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

doi:10.1007/s12630-020-01684-7

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. SkipperAlexis F. Turgeon, Ryan Zarychanski, David R. Boulware

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1201-1211
Number of pages	11
Journal	Canadian Journal of Anesthesia
Volume	67
Issue number	9
DOIs	https://doi.org/10.1007/s12630-020-01684-7
State	Published - Sep 1 2020

Bibliographical note

Funding Information:
American sponsor: David R. Boulware ; Canadian sponsor: Research Institute of the McGill University Health Centre ; American principal investigator: David R. Boulware ; Canadian principal investigators: Ryan Zarychanski , Todd C. Lee , Ilan Schwartz ; Trial design: David R. Boulware , Todd C. Lee , Kathy H. Hullsiek ; Research coordinators: Alyssa Agostinis , Nicole Marten , Zina Zaslawski ; Data collection: Ananta Bangdiwala , Emily G. McDonald , Matthew P. Cheng , Sarah Lofgren , Matt Pullen , Caleb Skipper , Katelyn A. Pastick ; Statistical analysis: Ananta Bangdiwala , Kathy Hullsiek , Nicole Engen ; Operational support: Sylvain A. Lother , Lauren J. MacKenzie , Alyssa Agostinis , Mahsa Abassi , Katelyn A. Pastick , Elizabeth C. Okafor , Matt Pullen , Lauren E. Kelly , Ananta Bangdiwala , David R. Boulware ; Protocol manuscript first draft: Sylvain A. Lother. Drs Emily G. McDonald and Todd C. Lee receive salary support from the Fonds de recherche du Qu?bec?Sant?. Dr. Cheng is a member of the scientific advisory board of GEn1E Lifesciences.?Ryan Zarychanski is the recipient of the Lyonel G Israsels Professorship in Hematology at the University of Manitoba. Dr. Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Additional authors declare no conflicts of interest. Version 1.36, March 25 2020. U.S. Funding by Jan and David Baszucki, Alliance of Minnesota Chinese Organizations, Minnesota Chinese Chamber of Commerce, and University of Minnesota. Canadian funding by the Manitoba Medical Service Foundation. The funders will not contribute to the design of the study; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. Purolator Canada provided in-kind courier support for the participating Canadian sites. This submission was handled by Dr. Gregory L. Bryson, Deputy Editor-in-Chief, Canadian Journal of Anesthesia.

Funding Information:
Drs Emily G. McDonald and Todd C. Lee receive salary support from the Fonds de recherche du Québec—Santé. Dr. Cheng is a member of the scientific advisory board of GEn1E Lifesciences. Ryan Zarychanski is the recipient of the Lyonel G Israsels Professorship in Hematology at the University of Manitoba. Dr. Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Additional authors declare no conflicts of interest.

Publisher Copyright:
© 2020, Canadian Anesthesiologists' Society.

Keywords

COVID-19
Hydroxychloroquine
SARS-CoV-2
clinical trials
coronavirus
healthcare worker
post-exposure prophylaxis
pre-emptive therapy
Severity of Illness Index
Double-Blind Method
Humans
Hydroxychloroquine/administration & dosage
Coronavirus Infections/prevention & control
Pandemics/prevention & control
Betacoronavirus/isolation & purification
Post-Exposure Prophylaxis/methods
Pneumonia, Viral/prevention & control

PubMed: MeSH publication types

Clinical Trial Protocol
Randomized Controlled Trial
Multicenter Study
Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1007/s12630-020-01684-7

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Lother, S. A., Abassi, M., Agostinis, A., Bangdiwala, A. S., Cheng, M. P., Drobot, G., Engen, N., Hullsiek, K. H., Kelly, L. E., Lee, T. C., Lofgren, S. M., MacKenzie, L. J., Marten, N., McDonald, E. G., Okafor, E. C., Pastick, K. A., Pullen, M. F., Rajasingham, R., Schwartz, I., ... Boulware, D. R. (2020). 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. Canadian Journal of Anesthesia, 67(9), 1201-1211. https://doi.org/10.1007/s12630-020-01684-7

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. / Lother, Sylvain A.; Abassi, Mahsa; Agostinis, Alyssa et al.
In: Canadian Journal of Anesthesia, Vol. 67, No. 9, 01.09.2020, p. 1201-1211.

Research output: Contribution to journal › Article › peer-review

Lother, SA, Abassi, M, Agostinis, A, Bangdiwala, AS, Cheng, MP, Drobot, G, Engen, N, Hullsiek, KH, Kelly, LE, Lee, TC, Lofgren, SM, MacKenzie, LJ, Marten, N, McDonald, EG, Okafor, EC, Pastick, KA, Pullen, MF , Rajasingham, R, Schwartz, I, Skipper, CP, Turgeon, AF, Zarychanski, R & Boulware, DR 2020, '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', Canadian Journal of Anesthesia, vol. 67, no. 9, pp. 1201-1211. https://doi.org/10.1007/s12630-020-01684-7

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title = "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",

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.",

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

note = "Funding Information: American sponsor: David R. Boulware ; Canadian sponsor: Research Institute of the McGill University Health Centre ; American principal investigator: David R. Boulware ; Canadian principal investigators: Ryan Zarychanski , Todd C. Lee , Ilan Schwartz ; Trial design: David R. Boulware , Todd C. Lee , Kathy H. Hullsiek ; Research coordinators: Alyssa Agostinis , Nicole Marten , Zina Zaslawski ; Data collection: Ananta Bangdiwala , Emily G. McDonald , Matthew P. Cheng , Sarah Lofgren , Matt Pullen , Caleb Skipper , Katelyn A. Pastick ; Statistical analysis: Ananta Bangdiwala , Kathy Hullsiek , Nicole Engen ; Operational support: Sylvain A. Lother , Lauren J. MacKenzie , Alyssa Agostinis , Mahsa Abassi , Katelyn A. Pastick , Elizabeth C. Okafor , Matt Pullen , Lauren E. Kelly , Ananta Bangdiwala , David R. Boulware ; Protocol manuscript first draft: Sylvain A. Lother. Drs Emily G. McDonald and Todd C. Lee receive salary support from the Fonds de recherche du Qu?bec?Sant?. Dr. Cheng is a member of the scientific advisory board of GEn1E Lifesciences.?Ryan Zarychanski is the recipient of the Lyonel G Israsels Professorship in Hematology at the University of Manitoba. Dr. Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Additional authors declare no conflicts of interest. Version 1.36, March 25 2020. U.S. Funding by Jan and David Baszucki, Alliance of Minnesota Chinese Organizations, Minnesota Chinese Chamber of Commerce, and University of Minnesota. Canadian funding by the Manitoba Medical Service Foundation. The funders will not contribute to the design of the study; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. Purolator Canada provided in-kind courier support for the participating Canadian sites. This submission was handled by Dr. Gregory L. Bryson, Deputy Editor-in-Chief, Canadian Journal of Anesthesia. Funding Information: Drs Emily G. McDonald and Todd C. Lee receive salary support from the Fonds de recherche du Qu{\'e}bec—Sant{\'e}. Dr. Cheng is a member of the scientific advisory board of GEn1E Lifesciences. Ryan Zarychanski is the recipient of the Lyonel G Israsels Professorship in Hematology at the University of Manitoba. Dr. Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Additional authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2020, Canadian Anesthesiologists' Society.",

year = "2020",

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doi = "10.1007/s12630-020-01684-7",

language = "English (US)",

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pages = "1201--1211",

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T1 - Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

T2 - study protocol for a pragmatic randomized-controlled trial

AU - Lother, Sylvain A.

AU - Abassi, Mahsa

AU - Agostinis, Alyssa

AU - Bangdiwala, Ananta S.

AU - Cheng, Matthew P.

AU - Drobot, Glen

AU - Engen, Nicole

AU - Hullsiek, Kathy H.

AU - Kelly, Lauren E.

AU - Lee, Todd C.

AU - Lofgren, Sarah M.

AU - MacKenzie, Lauren J.

AU - Marten, Nicole

AU - McDonald, Emily G.

AU - Okafor, Elizabeth C.

AU - Pastick, Katelyn A.

AU - Pullen, Matthew F.

AU - Rajasingham, Radha

AU - Schwartz, Ilan

AU - Skipper, Caleb P.

AU - Turgeon, Alexis F.

AU - Zarychanski, Ryan

AU - Boulware, David R.

N1 - Funding Information: American sponsor: David R. Boulware ; Canadian sponsor: Research Institute of the McGill University Health Centre ; American principal investigator: David R. Boulware ; Canadian principal investigators: Ryan Zarychanski , Todd C. Lee , Ilan Schwartz ; Trial design: David R. Boulware , Todd C. Lee , Kathy H. Hullsiek ; Research coordinators: Alyssa Agostinis , Nicole Marten , Zina Zaslawski ; Data collection: Ananta Bangdiwala , Emily G. McDonald , Matthew P. Cheng , Sarah Lofgren , Matt Pullen , Caleb Skipper , Katelyn A. Pastick ; Statistical analysis: Ananta Bangdiwala , Kathy Hullsiek , Nicole Engen ; Operational support: Sylvain A. Lother , Lauren J. MacKenzie , Alyssa Agostinis , Mahsa Abassi , Katelyn A. Pastick , Elizabeth C. Okafor , Matt Pullen , Lauren E. Kelly , Ananta Bangdiwala , David R. Boulware ; Protocol manuscript first draft: Sylvain A. Lother. Drs Emily G. McDonald and Todd C. Lee receive salary support from the Fonds de recherche du Qu?bec?Sant?. Dr. Cheng is a member of the scientific advisory board of GEn1E Lifesciences.?Ryan Zarychanski is the recipient of the Lyonel G Israsels Professorship in Hematology at the University of Manitoba. Dr. Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Additional authors declare no conflicts of interest. Version 1.36, March 25 2020. U.S. Funding by Jan and David Baszucki, Alliance of Minnesota Chinese Organizations, Minnesota Chinese Chamber of Commerce, and University of Minnesota. Canadian funding by the Manitoba Medical Service Foundation. The funders will not contribute to the design of the study; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. Purolator Canada provided in-kind courier support for the participating Canadian sites. This submission was handled by Dr. Gregory L. Bryson, Deputy Editor-in-Chief, Canadian Journal of Anesthesia. Funding Information: Drs Emily G. McDonald and Todd C. Lee receive salary support from the Fonds de recherche du Québec—Santé. Dr. Cheng is a member of the scientific advisory board of GEn1E Lifesciences. Ryan Zarychanski is the recipient of the Lyonel G Israsels Professorship in Hematology at the University of Manitoba. Dr. Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Additional authors declare no conflicts of interest. Publisher Copyright: © 2020, Canadian Anesthesiologists' Society.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

KW - COVID-19

KW - Hydroxychloroquine

KW - SARS-CoV-2

KW - clinical trials

KW - coronavirus

KW - healthcare worker

KW - post-exposure prophylaxis

KW - pre-emptive therapy

KW - Severity of Illness Index

KW - Double-Blind Method

KW - Humans

KW - Hydroxychloroquine/administration & dosage

KW - Coronavirus Infections/prevention & control

KW - Pandemics/prevention & control

KW - Betacoronavirus/isolation & purification

KW - Post-Exposure Prophylaxis/methods

KW - Pneumonia, Viral/prevention & control

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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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

Find It

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