Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial
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Abstract
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure.
Methods
We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19–compatible illness. We measured hydroxychloroquine whole-blood concentrations.
Results
We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was .72 (95% CI, .44–1.16; P = .18) and for twice-weekly was .74 (95% CI, .46–1.19; P = .22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82–120) with once-weekly and 200 ng/mL (IQR, 159–258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19–compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P = .08).
Conclusions
Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed COVID-19 or COVID-19–compatible illness among healthcare workers.
Clinical Trials Registration
Clinicaltrials.gov NCT04328467.
Article activity feed
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SciScore for 10.1101/2020.09.18.20197327: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Participants self-enrolled via a secure internet-based survey using the Research Electronic Data Capture (REDCap) system.(11) Participants provided a digitally captured informed consent signature after passing a comprehension assessment. Randomization Study Design: We conducted a randomized, double-blind, placebo-controlled clinical trial (Clinicaltrials.gov NCT04328467) to evaluate whether hydroxychloroquine could prevent Covid-19 in high-risk healthcare workers across the United States and Canada. Blinding Three blinded infectious diseases physicians independently adjudicated cases of symptomatic participants based on the above criteria. Power Analysis not… SciScore for 10.1101/2020.09.18.20197327: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Participants self-enrolled via a secure internet-based survey using the Research Electronic Data Capture (REDCap) system.(11) Participants provided a digitally captured informed consent signature after passing a comprehension assessment. Randomization Study Design: We conducted a randomized, double-blind, placebo-controlled clinical trial (Clinicaltrials.gov NCT04328467) to evaluate whether hydroxychloroquine could prevent Covid-19 in high-risk healthcare workers across the United States and Canada. Blinding Three blinded infectious diseases physicians independently adjudicated cases of symptomatic participants based on the above criteria. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Participants self-enrolled via a secure internet-based survey using the Research Electronic Data Capture (REDCap) system.(11) Participants provided a digitally captured informed consent signature after passing a comprehension assessment. REDCapsuggested: (REDCap, RRID:SCR_003445)We conducted analyses with SAS software version 9.4 SASsuggested: (SASqPCR, RRID:SCR_003056)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:The major limitation of this trial relates to the inherent challenges with PCR testing that have been well described-both the lack of U.S. availability and moderate reported sensitivity early in illness. The false-negative rate of PCR testing has been reported to be 38% (Range 18-65%) on the first day of symptoms, gradually decreasing thereafter.(24) In our study, 39% (38/97) had Covid-19-compatible symptoms with a negative PCR test; however 30 of those PCR tests were performed before symptoms began, when false negatives can be expected.(24) To address this, we included healthcare workers with symptomatic Covid-19–compatible illness despite negative PCR, but separately reported this group. Further supporting this decision, Covid-19–compatible symptoms warrant self-isolation from work for 14 days for healthcare providers and reporting to occupational health, per CDC guidelines, even if PCR testing is negative.(25) However, it is unknown what proportion of persons with symptomatically compatible disease truly have SARS CoV-2 infection, which remains a shared limitation to all outpatient Covid-19 trials in the absence of a diagnostic test with improved sensitivity. Hypothetically, if reported symptoms were due to another respiratory illness, such as influenza, they should have been evenly distributed between groups due to randomization. If one compares only PCR-confirmed disease, there was no statistical difference between groups. Secondly, our trial was limited by weekly self-r...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04328467 Active, not recruiting Pre-exposure Prophylaxis for SARS-Coronavirus-2 NCT04328467 Active, not recruiting Pre-exposure Prophylaxis for SARS-Coronavirus-2 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.
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SciScore for 10.1101/2020.09.18.20197327: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Participants self-enrolled via a secure internet-based survey using the Research Electronic Data Capture (REDCap) system.(11) Participants provided a digitally captured informed consent signature after passing a comprehension assessment. Randomization Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. Blinding Three blinded infectious diseases physicians independently adjudicated cases of symptomatic participants based on the above criteria. Power Analysis not detected. Sex as a biological variable The median age of participants was 41 years (interquartile … SciScore for 10.1101/2020.09.18.20197327: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Participants self-enrolled via a secure internet-based survey using the Research Electronic Data Capture (REDCap) system.(11) Participants provided a digitally captured informed consent signature after passing a comprehension assessment. Randomization Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. Blinding Three blinded infectious diseases physicians independently adjudicated cases of symptomatic participants based on the above criteria. Power Analysis not detected. Sex as a biological variable The median age of participants was 41 years (interquartile range, 34 to 49), and 51% (760 of 1483) were women. Table 2: Resources
Software and Algorithms Sentences Resources Participants self-enrolled via a secure internet-based survey using the Research Electronic Data Capture (REDCap) system.(11) Participants provided a digitally captured informed consent signature after passing a comprehension assessment. REDCapsuggested: (REDCap, RRID:SCR_003445)We conducted analyses with SAS software version 9.4 SASsuggested: (SASqPCR, RRID:SCR_003056)(SAS Institute), according to the intention-to-treat principle. SAS Institutesuggested: (Statistical Analysis System, RRID:SCR_008567)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:
The major limitation of this trial relates to the inherent challenges with PCR testing that have been well described-both the lack of U.S. availability and moderate reported sensitivity early in illness. The false-negative rate of PCR testing has been reported to be 38% (Range 1865%) on the first day of symptoms, gradually decreasing thereafter.(24) In our study, 39% (38/97) had Covid-19-compatible symptoms with a negative PCR test; however 30 of those PCR tests were performed before symptoms began, when false negatives can be expected.(24) To address this, we included healthcare workers with symptomatic Covid-19–compatible illness despite negative PCR, but separately reported this group. Further supporting this decision, Covid-19–compatible symptoms warrant self-isolation from work for 14 days for healthcare providers and reporting to occupational health, per CDC guidelines, even if PCR testing is negative.(25) However, it is unknown what proportion of persons with symptomatically compatible disease truly have SARS CoV-2 infection, which remains a shared limitation to all outpatient Covid-19 trials in the absence of a diagnostic test with improved sensitivity. Hypothetically, if reported symptoms were due to another respiratory illness, such as influenza, they should have been evenly distributed between groups due to randomization. If one compares only PCR-confirmed disease, there was no statistical difference between groups. Secondly, our trial was limited by weekly self-re...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04328467 Active, not recruiting Pre-exposure Prophylaxis for SARS-Coronavirus-2 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.
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 checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
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