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.
Identifieur interne : 001762 ( Main/Corpus ); précédent : 001761; suivant : 001763Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomized-controlled trial.
Auteurs : 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. BoulwareSource :
- Canadian journal of anaesthesia = Journal canadien d'anesthesie [ 1496-8975 ] ; 2020.
English descriptors
- KwdEn :
- Betacoronavirus (isolation & purification), COVID-19 (MeSH), Coronavirus Infections (prevention & control), Coronavirus Infections (transmission), Double-Blind Method (MeSH), Humans (MeSH), Hydroxychloroquine (administration & dosage), Pandemics (prevention & control), Pneumonia, Viral (prevention & control), Pneumonia, Viral (transmission), Post-Exposure Prophylaxis (methods), SARS-CoV-2 (MeSH), Severity of Illness Index (MeSH).
- MESH :
- chemical , administration & dosage : Hydroxychloroquine.
- isolation & purification : Betacoronavirus.
- methods : Post-Exposure Prophylaxis.
- prevention & control : Coronavirus Infections, Pandemics, Pneumonia, Viral.
- transmission : Coronavirus Infections, Pneumonia, Viral.
- COVID-19, Double-Blind Method, Humans, SARS-CoV-2, Severity of Illness Index.
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.
RéSUMé: CONTEXTE: Le syndrome respiratoire aigu sévère du coronavirus 2 (SARS-CoV-2) est apparu en décembre 2019, provoquant la pandémie de la COVID-19. À l’heure actuelle, il n’existe aucun traitement fondé sur des données probantes permettant de prévenir la COVID-19 suite à une exposition au virus ou de prévenir l’aggravation des symptômes suite à une infection confirmée. Nous décrivons la conception d’une étude clinique examinant l’utilisation d’hydroxychloroquine en tant que prophylaxie post-exposition (PPE) et de traitement préventif (TP) pour la COVID-19. MéTHODE: Nous réaliserons deux études cliniques imbriquées contrôlées par placebo, randomisées, à double insu, internationales et multicentriques examinant l’utilisation d’hydroxychloroquine pour : 1) la prophylaxie post-exposition des contacts asymptomatiques dans un même foyer ou les travailleurs de la santé exposés à la COVID-19 au cours des quatre derniers jours, et 2) le traitement préventif des patients symptomatiques en ambulatoire atteints de COVID-19 et présentant des symptômes pour une durée totale de moins de quatre jours. Nous recruterons 1500 patients pour chaque bras de l’étude (PPE et TP). Les participants seront randomisés à un ratio de 1 : 1 pour recevoir cinq jours d’hydroxychloroquine ou de placebo. Le critère d’évaluation principal de l’étude PPE sera l’incidence de COVID-19 symptomatique. Le critère d’évaluation principal de l’étude TP consistera en une échelle ordinale de la gravité de la maladie (pas d’hospitalisation, hospitalisation sans soins intensifs, hospitalisation avec soins intensifs, ou décès). La sélection des participants, le consentement éclairé et le suivi se feront exclusivement en ligne après avoir obtenu les consentements réglementaires et des comités d’éthique de la recherche appropriés au Canada et aux États-Unis. DISCUSSION: Ces études randomisées contrôlées complémentaires sont conçues de façon innovatrice et disposent de la puissance nécessaire pour répondre rapidement aux questions urgentes quant à l’efficacité de l’hydroxychloroquine pour réduire la transmission et la gravité de la maladie de la COVID-19 pendant une pandémie. Le suivi des participants ne sera pas réalisé en personne afin de faciliter les stratégies de distanciation sociale et de réduire le risque d’exposition du personnel de l’étude. Des approches innovatrices d’études sont nécessaires afin d’évaluer rapidement les options thérapeutiques pour mitiger l’impact global de cette pandémie. ENREGISTREMENT DE L’éTUDE: clinicaltrials.gov (NCT04308668); enregistrées le 16 mars 2020.
DOI: 10.1007/s12630-020-01684-7
PubMed: 32383125
PubMed Central: PMC7205369
Links to Exploration step
pubmed:32383125Le document en format XML
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Lother</name><affiliation><nlm:affiliation>Department of Internal Medicine, Section of Critical Care, University of Manitoba, Winnipeg, MB, Canada. slother@manitoba-physicians.ca.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Section of Infectious Diseases, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada. slother@manitoba-physicians.ca.</nlm:affiliation></affiliation></author><author><name sortKey="Abassi, Mahsa" sort="Abassi, Mahsa" uniqKey="Abassi M" first="Mahsa" last="Abassi">Mahsa Abassi</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Agostinis, Alyssa" sort="Agostinis, Alyssa" uniqKey="Agostinis A" first="Alyssa" last="Agostinis">Alyssa Agostinis</name><affiliation><nlm:affiliation>Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>School of Medicine, Trinity College Dublin, Dublin, Ireland.</nlm:affiliation></affiliation></author><author><name sortKey="Bangdiwala, Ananta S" sort="Bangdiwala, Ananta S" uniqKey="Bangdiwala A" first="Ananta S" last="Bangdiwala">Ananta S. Bangdiwala</name><affiliation><nlm:affiliation>Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Cheng, Matthew P" sort="Cheng, Matthew P" uniqKey="Cheng M" first="Matthew P" last="Cheng">Matthew P. 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Lofgren</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mackenzie, Lauren J" sort="Mackenzie, Lauren J" uniqKey="Mackenzie L" first="Lauren J" last="Mackenzie">Lauren J. Mackenzie</name><affiliation><nlm:affiliation>Section of Infectious Diseases, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Marten, Nicole" sort="Marten, Nicole" uniqKey="Marten N" first="Nicole" last="Marten">Nicole Marten</name><affiliation><nlm:affiliation>Critical Care Research, St-Boniface Hospital, Winnipeg, MB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Mcdonald, Emily G" sort="Mcdonald, Emily G" uniqKey="Mcdonald E" first="Emily G" last="Mcdonald">Emily G. Mcdonald</name><affiliation><nlm:affiliation>Clinical Practice Assessment Unit, Department of Medicine, McGill University, Montreal, QC, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Okafor, Elizabeth C" sort="Okafor, Elizabeth C" uniqKey="Okafor E" first="Elizabeth C" last="Okafor">Elizabeth C. Okafor</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Pastick, Katelyn A" sort="Pastick, Katelyn A" uniqKey="Pastick K" first="Katelyn A" last="Pastick">Katelyn A. Pastick</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Pullen, Matthew F" sort="Pullen, Matthew F" uniqKey="Pullen M" first="Matthew F" last="Pullen">Matthew F. Pullen</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Rajasingham, Radha" sort="Rajasingham, Radha" uniqKey="Rajasingham R" first="Radha" last="Rajasingham">Radha Rajasingham</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Schwartz, Ilan" sort="Schwartz, Ilan" uniqKey="Schwartz I" first="Ilan" last="Schwartz">Ilan Schwartz</name><affiliation><nlm:affiliation>Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Skipper, Caleb P" sort="Skipper, Caleb P" uniqKey="Skipper C" first="Caleb P" last="Skipper">Caleb P. Skipper</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Turgeon, Alexis F" sort="Turgeon, Alexis F" uniqKey="Turgeon A" first="Alexis F" last="Turgeon">Alexis F. Turgeon</name><affiliation><nlm:affiliation>CHU de Québec - Université Laval Research Centre, Population Health and Optimal Health Practices Research Unit Trauma - Emergency - Critical Care Medicine, Université Laval, Quebec, QC, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Faculty of Medicine, Université Laval, Quebec, QC, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Zarychanski, Ryan" sort="Zarychanski, Ryan" uniqKey="Zarychanski R" first="Ryan" last="Zarychanski">Ryan Zarychanski</name><affiliation><nlm:affiliation>Department of Internal Medicine, Section of Critical Care, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Internal Medicine, Section of Hematology and Oncology, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Boulware, David R" sort="Boulware, David R" uniqKey="Boulware D" first="David R" last="Boulware">David R. Boulware</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32383125</idno><idno type="pmid">32383125</idno><idno type="doi">10.1007/s12630-020-01684-7</idno><idno type="pmc">PMC7205369</idno><idno type="wicri:Area/Main/Corpus">001762</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">001762</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">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.</title><author><name sortKey="Lother, Sylvain A" sort="Lother, Sylvain A" uniqKey="Lother S" first="Sylvain A" last="Lother">Sylvain A. Lother</name><affiliation><nlm:affiliation>Department of Internal Medicine, Section of Critical Care, University of Manitoba, Winnipeg, MB, Canada. slother@manitoba-physicians.ca.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Section of Infectious Diseases, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada. slother@manitoba-physicians.ca.</nlm:affiliation></affiliation></author><author><name sortKey="Abassi, Mahsa" sort="Abassi, Mahsa" uniqKey="Abassi M" first="Mahsa" last="Abassi">Mahsa Abassi</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Agostinis, Alyssa" sort="Agostinis, Alyssa" uniqKey="Agostinis A" first="Alyssa" last="Agostinis">Alyssa Agostinis</name><affiliation><nlm:affiliation>Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>School of Medicine, Trinity College Dublin, Dublin, Ireland.</nlm:affiliation></affiliation></author><author><name sortKey="Bangdiwala, Ananta S" sort="Bangdiwala, Ananta S" uniqKey="Bangdiwala A" first="Ananta S" last="Bangdiwala">Ananta S. Bangdiwala</name><affiliation><nlm:affiliation>Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Cheng, Matthew P" sort="Cheng, Matthew P" uniqKey="Cheng M" first="Matthew P" last="Cheng">Matthew P. Cheng</name><affiliation><nlm:affiliation>Divisions of Infectious Diseases & Medical Microbiology, McGill University Health Centre, Montreal, QC, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>McGill Interdisciplinary Initiative in Infection and Immunity, Montreal, QC, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Drobot, Glen" sort="Drobot, Glen" uniqKey="Drobot G" first="Glen" last="Drobot">Glen Drobot</name><affiliation><nlm:affiliation>Department of Medicine, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Engen, Nicole" sort="Engen, Nicole" uniqKey="Engen N" first="Nicole" last="Engen">Nicole Engen</name><affiliation><nlm:affiliation>Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hullsiek, Kathy H" sort="Hullsiek, Kathy H" uniqKey="Hullsiek K" first="Kathy H" last="Hullsiek">Kathy H. Hullsiek</name><affiliation><nlm:affiliation>Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kelly, Lauren E" sort="Kelly, Lauren E" uniqKey="Kelly L" first="Lauren E" last="Kelly">Lauren E. Kelly</name><affiliation><nlm:affiliation>Department of Pediatrics and Child Health, Department of Pharmacology, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Lee, Todd C" sort="Lee, Todd C" uniqKey="Lee T" first="Todd C" last="Lee">Todd C. Lee</name><affiliation><nlm:affiliation>Clinical Practice Assessment Unit, Department of Medicine, McGill University, Montreal, QC, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Lofgren, Sarah M" sort="Lofgren, Sarah M" uniqKey="Lofgren S" first="Sarah M" last="Lofgren">Sarah M. Lofgren</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mackenzie, Lauren J" sort="Mackenzie, Lauren J" uniqKey="Mackenzie L" first="Lauren J" last="Mackenzie">Lauren J. Mackenzie</name><affiliation><nlm:affiliation>Section of Infectious Diseases, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Marten, Nicole" sort="Marten, Nicole" uniqKey="Marten N" first="Nicole" last="Marten">Nicole Marten</name><affiliation><nlm:affiliation>Critical Care Research, St-Boniface Hospital, Winnipeg, MB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Mcdonald, Emily G" sort="Mcdonald, Emily G" uniqKey="Mcdonald E" first="Emily G" last="Mcdonald">Emily G. Mcdonald</name><affiliation><nlm:affiliation>Clinical Practice Assessment Unit, Department of Medicine, McGill University, Montreal, QC, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Okafor, Elizabeth C" sort="Okafor, Elizabeth C" uniqKey="Okafor E" first="Elizabeth C" last="Okafor">Elizabeth C. Okafor</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Pastick, Katelyn A" sort="Pastick, Katelyn A" uniqKey="Pastick K" first="Katelyn A" last="Pastick">Katelyn A. Pastick</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Pullen, Matthew F" sort="Pullen, Matthew F" uniqKey="Pullen M" first="Matthew F" last="Pullen">Matthew F. Pullen</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Rajasingham, Radha" sort="Rajasingham, Radha" uniqKey="Rajasingham R" first="Radha" last="Rajasingham">Radha Rajasingham</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Schwartz, Ilan" sort="Schwartz, Ilan" uniqKey="Schwartz I" first="Ilan" last="Schwartz">Ilan Schwartz</name><affiliation><nlm:affiliation>Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Skipper, Caleb P" sort="Skipper, Caleb P" uniqKey="Skipper C" first="Caleb P" last="Skipper">Caleb P. Skipper</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Turgeon, Alexis F" sort="Turgeon, Alexis F" uniqKey="Turgeon A" first="Alexis F" last="Turgeon">Alexis F. Turgeon</name><affiliation><nlm:affiliation>CHU de Québec - Université Laval Research Centre, Population Health and Optimal Health Practices Research Unit Trauma - Emergency - Critical Care Medicine, Université Laval, Quebec, QC, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Faculty of Medicine, Université Laval, Quebec, QC, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Zarychanski, Ryan" sort="Zarychanski, Ryan" uniqKey="Zarychanski R" first="Ryan" last="Zarychanski">Ryan Zarychanski</name><affiliation><nlm:affiliation>Department of Internal Medicine, Section of Critical Care, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Internal Medicine, Section of Hematology and Oncology, University of Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Boulware, David R" sort="Boulware, David R" uniqKey="Boulware D" first="David R" last="Boulware">David R. Boulware</name><affiliation><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Canadian journal of anaesthesia = Journal canadien d'anesthesie</title><idno type="eISSN">1496-8975</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Betacoronavirus (isolation & purification)</term><term>COVID-19 (MeSH)</term><term>Coronavirus Infections (prevention & control)</term><term>Coronavirus Infections (transmission)</term><term>Double-Blind Method (MeSH)</term><term>Humans (MeSH)</term><term>Hydroxychloroquine (administration & dosage)</term><term>Pandemics (prevention & control)</term><term>Pneumonia, Viral (prevention & control)</term><term>Pneumonia, Viral (transmission)</term><term>Post-Exposure Prophylaxis (methods)</term><term>SARS-CoV-2 (MeSH)</term><term>Severity of Illness Index (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Hydroxychloroquine</term></keywords><keywords scheme="MESH" qualifier="isolation & purification" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Post-Exposure Prophylaxis</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Coronavirus Infections</term><term>Pandemics</term><term>Pneumonia, Viral</term></keywords><keywords scheme="MESH" qualifier="transmission" xml:lang="en"><term>Coronavirus Infections</term><term>Pneumonia, Viral</term></keywords><keywords scheme="MESH" xml:lang="en"><term>COVID-19</term><term>Double-Blind Method</term><term>Humans</term><term>SARS-CoV-2</term><term>Severity of Illness Index</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>DISCUSSION</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>TRIALS REGISTRATION</b></p><p>clinicaltrials.gov (NCT04308668); registered 16 March, 2020.</p></div><div type="abstract" xml:lang="fr">RéSUMé: CONTEXTE: Le syndrome respiratoire aigu sévère du coronavirus 2 (SARS-CoV-2) est apparu en décembre 2019, provoquant la pandémie de la COVID-19. À l’heure actuelle, il n’existe aucun traitement fondé sur des données probantes permettant de prévenir la COVID-19 suite à une exposition au virus ou de prévenir l’aggravation des symptômes suite à une infection confirmée. Nous décrivons la conception d’une étude clinique examinant l’utilisation d’hydroxychloroquine en tant que prophylaxie post-exposition (PPE) et de traitement préventif (TP) pour la COVID-19. MéTHODE: Nous réaliserons deux études cliniques imbriquées contrôlées par placebo, randomisées, à double insu, internationales et multicentriques examinant l’utilisation d’hydroxychloroquine pour : 1) la prophylaxie post-exposition des contacts asymptomatiques dans un même foyer ou les travailleurs de la santé exposés à la COVID-19 au cours des quatre derniers jours, et 2) le traitement préventif des patients symptomatiques en ambulatoire atteints de COVID-19 et présentant des symptômes pour une durée totale de moins de quatre jours. Nous recruterons 1500 patients pour chaque bras de l’étude (PPE et TP). Les participants seront randomisés à un ratio de 1 : 1 pour recevoir cinq jours d’hydroxychloroquine ou de placebo. Le critère d’évaluation principal de l’étude PPE sera l’incidence de COVID-19 symptomatique. Le critère d’évaluation principal de l’étude TP consistera en une échelle ordinale de la gravité de la maladie (pas d’hospitalisation, hospitalisation sans soins intensifs, hospitalisation avec soins intensifs, ou décès). La sélection des participants, le consentement éclairé et le suivi se feront exclusivement en ligne après avoir obtenu les consentements réglementaires et des comités d’éthique de la recherche appropriés au Canada et aux États-Unis. DISCUSSION: Ces études randomisées contrôlées complémentaires sont conçues de façon innovatrice et disposent de la puissance nécessaire pour répondre rapidement aux questions urgentes quant à l’efficacité de l’hydroxychloroquine pour réduire la transmission et la gravité de la maladie de la COVID-19 pendant une pandémie. Le suivi des participants ne sera pas réalisé en personne afin de faciliter les stratégies de distanciation sociale et de réduire le risque d’exposition du personnel de l’étude. Des approches innovatrices d’études sont nécessaires afin d’évaluer rapidement les options thérapeutiques pour mitiger l’impact global de cette pandémie. ENREGISTREMENT DE L’éTUDE: clinicaltrials.gov (NCT04308668); enregistrées le 16 mars 2020.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">32383125</PMID><DateCompleted><Year>2020</Year><Month>08</Month><Day>24</Day></DateCompleted><DateRevised><Year>2021</Year><Month>01</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1496-8975</ISSN><JournalIssue CitedMedium="Internet"><Volume>67</Volume><Issue>9</Issue><PubDate><Year>2020</Year><Month>09</Month></PubDate></JournalIssue><Title>Canadian journal of anaesthesia = Journal canadien d'anesthesie</Title><ISOAbbreviation>Can J Anaesth</ISOAbbreviation></Journal><ArticleTitle>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.</ArticleTitle><Pagination><MedlinePgn>1201-1211</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1007/s12630-020-01684-7</ELocationID><Abstract><AbstractText Label="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.</AbstractText><AbstractText Label="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.</AbstractText><AbstractText Label="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.</AbstractText><AbstractText Label="TRIALS REGISTRATION">clinicaltrials.gov (NCT04308668); registered 16 March, 2020.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lother</LastName><ForeName>Sylvain A</ForeName><Initials>SA</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine, Section of Critical Care, University of Manitoba, Winnipeg, MB, Canada. slother@manitoba-physicians.ca.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Section of Infectious Diseases, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada. slother@manitoba-physicians.ca.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Abassi</LastName><ForeName>Mahsa</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Agostinis</LastName><ForeName>Alyssa</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>School of Medicine, Trinity College Dublin, Dublin, Ireland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bangdiwala</LastName><ForeName>Ananta S</ForeName><Initials>AS</Initials><AffiliationInfo><Affiliation>Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cheng</LastName><ForeName>Matthew P</ForeName><Initials>MP</Initials><AffiliationInfo><Affiliation>Divisions of Infectious Diseases & Medical Microbiology, McGill University Health Centre, Montreal, QC, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>McGill Interdisciplinary Initiative in Infection and Immunity, Montreal, QC, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Drobot</LastName><ForeName>Glen</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Manitoba, Winnipeg, MB, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Engen</LastName><ForeName>Nicole</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hullsiek</LastName><ForeName>Kathy H</ForeName><Initials>KH</Initials><AffiliationInfo><Affiliation>Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kelly</LastName><ForeName>Lauren E</ForeName><Initials>LE</Initials><AffiliationInfo><Affiliation>Department of Pediatrics and Child Health, Department of Pharmacology, University of Manitoba, Winnipeg, MB, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Todd C</ForeName><Initials>TC</Initials><AffiliationInfo><Affiliation>Clinical Practice Assessment Unit, Department of Medicine, McGill University, Montreal, QC, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lofgren</LastName><ForeName>Sarah M</ForeName><Initials>SM</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>MacKenzie</LastName><ForeName>Lauren J</ForeName><Initials>LJ</Initials><AffiliationInfo><Affiliation>Section of Infectious Diseases, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marten</LastName><ForeName>Nicole</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Critical Care Research, St-Boniface Hospital, Winnipeg, MB, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McDonald</LastName><ForeName>Emily G</ForeName><Initials>EG</Initials><AffiliationInfo><Affiliation>Clinical Practice Assessment Unit, Department of Medicine, McGill University, Montreal, QC, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Okafor</LastName><ForeName>Elizabeth C</ForeName><Initials>EC</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pastick</LastName><ForeName>Katelyn A</ForeName><Initials>KA</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pullen</LastName><ForeName>Matthew F</ForeName><Initials>MF</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rajasingham</LastName><ForeName>Radha</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schwartz</LastName><ForeName>Ilan</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Skipper</LastName><ForeName>Caleb P</ForeName><Initials>CP</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Turgeon</LastName><ForeName>Alexis F</ForeName><Initials>AF</Initials><AffiliationInfo><Affiliation>CHU de Québec - Université Laval Research Centre, Population Health and Optimal Health Practices Research Unit Trauma - Emergency - Critical Care Medicine, Université Laval, Quebec, QC, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Faculty of Medicine, Université Laval, Quebec, QC, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zarychanski</LastName><ForeName>Ryan</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine, Section of Critical Care, University of Manitoba, Winnipeg, MB, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Internal Medicine, Section of Hematology and Oncology, University of Manitoba, Winnipeg, MB, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Boulware</LastName><ForeName>David R</ForeName><Initials>DR</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Minnesota, Minneapolis, MN, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>ClinicalTrials.gov</DataBankName><AccessionNumberList><AccessionNumber>NCT04308668</AccessionNumber></AccessionNumberList></DataBank></DataBankList><GrantList CompleteYN="Y"><Grant><GrantID>K23 AI138851</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>K23 MH121220</GrantID><Acronym>MH</Acronym><Agency>NIMH NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>UL1 TR002494</GrantID><Acronym>TR</Acronym><Agency>NCATS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D000078325">Clinical Trial Protocol</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016448">Multicenter Study</PublicationType><PublicationType UI="D016449">Randomized Controlled Trial</PublicationType></PublicationTypeList><VernacularTitle>Prophylaxie post-exposition ou traitement préventif pour le syndrome respiratoire aigu sévère du coronavirus 2 (SARS-CoV-2) : protocole d’étude pour une étude randomisée contrôlée pragmatique.</VernacularTitle><ArticleDate DateType="Electronic"><Year>2020</Year><Month>05</Month><Day>07</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Can J Anaesth</MedlineTA><NlmUniqueID>8701709</NlmUniqueID><ISSNLinking>0832-610X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>4QWG6N8QKH</RegistryNumber><NameOfSubstance UI="D006886">Hydroxychloroquine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000073640" MajorTopicYN="N">Betacoronavirus</DescriptorName><QualifierName UI="Q000302" MajorTopicYN="N">isolation & purification</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000086382" MajorTopicYN="N">COVID-19</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName><QualifierName UI="Q000635" MajorTopicYN="N">transmission</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004311" MajorTopicYN="N">Double-Blind Method</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006886" MajorTopicYN="N">Hydroxychloroquine</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058873" MajorTopicYN="N">Pandemics</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011024" MajorTopicYN="N">Pneumonia, Viral</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName><QualifierName UI="Q000635" MajorTopicYN="N">transmission</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D056990" MajorTopicYN="N">Post-Exposure Prophylaxis</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000086402" MajorTopicYN="N">SARS-CoV-2</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012720" MajorTopicYN="N">Severity of Illness Index</DescriptorName></MeshHeading></MeshHeadingList><OtherAbstract Type="Publisher" Language="fre"><AbstractText>RéSUMé: CONTEXTE: Le syndrome respiratoire aigu sévère du coronavirus 2 (SARS-CoV-2) est apparu en décembre 2019, provoquant la pandémie de la COVID-19. À l’heure actuelle, il n’existe aucun traitement fondé sur des données probantes permettant de prévenir la COVID-19 suite à une exposition au virus ou de prévenir l’aggravation des symptômes suite à une infection confirmée. Nous décrivons la conception d’une étude clinique examinant l’utilisation d’hydroxychloroquine en tant que prophylaxie post-exposition (PPE) et de traitement préventif (TP) pour la COVID-19. MéTHODE: Nous réaliserons deux études cliniques imbriquées contrôlées par placebo, randomisées, à double insu, internationales et multicentriques examinant l’utilisation d’hydroxychloroquine pour : 1) la prophylaxie post-exposition des contacts asymptomatiques dans un même foyer ou les travailleurs de la santé exposés à la COVID-19 au cours des quatre derniers jours, et 2) le traitement préventif des patients symptomatiques en ambulatoire atteints de COVID-19 et présentant des symptômes pour une durée totale de moins de quatre jours. Nous recruterons 1500 patients pour chaque bras de l’étude (PPE et TP). Les participants seront randomisés à un ratio de 1 : 1 pour recevoir cinq jours d’hydroxychloroquine ou de placebo. Le critère d’évaluation principal de l’étude PPE sera l’incidence de COVID-19 symptomatique. Le critère d’évaluation principal de l’étude TP consistera en une échelle ordinale de la gravité de la maladie (pas d’hospitalisation, hospitalisation sans soins intensifs, hospitalisation avec soins intensifs, ou décès). La sélection des participants, le consentement éclairé et le suivi se feront exclusivement en ligne après avoir obtenu les consentements réglementaires et des comités d’éthique de la recherche appropriés au Canada et aux États-Unis. DISCUSSION: Ces études randomisées contrôlées complémentaires sont conçues de façon innovatrice et disposent de la puissance nécessaire pour répondre rapidement aux questions urgentes quant à l’efficacité de l’hydroxychloroquine pour réduire la transmission et la gravité de la maladie de la COVID-19 pendant une pandémie. Le suivi des participants ne sera pas réalisé en personne afin de faciliter les stratégies de distanciation sociale et de réduire le risque d’exposition du personnel de l’étude. Des approches innovatrices d’études sont nécessaires afin d’évaluer rapidement les options thérapeutiques pour mitiger l’impact global de cette pandémie. ENREGISTREMENT DE L’éTUDE: clinicaltrials.gov (NCT04308668); enregistrées le 16 mars 2020.</AbstractText></OtherAbstract><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">COVID-19</Keyword><Keyword MajorTopicYN="Y">Hydroxychloroquine</Keyword><Keyword MajorTopicYN="Y">SARS-CoV-2</Keyword><Keyword MajorTopicYN="Y">clinical trials</Keyword><Keyword MajorTopicYN="Y">coronavirus</Keyword><Keyword MajorTopicYN="Y">healthcare worker</Keyword><Keyword MajorTopicYN="Y">post-exposure prophylaxis</Keyword><Keyword MajorTopicYN="Y">pre-emptive therapy</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>04</Month><Day>21</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>04</Month><Day>21</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>5</Month><Day>10</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>8</Month><Day>25</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>5</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32383125</ArticleId><ArticleId IdType="doi">10.1007/s12630-020-01684-7</ArticleId><ArticleId IdType="pii">10.1007/s12630-020-01684-7</ArticleId><ArticleId IdType="pmc">PMC7205369</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. 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