Trial NCT04308668
Publication Skipper CP, Ann Intern Med (2020) (published paper)
Dates: 22-mars-20 to 05-juin-20
Funding: Private (Private donors)
Conflict of interest: Yes

Methods
RCT
Blinding: Participants and outcome assessor
Location : Multicenter / USA, Canada
Follow-up duration (days): 14
Inclusion criteria
  • Registry and Protocol:
    Provision of informed consent
    Exposure to a COVID19 case within 4 days as either a household contact or occupational exposure, OR
    Symptomatic COVID19 case with confirmed diagnosis within 4 days of symptom onset OR symptomatic high risk exposure with known COVID19 contact and within 4 days of symptom onset

    Report:
    We enrolled nonhospitalized adults who were required to have 4 or fewer days of symptoms and either PCR-confirmed SARS-CoV-2 infection or compatible symptoms after a high-risk exposure to a person with PCR-confirmed COVID-19 within the past 14 days. High-risk exposure was defined as an immediate household contact or a close occupational exposure to someone with COVID-19 (for example, health care worker or first responder). Health care workers who had COVID-19???compatible symptoms and high-risk exposure but whose contact had PCR results pending were enrolled after symptom review by an infectious diseases physician. All of these participants met the COVID-19 case definition of the U.S. Council of State and Territorial Epidemiologists (Supplement) (10).
    Participants in a third group had a high-risk exposure and were asymptomatic at the time of consent for a companion postexposure prophylaxis trial, which had the same inclusion and exclusion criteria (11)
  • however, these participants became symptomatic before starting their study medicine on day 1 and were analyzed as part of this trial.
Exclusion criteria
  • Supplemental Methods 2:
    Symptoms >4 days (per inclusion criteria)
    Age <18 years old
    Current hospitalization
    Hydroxychloroquine allergy
    Retinal eye disease
    Known glucose-6 phosphate dehydrogenase deficiency
    Known chronic kidney disease (stage 4 or 5 or receiving dialysis)
    Known porphyria
    Weight less than 40 kg
    Receiving chemotherapy
    Current use of hydroxychloroquine, chloroquine
    Current use of cardiac arrhythmia medicines of: flecainide
  • amiodarone
  • digoxin
  • procainamide
  • or sotalol.
    In Canada, additional exclusions mandated by regulatory authorities were: pregnancy, breastfeeding
  • severe diarrhea or vomiting
  • known cirrhosis with encephalopathy or ascites
  • known prolonged cardiac QT interval, ventricular arrhythmia, or history of sudden cardiac death
  • or QT-prolonging medicines (as below) (3)
    On April 20, 2020, additional U.S. exclusions were added for weight less than 50kg, structural or ischemic heart disease, personal or family history of cardiac QT prolongation, and QT-prolonging medications (as below).
    Concomitant QT prolonging medications included current use of:
    QT prolonging medicines of:
    Antimicrobials: azithromycin clarithromycin, erythromycin, ciprofloxacin, levofloxacin, moxifloxacin, ketoconazole, itraconazole, or mefloquine
    Antidepressants: amitriptyline, citalopram, desipramine, escitalopram, imipramine, doxepin, fluoxetine, wellbutrin, or venlafaxine
    Antipsychotic or mood stabilizers: haloperidol, droperidol, lithium, quetiapine, thioridazine, ziprasidone
    Methadone
    Sumatriptan, zolmitriptan
    The prohibition of azithromycin and other QT prolonging medicines was at the express direction of the U.S. FDA as potentially unsafe in an outpatient clinical trial.
Interventions
Treatment
Hydroxychloroquine
800 mg orally once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days
Control
Placebo
folic acid 400 mcg / lactose

Participants
Randomized
participants :
Hydroxychloroquine=244
Placebo=247
Characteristics of participants
N= 491
Mean age : NR
185 males
Severity : Mild: n= 423/ Asymptomatic: n=0
Number of vaccinated participants: NR
Primary outcome
In the register
Incidence of COVID19 Disease among those who are asymptomatic at baseline [ Time Frame: 14 days ]
Number of participants at 14 days post enrollment with active COVID19 disease.
Overall change in disease severity over 14 days among those who are symptomatic at baseline [ Time Frame: 14 days ]
Repeated Measure mixed regression model of change in: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)
In the report
Ordinal outcome by day 14 of not hospitalized, hospitalized, or intensive care unit stay or death
Documents
available

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Yes
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment "In addition to the published report and supplementary file, the study registry, protocol and SAP were used in data extraction and risk of bias assessment. 100 participants that were randomized in a prevention trial (https://www.nejm.org/doi/full/10.1056/NEJMoa2016638?query=TOC) but became symptomatic by D1 were included in this trial. There is no change from the trial registration in the intervention and control treatments. All outcomes specified in the protocol/registry are reported in the paper. The primary outcome was modified while still blinded due to the pooled event rate of the initial primary outcome (ordinal outcome by day 14 of not hospitalized, hospitalized, or intensive care unit stay or death) being substantially lower than the initial 10% expectation (original sample size calculations as described in Statistical Analysis section). The target sample size was thus modified and reduced following the change in outcome and the decision to stop recruitment was made by the DSMB."