Clinical trial NCT04349371
Conditions: COVID Coronavirus Infection
Keywords: SARS-CoV-2 Coronavirus
Sponsor: Columbia University
Start date: 2020-04-21; Completion date: 2021-02-11
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to determine the clinical efficacy of Chloroquine (CQ) in health care workers with moderate to high risk of exposure to COVID-19 in preventing symptomatic COVID-19 infections. Secondary endpoints will explore the efficacy of CQ in preventing any infection as defined by seroconversion to positive anti-COVID antibody status.

Detailed description:
Chloroquine (CQ) phosphate is an immunomodulatory drug that has been approved by the FDA for prophylaxis of and treatment of malaria, treatment of lupus erythematosus, and treatment of rheumatoid arthritis. Anecdotal data and in-vitro studies suggests potential benefit of chloroquine in treating COVID-19 patients. The use of CQ to treat COVID-19 patients have been demonstrated to be effective in inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The use of CQ in health care workers with moderate to high risk of exposure to COVID-19 in could prevent symptomatic COVID 19 infections. 350 participants will be randomized (like a flip of a coin) to a 3 month chloroquine versus an identical course of placebo. A placebo is a sugar pill which has no active ingredient. will attend one in person visit during month 0 for screening and randomization, and if possible during the last visit at month 3. During month 1 and 2 the in person visits are optional and the PI can follow up with subjects through telemedicine or phone call. Informed consent, inclusion/exclusion criteria, demographic, medical/ disease history/ comorbidity/ medical records review, prior/ concomitant meds and procedures, and adverse events will be collected from patient during screening visit 1 (month 0). Limited physical assessment, vitals, blood serum, investigational product compliance review, assessment of adverse events, serious adverse events, adverse events of special interest, and endpoint assessments are also collected during visit 1. Prior/concomitant medications and procedures, adverse events, study drug compliance review, adverse events of special interest, adverse events of special interest and endpoint assessments will be reviewed at every visit. Blood serum will be collected during visits 1 (month 0) and at visit 4 (month 3) if subject can come to the visit physically. By the end of the study, the investigators hope that there is decrease of symptomatic illness in at risk healthcare workers and a decrease in symptomatic COVID infection.

Arms: arm 1: Participants will receive CQ supply for 3 months. Patients will receive a supply of 36 -- 250 mg tabs or placebo that will last 3 months (enough for taking two tabs of 250mg for every day for one week and then two tabs of 250mg for 1 day a week thereafter for study duration of 3 months). Subjects with severe GI intolerance can take 1 tablet of 250mg daily for the first week and 1 tablet per week for the remainder of the 3 month study duration. Patients will attend 1 in person visits (month 0) and an additional visit during month 3 if possible with the physician where they will be evaluated for safety assessments including vital signs, physical exams, blood collection, and assessment of endpoints. During month 1, 2, and 3 participants will be followed up regarding concomitant medications and adverse events over the phone call. arm 2: Participants will receive placebo supply for 3 months. Patients will attend 1 in person visits (month 0) and an additional visit during month 3 if possible with the physician where they will be evaluated for safety assessments including vital signs, physical exams, blood collection, and assessment of endpoints. During month 1, 2, and 3 participants will be followed up regarding concomitant medications and adverse events over the phone call.
Interventions: intervention 1: Chloroquine intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Subjects will take two tabs of 250mg for every day for one week and then two tabs of 250mg for 1 day a week thereafter for study duration of 3 months). Subjects with severe GI intolerance can take 1 tablet of 250mg daily for the first week and 1 tablet per week for the remainder of the 3 month study duration. intervention 2: Subjects will take two tabs of placebo for every day for one week and then two tabs of placebo for 1 day a week thereafter for study duration of 3 months).

Protocol documents:
Prot_SAP_000.pdf: 
NCT04349371 
 
Title: Chloroquine (CQ) prophylaxis for Health Care Workers at risk for COVID  
Short title: Saved by CQ  
Clinical Phase: II  
PI: Anca Askanase, MD MPH  
Co-investigator: Jon Giles, MD MPH  
Protocol Version: 3.0 (IRB approved 11/09/2020) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Primary Objective: The primary objective is to determine the clinical efficacy of CQ in health 
care workers with moderate to high risk of exposure to COVID-19 in preventing symptomatic 
COVID-19 infections.  
 
Secondary Objectives: Secondary endpoints will explore the efficacy of CQ in preventing any 
infection as defined by seroconversion to positive anti-COVID antibody status.  
 
Study Design: Double blind, placebo controlled, randomized study of CQ in health care workers 
with risk of COVID exposure. The primary objective is to determine the clinical efficacy of CQ 
in health care workers with moderate to high risk of exposure to COVID-19 in preventing 
symptomatic COVID-19 infections. Safety assessments include AEs, vital signs, ECGs, and 
physical examinations.  
 
Stratification will be based and levels of exposure: -moderate risk: defined by patient facing 
work in outpatient/in-house clinic at least 2 days/week -high risk: ICU/ER/procedure rooms with 
aerosolized particles and high risk of contamination Stratification based on age: -Under 50 years 
of age -Older than 50 years of age  
 
Sample size: 175 patients/group. Sample size based on a projection that 15% of healthcare 
workers will develop symptomatic COVID-19 illness and an anticipated 67% reduction in rate 
(i.e. 5%) among those treated with CQ. 175 patients per group, allowing for a 10% dropout rate, 
will permit detection of a difference of this magnitude or greater for the primary endpoint, 
assuming a two-tailed alpha and 80% power. The trial is not powered on any secondary 
outcomes or interim analyses.  
 
Study Duration: -1 month accrual of patients with treatment duration of 2-3 months or until 
exposure levels become negligible - 2 month follow up visit, 3 month follow up visit  
 
Treatment Description: 3 Patients will receive CQ 500 mg every day for one week, then 500 
mg weekly for the duration of the exposure. A dose of 250 mg daily will be allowed for severe 
GI intolerance.  
 
Primary Endpoint: Decrease by 67% in number of symptomatic illness in at risk healthcare 
workers; a decrease in symptomatic COVID infections from 15% to 5% in the treatment arm. 
 
Co-primary Endpoint: Decrease by 70% in number of severe illness in at risk healthcare 
workers.  
 
Secondary Endpoints: 1. Decrease by 67% in number of sero-conversions in at risk healthcare 
workers. 2. Percent of patients with adverse events NCI-CTCAE Grade 3 or higher. 3. Percent of 
patients with GI intolerance.  
 
Inclusion Criteria: 1) Age ≥18 years, 2) Employment by New York Presbyterian Hospital 3) 
Clear assignment to areas of the hospital that involve patient contact and possible exposures for 
at least 2 days a week >/= 8 hours a day  


Exclusion Criteria: 1) Individuals who are taking CQ for other indications 2) New use of 
NSAIDs 3) High risk background medications not limited to immunosuppressive regimens, 
steroids, anti-B cell therapies, anti-cytokine therapies, chemotherapies, JAK-inhibitors 4) 
Individuals with a history of retinopathy that would contraindicate the use of CQ 5) Known 
allergy to CQ or chloroquine 6) Known QT prolongation and torsades de point 7) Have 
screening electrocardiogram (ECG) abnormalities that, in the opinion of the investigator, are 
clinically significant and indicate an unacceptable risk for the patient’s participation in the study. 
8) Any individual with QTc over 500 msec will be excluded. 8) Individuals who have history of 
any cardiac disease. 9) Individuals with history of renal disease 10) Individuals who are taking 
any QT prolonging meds such as but limited to:  Antipsychotics: Haloperidol, Ziprasidone, 
Quetiapine, Thioridazine, Olanzapine, Risperidone  Antiarrhythmics: Amiodarone, Sotalol, 
Dofetilide, Procainamide, Quinidine, Flecainide  Antibiotics: Macrolides, Fluoroquinolones  
Antidepressants: Amitriptyline, Imipramine, Citalopram,  Others: Methadone, Sumatriptan, 
Ondansetron, Cisapride 
 
Study Stopping Rules  
Study enrollment will be put on temporary hold and expedited reports will be prepared and 
reported to the DSMB for an ad hoc meeting if any the following occur: 1) Severe GI intolerance 
to chloroquine 2) Anaphylactic/high risk reaction to chloroquine 3) Symptomatic COVID-19 
infection 4) QT prolongation and torsades de point that, in the opinion of the investigator, are 
clinically significant and indicate an unacceptable risk for the patient’s participation in the study. 
2) The occurrence of NCI-CTCAE Grade 3 or higher adverse events (including serious adverse 
events) that are related to study drug in 1 of the first 6 subjects, 2 of the first 23 or 3 of the first 
45 or 5 subjects at any time. (It is estimated that the prevalence of Grade 3 or higher adverse 
events in the placebo group will be about 1 percent.), 3) At the request of the DSMB. The DSMB 
may only stop the trial for safety concerns. DSMB members: Dr. Teja Kapoor, Dr. Yevgenya 
Gartshteyn, Dr. Daniel DeMizio. The DSMB will meet monthly to evaluate any safety and 
unforeseen protocol issues.  
 
ECG  
Per the Food and Drug Administration Emergency Use Authorization guidelines with respect to 
chloroquine, a single 12-lead standard ECG will be obtained locally at Visit 1 and read by a 
qualified physician (the investigator or qualified designee) at the site to determine whether the 
patient meets entry criteria. However if the subject had received an ECG test within the past 12 
months and no abnormalities were found, the ECG does not have to be obtained. An ECG test 
will be administered at the end of the study. Electrocardiograms may be obtained at additional 
times, when deemed clinically necessary. If the patient presents with unanticipated ECG 
findings, they will be referred to a cardiology specialist immediately. Patients with QTc between 
460-500 msec will be reviewed with a Cardiologist before initiating treatment. Randomization: 
Randomization to the study drug versus the placebo will be performed in a 1:1 fashion. Simple 
randomization without blocking or stratification will be followed, with treatment allocation 
according to a pre-specified computer-generated randomization list provided to the research 
pharmacy. 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. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a patient’s treatment assignment is warranted. 


Patient safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the Research Pharmacy prior to unblinding a patient’s treatment assignment unless this 
could delay emergency treatment of the patient. All calls resulting in an unblinding event are 
recorded and reported to the IRB. If an investigator, site personnel performing assessments, or 
patient is unblinded, the patient must be discontinued from the study unless there are ethical 
reasons to have the patient remain in the study.  
 
Statistical analysis  
Summary statistics for outcomes and predictor variables will be calculated, with comparisons 
made using Student's t-test and Wilcoxon rank-sum test for normally and non-normally 
distributed continuous variables, respectively. Counts and percentages will be calculated for 
categorical variables and compared using χ2 or Fisher's exact test as appropriate. COVID disease 
status will be ascertained based on medical records review for severe hospitalized patients, self-
reported history of viral illness with serological confirmation of antiCOVID status, and anti-
COVID antibody status. The association between CQ and disease will be explored. Efficacy 
analyses included all the patients who underwent randomization and who received at least one 
dose of CQ or placebo (modified intention-to-treat population). The primary end point, the 
percentage of patients with COVID infection at study end, will be compared in the CQ group and 
in the placebo group with the use of a stratified Cochran–Mantel–Haenszel test, with strata 
corresponding to the stratification factors (age and exposure levels). To isolate the association 
between CQ and possible confounders we will defined as those variables associated with both 
the outcome and the independent variable (CQ). Statistical calculations will be performed using 
STATA version 12. A two-tailed α of 0.05 was defined as the level of statistical significance for 
all tests.  
 
Rationale:  
We generally consider hydroxychloroquine and chloroquine as being effective in lupus, in part 
due to inhibition of type I interferon (considered our innate first line defense antiviral response), 
which has often raised concern about susceptibility to viral infection. However, data are 
accumulating at a very rapid rate that there may be a paradox. By raising endosomal pH (one of 
the mechanisms that leads to decreased TLR ligation and decreased IFN) COVID viral 
replication itself is decreased16 . Since acidification is crucial for endosome maturation and 
function, Liu and colleagues suggest that endosome maturation could be blocked at intermediate 
stages of endocytosis, which would then result in decreased transport of virions to the ultimate 
releasing site. A study by Goa et al. suggests that chloroquine has efficacy against the associated 
pneumonia in multicenter clinical trials conducted in China. Additionally, there have been two 
other small trials that raise more questions than provide definitive answers to the question of 
hydroxychloroquine efficacy in COVID-19. Specifically, the study by Gautret at al. was a single 
arm protocol in which 20 confirmed COVID-19 patients were given 600mg of 
hydroxychloroquine daily (and is some cases azithromycin) and their viral load in 
nasopharyngeal swabs was tested. Six patients were asymptomatic, 22 had upper respiratory tract 
infection symptoms and eight had lower respiratory tract infection symptoms. A significant 
reduction of viral carriage was reported. Of note, levels of HCQ were in accord or lower than 
those seen in our lupus patients prescribed 5mg/kg. The heterogeneity of the patients included, 
selection of the control population, high rate of lost to follow- 6 up and handling of missing 


observations raise concerns about their conclusions. The other trial is a 30 patient, placebo-
controlled study of hydroxychloroquine in patients with relatively mild COVID-19 infections, 
using 400 mg of HCQ daily, did not show any differences between drug and placebo groups in 
viral clearance, duration of hospitalization, and radiological progression of COVID-19 
pneumonia. CQ and HCQ have been used interchangeably in the treatment and prophylaxis of 
malaria as well as the treatment of SLE. The current study proposes to evaluate the efficacy of 
CQ in preventing COVID-19 infections.