Endpoints for randomized controlled clinical trials for COVID-19 treatments.
Identifieur interne : 001035 ( Main/Exploration ); précédent : 001034; suivant : 001036Endpoints for randomized controlled clinical trials for COVID-19 treatments.
Auteurs : Lori E. Dodd [États-Unis] ; Dean Follmann [États-Unis] ; Jing Wang [États-Unis] ; Franz Koenig [Autriche] ; Lisa L. Korn [États-Unis] ; Christian Schoergenhofer [Autriche] ; Michael Proschan [États-Unis] ; Sally Hunsberger [États-Unis] ; Tyler Bonnett [États-Unis] ; Mat Makowski [États-Unis] ; Drifa Belhadi [France] ; Yeming Wang [République populaire de Chine] ; Bin Cao [République populaire de Chine] ; France Mentre [France] ; Thomas Jaki [Royaume-Uni]Source :
- Clinical trials (London, England) [ 1740-7753 ] ; 2020.
Abstract
BACKGROUND
Endpoint choice for randomized controlled trials of treatments for novel coronavirus-induced disease (COVID-19) is complex. Trials must start rapidly to identify treatments that can be used as part of the outbreak response, in the midst of considerable uncertainty and limited information. COVID-19 presentation is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks to over a month and can end in death. While improvement in mortality would provide unquestionable evidence about the clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical, particularly given a multitude of putative therapies to evaluate. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly given the variable time course of COVID-19. Outcomes measured at fixed time points, such as a comparison of severity scores between treatment and control at day 14, may risk missing the time of clinical benefit. An endpoint such as time to improvement (or recovery) avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of "recovered" versus "not recovered."
METHODS
We evaluate statistical power for possible trial endpoints for COVID-19 treatment trials using simulation models and data from two recent COVID-19 treatment trials.
RESULTS
Power for fixed time-point methods depends heavily on the time selected for evaluation. Time-to-event approaches have reasonable statistical power, even when compared with a fixed time-point method evaluated at the optimal time.
DISCUSSION
Time-to-event analysis methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses.
DOI: 10.1177/1740774520939938
PubMed: 32674594
Affiliations:
- Autriche, France, Royaume-Uni, République populaire de Chine, États-Unis
- Angleterre, Angleterre de l'Est, Connecticut, Maryland, Vienne (Autriche), Île-de-France
- Cambridge, Paris, Pékin, Vienne (Autriche)
- Université de Cambridge
Links toward previous steps (curation, corpus...)
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Dodd</name><affiliation wicri:level="2"><nlm:affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Follmann, Dean" sort="Follmann, Dean" uniqKey="Follmann D" first="Dean" last="Follmann">Dean Follmann</name><affiliation wicri:level="2"><nlm:affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Wang, Jing" sort="Wang, Jing" uniqKey="Wang J" first="Jing" last="Wang">Jing Wang</name><affiliation wicri:level="2"><nlm:affiliation>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Koenig, Franz" sort="Koenig, Franz" uniqKey="Koenig F" first="Franz" last="Koenig">Franz Koenig</name><affiliation wicri:level="3"><nlm:affiliation>Center for Medical Statistics, Informatics and Intelligent Systems; Medical University of Vienna, Vienna, Austria.</nlm:affiliation><country xml:lang="fr">Autriche</country><wicri:regionArea>Center for Medical Statistics, Informatics and Intelligent Systems; Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Korn, Lisa L" sort="Korn, Lisa L" uniqKey="Korn L" first="Lisa L" last="Korn">Lisa L. Korn</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine (Rheumatology, Allergy, and Immunology Section) and Department of Immunobiology, Yale University, New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine (Rheumatology, Allergy, and Immunology Section) and Department of Immunobiology, Yale University, New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Schoergenhofer, Christian" sort="Schoergenhofer, Christian" uniqKey="Schoergenhofer C" first="Christian" last="Schoergenhofer">Christian Schoergenhofer</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.</nlm:affiliation><country xml:lang="fr">Autriche</country><wicri:regionArea>Department of Clinical Pharmacology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Proschan, Michael" sort="Proschan, Michael" uniqKey="Proschan M" first="Michael" last="Proschan">Michael Proschan</name><affiliation wicri:level="2"><nlm:affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Hunsberger, Sally" sort="Hunsberger, Sally" uniqKey="Hunsberger S" first="Sally" last="Hunsberger">Sally Hunsberger</name><affiliation wicri:level="2"><nlm:affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Bonnett, Tyler" sort="Bonnett, Tyler" uniqKey="Bonnett T" first="Tyler" last="Bonnett">Tyler Bonnett</name><affiliation wicri:level="2"><nlm:affiliation>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Makowski, Mat" sort="Makowski, Mat" uniqKey="Makowski M" first="Mat" last="Makowski">Mat Makowski</name><affiliation wicri:level="2"><nlm:affiliation>The Emmes Company, LLC, Rockville, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Emmes Company, LLC, Rockville, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Belhadi, Drifa" sort="Belhadi, Drifa" uniqKey="Belhadi D" first="Drifa" last="Belhadi">Drifa Belhadi</name><affiliation wicri:level="3"><nlm:affiliation>Université de Paris, IAME, Inserm, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Université de Paris, IAME, Inserm, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>AP-HP, Hôpital Bichat, DEBRC, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>AP-HP, Hôpital Bichat, DEBRC, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Wang, Yeming" sort="Wang, Yeming" uniqKey="Wang Y" first="Yeming" last="Wang">Yeming Wang</name><affiliation wicri:level="3"><nlm:affiliation>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Cao, Bin" sort="Cao, Bin" uniqKey="Cao B" first="Bin" last="Cao">Bin Cao</name><affiliation wicri:level="3"><nlm:affiliation>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Mentre, France" sort="Mentre, France" uniqKey="Mentre F" first="France" last="Mentre">France Mentre</name><affiliation wicri:level="3"><nlm:affiliation>Université de Paris, IAME, Inserm, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Université de Paris, IAME, Inserm, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>AP-HP, Hôpital Bichat, DEBRC, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>AP-HP, Hôpital Bichat, DEBRC, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Jaki, Thomas" sort="Jaki, Thomas" uniqKey="Jaki T" first="Thomas" last="Jaki">Thomas Jaki</name><affiliation wicri:level="1"><nlm:affiliation>Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Mathematics and Statistics, Lancaster University, Lancaster</wicri:regionArea><wicri:noRegion>Lancaster</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Biostatistics Unit, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32674594</idno><idno type="pmid">32674594</idno><idno type="doi">10.1177/1740774520939938</idno><idno type="wicri:Area/Main/Corpus">000944</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000944</idno><idno type="wicri:Area/Main/Curation">000944</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000944</idno><idno type="wicri:Area/Main/Exploration">000944</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Endpoints for randomized controlled clinical trials for COVID-19 treatments.</title><author><name sortKey="Dodd, Lori E" sort="Dodd, Lori E" uniqKey="Dodd L" first="Lori E" last="Dodd">Lori E. Dodd</name><affiliation wicri:level="2"><nlm:affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Follmann, Dean" sort="Follmann, Dean" uniqKey="Follmann D" first="Dean" last="Follmann">Dean Follmann</name><affiliation wicri:level="2"><nlm:affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Wang, Jing" sort="Wang, Jing" uniqKey="Wang J" first="Jing" last="Wang">Jing Wang</name><affiliation wicri:level="2"><nlm:affiliation>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Koenig, Franz" sort="Koenig, Franz" uniqKey="Koenig F" first="Franz" last="Koenig">Franz Koenig</name><affiliation wicri:level="3"><nlm:affiliation>Center for Medical Statistics, Informatics and Intelligent Systems; Medical University of Vienna, Vienna, Austria.</nlm:affiliation><country xml:lang="fr">Autriche</country><wicri:regionArea>Center for Medical Statistics, Informatics and Intelligent Systems; Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Korn, Lisa L" sort="Korn, Lisa L" uniqKey="Korn L" first="Lisa L" last="Korn">Lisa L. Korn</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine (Rheumatology, Allergy, and Immunology Section) and Department of Immunobiology, Yale University, New Haven, CT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine (Rheumatology, Allergy, and Immunology Section) and Department of Immunobiology, Yale University, New Haven, CT</wicri:regionArea><placeName><region type="state">Connecticut</region></placeName></affiliation></author><author><name sortKey="Schoergenhofer, Christian" sort="Schoergenhofer, Christian" uniqKey="Schoergenhofer C" first="Christian" last="Schoergenhofer">Christian Schoergenhofer</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.</nlm:affiliation><country xml:lang="fr">Autriche</country><wicri:regionArea>Department of Clinical Pharmacology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Proschan, Michael" sort="Proschan, Michael" uniqKey="Proschan M" first="Michael" last="Proschan">Michael Proschan</name><affiliation wicri:level="2"><nlm:affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Hunsberger, Sally" sort="Hunsberger, Sally" uniqKey="Hunsberger S" first="Sally" last="Hunsberger">Sally Hunsberger</name><affiliation wicri:level="2"><nlm:affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Bonnett, Tyler" sort="Bonnett, Tyler" uniqKey="Bonnett T" first="Tyler" last="Bonnett">Tyler Bonnett</name><affiliation wicri:level="2"><nlm:affiliation>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Makowski, Mat" sort="Makowski, Mat" uniqKey="Makowski M" first="Mat" last="Makowski">Mat Makowski</name><affiliation wicri:level="2"><nlm:affiliation>The Emmes Company, LLC, Rockville, MD, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Emmes Company, LLC, Rockville, MD</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Belhadi, Drifa" sort="Belhadi, Drifa" uniqKey="Belhadi D" first="Drifa" last="Belhadi">Drifa Belhadi</name><affiliation wicri:level="3"><nlm:affiliation>Université de Paris, IAME, Inserm, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Université de Paris, IAME, Inserm, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>AP-HP, Hôpital Bichat, DEBRC, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>AP-HP, Hôpital Bichat, DEBRC, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Wang, Yeming" sort="Wang, Yeming" uniqKey="Wang Y" first="Yeming" last="Wang">Yeming Wang</name><affiliation wicri:level="3"><nlm:affiliation>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Cao, Bin" sort="Cao, Bin" uniqKey="Cao B" first="Bin" last="Cao">Bin Cao</name><affiliation wicri:level="3"><nlm:affiliation>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Mentre, France" sort="Mentre, France" uniqKey="Mentre F" first="France" last="Mentre">France Mentre</name><affiliation wicri:level="3"><nlm:affiliation>Université de Paris, IAME, Inserm, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Université de Paris, IAME, Inserm, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>AP-HP, Hôpital Bichat, DEBRC, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>AP-HP, Hôpital Bichat, DEBRC, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Jaki, Thomas" sort="Jaki, Thomas" uniqKey="Jaki T" first="Thomas" last="Jaki">Thomas Jaki</name><affiliation wicri:level="1"><nlm:affiliation>Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Mathematics and Statistics, Lancaster University, Lancaster</wicri:regionArea><wicri:noRegion>Lancaster</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Biostatistics Unit, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author></analytic><series><title level="j">Clinical trials (London, England)</title><idno type="eISSN">1740-7753</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>Endpoint choice for randomized controlled trials of treatments for novel coronavirus-induced disease (COVID-19) is complex. Trials must start rapidly to identify treatments that can be used as part of the outbreak response, in the midst of considerable uncertainty and limited information. COVID-19 presentation is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks to over a month and can end in death. While improvement in mortality would provide unquestionable evidence about the clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical, particularly given a multitude of putative therapies to evaluate. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly given the variable time course of COVID-19. Outcomes measured at fixed time points, such as a comparison of severity scores between treatment and control at day 14, may risk missing the time of clinical benefit. An endpoint such as time to improvement (or recovery) avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of "recovered" versus "not recovered."</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>We evaluate statistical power for possible trial endpoints for COVID-19 treatment trials using simulation models and data from two recent COVID-19 treatment trials.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>Power for fixed time-point methods depends heavily on the time selected for evaluation. Time-to-event approaches have reasonable statistical power, even when compared with a fixed time-point method evaluated at the optimal time.</p></div><div type="abstract" xml:lang="en"><p><b>DISCUSSION</b></p><p>Time-to-event analysis methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses.</p></div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32674594</PMID><DateRevised><Year>2020</Year><Month>07</Month><Day>17</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1740-7753</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Jul</Month><Day>16</Day></PubDate></JournalIssue><Title>Clinical trials (London, England)</Title><ISOAbbreviation>Clin Trials</ISOAbbreviation></Journal><ArticleTitle>Endpoints for randomized controlled clinical trials for COVID-19 treatments.</ArticleTitle><Pagination><MedlinePgn>1740774520939938</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1177/1740774520939938</ELocationID><Abstract><AbstractText Label="BACKGROUND" NlmCategory="UNASSIGNED">Endpoint choice for randomized controlled trials of treatments for novel coronavirus-induced disease (COVID-19) is complex. Trials must start rapidly to identify treatments that can be used as part of the outbreak response, in the midst of considerable uncertainty and limited information. COVID-19 presentation is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks to over a month and can end in death. While improvement in mortality would provide unquestionable evidence about the clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical, particularly given a multitude of putative therapies to evaluate. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly given the variable time course of COVID-19. Outcomes measured at fixed time points, such as a comparison of severity scores between treatment and control at day 14, may risk missing the time of clinical benefit. An endpoint such as time to improvement (or recovery) avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of "recovered" versus "not recovered."</AbstractText><AbstractText Label="METHODS" NlmCategory="UNASSIGNED">We evaluate statistical power for possible trial endpoints for COVID-19 treatment trials using simulation models and data from two recent COVID-19 treatment trials.</AbstractText><AbstractText Label="RESULTS" NlmCategory="UNASSIGNED">Power for fixed time-point methods depends heavily on the time selected for evaluation. Time-to-event approaches have reasonable statistical power, even when compared with a fixed time-point method evaluated at the optimal time.</AbstractText><AbstractText Label="DISCUSSION" NlmCategory="UNASSIGNED">Time-to-event analysis methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Dodd</LastName><ForeName>Lori E</ForeName><Initials>LE</Initials><Identifier Source="ORCID">https://orcid.org/0000-0002-3433-5429</Identifier><AffiliationInfo><Affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Follmann</LastName><ForeName>Dean</ForeName><Initials>D</Initials><Identifier Source="ORCID">https://orcid.org/0000-0003-4073-0393</Identifier><AffiliationInfo><Affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Jing</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Koenig</LastName><ForeName>Franz</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Center for Medical Statistics, Informatics and Intelligent Systems; Medical University of Vienna, Vienna, Austria.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Korn</LastName><ForeName>Lisa L</ForeName><Initials>LL</Initials><AffiliationInfo><Affiliation>Department of Medicine (Rheumatology, Allergy, and Immunology Section) and Department of Immunobiology, Yale University, New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schoergenhofer</LastName><ForeName>Christian</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Proschan</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hunsberger</LastName><ForeName>Sally</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Biostatistics Research Branch, National Institute Allergy and Infectious Diseases, Bethesda, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bonnett</LastName><ForeName>Tyler</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Makowski</LastName><ForeName>Mat</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>The Emmes Company, LLC, Rockville, MD, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Belhadi</LastName><ForeName>Drifa</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Université de Paris, IAME, Inserm, Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Hôpital Bichat, DEBRC, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Yeming</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cao</LastName><ForeName>Bin</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, Beijing, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>China-Japan Friendship Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mentre</LastName><ForeName>France</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Université de Paris, IAME, Inserm, Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Hôpital Bichat, DEBRC, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jaki</LastName><ForeName>Thomas</ForeName><Initials>T</Initials><Identifier Source="ORCID">https://orcid.org/0000-0002-1096-188X</Identifier><AffiliationInfo><Affiliation>Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>07</Month><Day>16</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Clin Trials</MedlineTA><NlmUniqueID>101197451</NlmUniqueID><ISSNLinking>1740-7745</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">COVID-19</Keyword><Keyword MajorTopicYN="N">WHO ordinal scale</Keyword><Keyword MajorTopicYN="N">censoring</Keyword><Keyword MajorTopicYN="N">clinical trials</Keyword><Keyword MajorTopicYN="N">endpoints</Keyword><Keyword MajorTopicYN="N">log-rank test</Keyword><Keyword MajorTopicYN="N">proportional odds model</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>7</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>7</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>7</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32674594</ArticleId><ArticleId IdType="doi">10.1177/1740774520939938</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Autriche</li><li>France</li><li>Royaume-Uni</li><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Angleterre de l'Est</li><li>Connecticut</li><li>Maryland</li><li>Vienne (Autriche)</li><li>Île-de-France</li></region><settlement><li>Cambridge</li><li>Paris</li><li>Pékin</li><li>Vienne (Autriche)</li></settlement><orgName><li>Université de Cambridge</li></orgName></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Dodd, Lori E" sort="Dodd, Lori E" uniqKey="Dodd L" first="Lori E" last="Dodd">Lori E. Dodd</name></region><name sortKey="Bonnett, Tyler" sort="Bonnett, Tyler" uniqKey="Bonnett T" first="Tyler" last="Bonnett">Tyler Bonnett</name><name sortKey="Follmann, Dean" sort="Follmann, Dean" uniqKey="Follmann D" first="Dean" last="Follmann">Dean Follmann</name><name sortKey="Hunsberger, Sally" sort="Hunsberger, Sally" uniqKey="Hunsberger S" first="Sally" last="Hunsberger">Sally Hunsberger</name><name sortKey="Korn, Lisa L" sort="Korn, Lisa L" uniqKey="Korn L" first="Lisa L" last="Korn">Lisa L. Korn</name><name sortKey="Makowski, Mat" sort="Makowski, Mat" uniqKey="Makowski M" first="Mat" last="Makowski">Mat Makowski</name><name sortKey="Proschan, Michael" sort="Proschan, Michael" uniqKey="Proschan M" first="Michael" last="Proschan">Michael Proschan</name><name sortKey="Wang, Jing" sort="Wang, Jing" uniqKey="Wang J" first="Jing" last="Wang">Jing Wang</name></country><country name="Autriche"><region name="Vienne (Autriche)"><name sortKey="Koenig, Franz" sort="Koenig, Franz" uniqKey="Koenig F" first="Franz" last="Koenig">Franz Koenig</name></region><name sortKey="Schoergenhofer, Christian" sort="Schoergenhofer, Christian" uniqKey="Schoergenhofer C" first="Christian" last="Schoergenhofer">Christian Schoergenhofer</name></country><country name="France"><region name="Île-de-France"><name sortKey="Belhadi, Drifa" sort="Belhadi, Drifa" uniqKey="Belhadi D" first="Drifa" last="Belhadi">Drifa Belhadi</name></region><name sortKey="Belhadi, Drifa" sort="Belhadi, Drifa" uniqKey="Belhadi D" first="Drifa" last="Belhadi">Drifa Belhadi</name><name sortKey="Mentre, France" sort="Mentre, France" uniqKey="Mentre F" first="France" last="Mentre">France Mentre</name><name sortKey="Mentre, France" sort="Mentre, France" uniqKey="Mentre F" first="France" last="Mentre">France Mentre</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Wang, Yeming" sort="Wang, Yeming" uniqKey="Wang Y" first="Yeming" last="Wang">Yeming Wang</name></noRegion><name sortKey="Cao, Bin" sort="Cao, Bin" uniqKey="Cao B" first="Bin" last="Cao">Bin Cao</name><name sortKey="Cao, Bin" sort="Cao, Bin" uniqKey="Cao B" first="Bin" last="Cao">Bin Cao</name><name sortKey="Wang, Yeming" sort="Wang, Yeming" uniqKey="Wang Y" first="Yeming" last="Wang">Yeming Wang</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Jaki, Thomas" sort="Jaki, Thomas" uniqKey="Jaki T" first="Thomas" last="Jaki">Thomas Jaki</name></noRegion><name sortKey="Jaki, Thomas" sort="Jaki, Thomas" uniqKey="Jaki T" first="Thomas" last="Jaki">Thomas Jaki</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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