing  
(e.g., if lost to follow-up) 
• Duration, in days, of COVID-19 symptoms (cough, shortness of breath, and/or fever) 
• Hospitalization for COVID-19 
• Mechanical ventilation for COVID-19 
• Mortality attributed to COVID-19 
 
Additional notes on statistical design and analysis 
 
This is a single-center, double-blinded, placebo-controlled, randomized internal pilot trial of a  
larger phase 2-3 seamless clinical trial. The trial objective is to evaluate if hydroxychloroquine  
post exposure prophylaxis (hPEP) given over a 2-week period will reduce symptomatic  
secondary attack rate of COVID-19 in household contacts of known or suspected COVID-19  
patients. The study endpoint is symptomatic, lab-confirmed COVID-19 during the 2-week study  
period. In this pilot trial, we plan to randomize a total N=1600 participants to the treatment  
(hPEP) and the placebo in a 1:1 ratio, stratified by chromosomal sex and age group (<55 yo vs  
55+). 
 

The primary analysis will be comparing the rates of symptomatic, lab-confirmed COVID-19 in all  
randomized participants using one-sided Fisher’s exact test. Intent-to-treat analysis will be  
used. Secondary endpoints include duration of COVID-19 symptoms without confirmatory test,  
hospitalization for COVID-19, requiring mechanical ventilation, and mortality. Statistical analysis  
of the secondary endpoints will be intent-to-treat, using Mann-Whitney test for numerical  
outcomes and Fisher’s test for categorical outcomes. Adverse events and serious adverse  
events will be compared using Fisher’s exact test. Interim analysis will be performed to monitor  
for futility using a Bayesian criterion. Specifically, an early stopping consideration will be  
invoked if it is unlikely that poor outcome of hPEP is lower than that of placebo; i.e., its posterior  
probability is smaller than alpha. The value of alpha will be determined before the first interim  
analysis. 
 
Go and no-go decision and power consideration 
 
We will plan to move forward to the phase 3 trial if at the end of the pilot phase, the primary  
analysis has a one-sided p-value less than 0.10. Assuming the placebo rate of COVID-19  
outcome is 10.5%, the proposed sample size in the internal pilot will result in an 80% probability  
of moving forward if the study drug reduces risk by 30% (i.e., from 10.5% to 7.3%). 
 
In addition, the pilot data will be used to re-estimate the sample size in the phase 3 trial, and will  
be used in the final analysis using adjusted analysis using weighted statistics so as to preserve  
the overall type I error. Details of sample size re-estimation will be determined before the pilot  
trial data is unblinded. 
 
3. Study Procedures 
a. Procedures 
i. Questionnaires: questionnaires will be performed by telephone by trained  
research assistants or via web-based questionnaire to support remote  
administration and immediate data capture. 
1. Screening questionnaire (first call): inclusion and exclusion criteria 
2. Medical history questionnaire (first call): additional questions  
regarding medications used, number of persons in household 
3. Follow-up questionnaires 
a. Symptoms (respiratory, non-respiratory) 
b. Trial medicine adherence 
c. Psychosocial Behavior (Day7 only) 
ii. Active surveillance for health care utilization and COVID-19 testing at  
NYP/CUIMC 
1. Participants will be referred for clinical COVID-19 testing if  
deemed PUI by the study investigator(s)  
b. Study Drugs 
i. Hydroxychloroquine dose pack: 5-day course of hydroxychloroquine  
sulfate (brand name, Plaquenil). Each participant will receive 12 tablets of  
hydroxychloroquine sulfate 200mg. They will be instructed to take two  
tablets (400mg) twice daily on day 1; for days 2-5, they will be instructed  
to take one table (200mg) twice daily.  
ii. Placebo daily: Participants randomized to the placebo will receive an  
identical container of 12 placebo pills, with the same instructions for  

administration. 
c. Confidentiality of Study Data: The consent form signed by the participant will  
provide written assurance that all individual data collected in the study will be  
kept confidential to the extent provided by the Privacy Act of 1974. Any personal  
identifiers will be maintained on limited-access, secure servers and never put on  
endpoint devices so that confidential data are not released. Participants will be  
informed that: (1) the only people who will know that they are research  
participants are members of the research team and, if appropriate, their  
physicians or health care providers; (2) no individual identifying information about  
them will be disclosed to others, except if required by law; and (3) when the  
results of the study are published or discussed in conferences, no information will  
be included that would reveal their identity. Coded research data will be stored  
on password-protected, secure servers hosted by the Division of General  
Medicine and certified by CUIMC IT the CUIMC Radiology PACS, and in locked  
filing cabinets in General Medicine, and potentially on endpoint devices that will,  
in all cases, be encrypted. Identifiable data will be stored in the General Medicine  
Server described above and in locked filing cabinets in separately partitioned  
drives/cabinets. The linking file will be similarly protected with limited access. 
d. Potential Risks:  
i. Retinopathy: Hydroxychloroquine treatment has been associated with  
development of retinopathy, particularly at doses >5mg/kg/day. We will  
exclude participants <40 kg for whom the study dose might exceed this  
threshold. We will also exclude persons with established retinopathy from  
the study.  
ii. Hematologic abnormalities: we will exclude individuals with known G6PD  
deficiency or hematologic malignancy. 
iii. Allergy: we will exclude participants with known sensitivity to  
hydroxychloroquine. 
iv. Arrhythmia: we will exclude individuals with known arrhythmia or use of  
anti-arrhythmic medications. 
e. Protections Against Risks:  
i. In addition to strict exclusion criteria, we will monitor participants for  
signs/symptoms of potential adverse effects of the study drug by daily  
follow-up for 7 days. On Day 7, a specific interview concerning acute  
side-effects of the study medication will be conducted. If any adverse  
drug effects are suspected based upon symptomatic report, the study  
physician will determine whether the symptoms are attributable to the  
study drug. Beyond the two-week period of initial follow-up, we will  
encourage all participants to reach out to the study coordinator for  
palpitations, dyspnea on exertion, or visual disturbances occurring up to  
30 days after completion of participation. Serious adverse events (SAEs)  
will be recorded for the full duration of subject participation, however only  
adverse events of special interest will be recorded upon the Day 7 acute  
side-effect interview. 
ii. To mitigate risks of COVID-19 among participants, all participants will  
receive counseling and information regarding current CDC guidelines for  
exposed household contacts of COVID-19 patients (e.g., decontamination  
of surfaces, avoidance of unprotected contacts with the index case). 

f. Potential Benefits: if the study drug is effective, those randomized to the study  
drug may benefit from improved COVID-19 outcomes. If benefit is demonstrated,  
participants randomized to the control arm will have the opportunity to obtain the  
study drug after study completion. The societal benefits are potentially large. 
g. Alternatives: non-participation.Data Safety and Monitoring Plan: A local Data and  
Safety Monitoring Committee (DSMC) has been established, with Dr. Bathon  
(rheumatology) as Chairman of the committee. In addition, the committee will  
consist of two other members, a pharmacist (TBD) and a statistician (Dr. Ying  
Wei). The DSMC will meet to review all safety data from the patients after the  
first 100 randomized patients completing their 2-week follow-up, and every 400  
randomized patients thereafter. The unblinded statistician will prepare the data  
for DSMC’s review. Each meeting will consist of an open session that includes  
the study investigators, and a closed session with only the unblinded statistician  
and the DSMC members. 
 
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