Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19
This article has been Reviewed by the following groups
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
- Evaluated articles (ScreenIT)
Abstract
Background
Use of hydroxychloroquine in hospitalized patients with coronavirus disease 2019 (COVID-19), especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from 3 outpatient randomized clinical trials.
Methods
We conducted 3 randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, postexposure prophylaxis, and early treatment for COVID-19 using an internet-based design. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings.
Results
We enrolled 2795 participants. The median age of research participants (interquartile range) was 40 (34–49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2544 (91%) participants reported side effect data, and 748 (29%) reported at least 1 medication side effect. Side effects were reported in 40% with once-daily, 36% with twice-weekly, 31% with once-weekly hydroxychloroquine, compared with 19% with placebo. The most common side effects were upset stomach or nausea (25% with once-daily, 19% with twice-weekly, and 18% with once-weekly hydroxychloroquine, vs 11% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for once-daily, 17% twice-weekly, and 13% once-weekly hydroxychloroquine, vs 7% for placebo). Two individuals were hospitalized for atrial arrhythmias, 1 on placebo and 1 on twice-weekly hydroxychloroquine. No sudden deaths occurred.
Conclusions
Data from 3 outpatient COVID-19 trials demonstrated that gastrointestinal side effects were common but mild with the use of hydroxychloroquine, while serious side effects were rare. No deaths occurred related to hydroxychloroquine. Randomized clinical trials, in cohorts of healthy outpatients, can safely investigate whether hydroxychloroquine is efficacious for COVID-19.
ClinicalTrials.gov Identifier
NCT04308668 for postexposure prophylaxis and early treatment trials; NCT04328467 for pre-exposure prophylaxis trial.
Article activity feed
-
SciScore for 10.1101/2020.07.16.20155531: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The Institutional Review Board (IRB) in Ontario also mandated that a physician perform a complete review of medications for participants above age 65, to exclude those with important drug-drug interactions. Randomization Study Design: We conducted three randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as prophylaxis and treatment for COVID-19 disease. Blinding not detected. Power Analysis not detected. Sex as a biological variable Women who were pregnant or breastfeeding were excluded, as were patients with: severe diarrhea or vomiting; known cirrhosis with a history of encephalopathy or ascites; known prolonged cardiac QTc … SciScore for 10.1101/2020.07.16.20155531: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The Institutional Review Board (IRB) in Ontario also mandated that a physician perform a complete review of medications for participants above age 65, to exclude those with important drug-drug interactions. Randomization Study Design: We conducted three randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as prophylaxis and treatment for COVID-19 disease. Blinding not detected. Power Analysis not detected. Sex as a biological variable Women who were pregnant or breastfeeding were excluded, as were patients with: severe diarrhea or vomiting; known cirrhosis with a history of encephalopathy or ascites; known prolonged cardiac QTc interval, history of ventricular arrhythmia or history of sudden cardiac death; patients taking additional medicines that had a high risk of prolonging the electrocardiogram QTc interval in conjunction with hydroxychloroquine. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Despite our rational design of these clinical trials, several limitations still exist. A significant limitation of our studies is related to their pragmatic nature, which relied on accurate self-reporting. We did not prospectively record or evaluate for laboratory abnormalities or QTc changes. While we have outcome data on 93% of participants who have completed the studies, it is possible, given the passive nature of self-reported follow-up, that those lost-to-follow-up may have had an adverse event that was not reported to our study team or their designated emergency contacts. Additionally, our cohorts are relatively young, with a median age of 40. They had few comorbidities and were on few medications. They were also predominantly healthcare workers, comprising a population of individuals with high health literacy. All these factors make our outpatient research participants healthier than most hospitalized patients in North America. Finally, our study exclusively included outpatients. Patients admitted to hospital are generally older and have more comorbidities. They also are more likely to have cardiac complications of COVID-19 and thus may be more susceptible to develop adverse effects from hydroxychloroquine.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04308668 Completed Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coro… NCT04328467 Active, not recruiting Pre-exposure Prophylaxis for SARS-Coronavirus-2 NCT04332991 Completed Outcomes Related to COVID-19 Treated With Hydroxychloroquine… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
-
SciScore for 10.1101/2020.07.16.20155531: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement The Institutional Review Board (IRB) in Ontario also mandated that a physician perform a complete review of medications for participants above age 65, to exclude those with important drug-drug interactions. Randomization Data from three randomized clinical trials using hydroxychloroquine for the prevention and treatment of COVID-19 did not suggest significant safety concerns. Blinding not detected. Power Analysis not detected. Sex as a biological variable Women who were pregnant or breastfeeding were excluded, as were patients with: severe diarrhea or vomiting; known cirrhosis with a history of encephalopathy or ascites; known prolonged cardiac QTc … SciScore for 10.1101/2020.07.16.20155531: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement The Institutional Review Board (IRB) in Ontario also mandated that a physician perform a complete review of medications for participants above age 65, to exclude those with important drug-drug interactions. Randomization Data from three randomized clinical trials using hydroxychloroquine for the prevention and treatment of COVID-19 did not suggest significant safety concerns. Blinding not detected. Power Analysis not detected. Sex as a biological variable Women who were pregnant or breastfeeding were excluded, as were patients with: severe diarrhea or vomiting; known cirrhosis with a history of encephalopathy or ascites; known prolonged cardiac QTc interval, history of ventricular arrhythmia or history of sudden cardiac death; patients taking additional medicines that had a high risk of prolonging the electrocardiogram QTc interval in conjunction with hydroxychloroquine. Table 2: Resources
Data from additional tools added to each annotation on a weekly basis.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.
-
