Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomized-controlled trial

Sylvain A Lother, Mahsa Abassi, Alyssa Agostinis, Ananta S Bangdiwala, Matthew P Cheng, Glen Drobot, Nicole Engen, Kathy H Hullsiek, Lauren E Kelly, Todd C Lee, Sarah M Lofgren, Lauren J MacKenzie, Nicole Marten, Emily G McDonald, Elizabeth C Okafor, Katelyn A Pastick, Matthew F Pullen, Radha Rajasingham, Ilan Schwartz, Caleb P Skipper, Alexis F Turgeon, Ryan Zarychanski, David R Boulware, Sylvain A Lother, Mahsa Abassi, Alyssa Agostinis, Ananta S Bangdiwala, Matthew P Cheng, Glen Drobot, Nicole Engen, Kathy H Hullsiek, Lauren E Kelly, Todd C Lee, Sarah M Lofgren, Lauren J MacKenzie, Nicole Marten, Emily G McDonald, Elizabeth C Okafor, Katelyn A Pastick, Matthew F Pullen, Radha Rajasingham, Ilan Schwartz, Caleb P Skipper, Alexis F Turgeon, Ryan Zarychanski, David R Boulware

Abstract

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease (COVID-19) pandemic. Currently, there is a lack of evidence-based therapies to prevent COVID-19 following exposure to the virus, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis (PEP) and pre-emptive therapy (PET) for COVID-19.

Methods: We will conduct two nested multicentre international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) PEP of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) PET for symptomatic outpatients with COVID-19 showing symptoms for less than four days. We will recruit 1,500 patients each for the PEP and PET trials. Participants will be randomized 1:1 to receive five days of hydroxychloroquine or placebo. The primary PEP trial outcome will be the incidence of symptomatic COVID-19. The primary PET trial outcome will be an ordinal scale of disease severity (not hospitalized, hospitalized without intensive care, hospitalization with intensive care, or death). Participant screening, informed consent, and follow-up will be exclusively internet-based with appropriate regulatory and research ethics board approvals in Canada and the United States.

Discussion: These complementary randomized-controlled trials are innovatively designed and adequately powered to rapidly answer urgent questions regarding the effectiveness of hydroxychloroquine to reduce virus transmission and disease severity of COVID-19 during a pandemic. In-person participant follow-up will not be conducted to facilitate social distancing strategies and reduce risks of exposure to study personnel. Innovative trial approaches are needed to urgently assess therapeutic options to mitigate the global impact of this pandemic.

Trials registration: clinicaltrials.gov (NCT04308668); registered 16 March, 2020.

Keywords: COVID-19; Hydroxychloroquine; SARS-CoV-2; clinical trials; coronavirus; healthcare worker; post-exposure prophylaxis; pre-emptive therapy.

Figures

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Figure
Participant schedule of enrolment, interventions, and assessments. *Follow-up out to day 90 if participants remain hospitalized.

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Source: PubMed

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