lancet-header

Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com.

Effects of Remdesivir in Hospitalized Patients with COVID-19: Systematic Review and Individual Patient Data Meta-Analysis of Randomized Clinical Trials

32 Pages Posted: 11 Oct 2022

See all articles by Alain Amstutz

Alain Amstutz

Basel University - CLEAR Methods Center

Benjamin Speich

University of Basel - University Hospital Basel

France Mentré

Hôpital Bichat, APHP

Corina Silvia Rueegg

Oslo University Hospital

Drifa Belhadi

University of Paris

Lambert Assoumou

Sorbonne University - Institut Pierre-Louis d'Epidémiologie et de Santé Publique

Charles Burdet

Hôpital Bichat, APHP

Srinivas Murthy

University of British Columbia (UBC)

Lori Elizabeth Dodd

University of North Carolina (UNC) at Chapel Hill - National Institute of Health

Yeming Wang

Government of the People's Republic of China - Department of Pulmonary and Critical Care Medicine

Kari Tikkinen

Helsinki University Hospital

Florence Ader

Hospices Civils de Lyon - Département des Maladies Infectieuses et Tropicales; University of Claude Bernard Lyon 1 - ENS Lyon

Maya Hites

Université Libre de Bruxelles (ULB)

Maude Bouscambert-Duchamp

University of Claude Bernard Lyon 1

Mary-Anne Trabaud

Hospices Civils de Lyon - Laboratoire de Virologie

Mike Fralick

University of Toronto

Todd Campbell Lee

McGill University - Division of Experimental Medicine

Ruxandra Pinto

Sunnybrook Health Sciences Centre

Andreas Barratt-Due

Oslo University Hospital

Fridtjof Lund-Johansen

University of Oslo - Department of Immunology and Transfusion Medicine

Fredrik Müller

Oslo University Hospital

Olli Nevalainen

affiliation not provided to SSRN

Bin Cao

China-Japan Friendship Hospital - Department of Pulmonary and Critical Care Medicine

Tyler Bonnett

University of North Carolina (UNC) at Chapel Hill - National Institute of Health

Alexandra Griessbach

University of Basel - University Hospital Basel

Ala Taji Heravi

University of Basel - University Hospital Basel

Christof Schönenberger

University of Basel - University Hospital Basel

Perrine Janiaud

University of Basel - University Hospital Basel

Laura Werlen

University of Basel - University Hospital Basel

Soheila Aghlmandi

University of Basel - Basel Institute for Clinical Epidemiology and Biostatistics

Stefan Schandelmaier

University of Basel - University Hospital Basel

Yazdan Yazdanpanah

Hôpital Bichat - Claude-Bernard - INSERM, IAME Infectious Diseases Department

Dominique Costagliola

Sorbonne University - Institut Pierre Louis d'Épidémiologie et de Santé Publique IPLESP

Inge Christoffer Olsen

Oslo University Hospital

Matthias Briel

University of Basel - University Hospital Basel

More...

Abstract

Background: The evidence from randomized trials on remdesivir for hospitalized patients with coronavirus disease 2019 (COVID-19) is conflicting. We conducted a systematic review and individual patient data meta-analysis (IPDMA) to assess the benefits and harms of remdesivir compared to placebo or usual care in hospitalized patients and whether treatment effects differed in prespecified subgroups.

Methods: We systematically searched electronic databases and registries through April 11th 2022. The primary outcome was all-cause mortality at day 28. We used multivariable hierarchical regression  adjusting for respiratory support status, age, and enrollment period to investigate effect modifiers. PROSPERO (CRD42021257134).

Findings: Out of nine eligible RCTs, six provided individual data of 3729 hospitalized COVID-19 patients recruited between February 2020 and January 2021. Within 28 days of randomization, 229 of 1886 patients (12.0%) assigned to remdesivir and 268 of 1780 (15.1%) assigned to no remdesivir died (adjusted odds ratio [aOR] 0.82; 95% confidence interval [CI], 0.67-1.00; p=0.054). We found evidence for a subgroup effect according to respiratory support status at baseline (interaction p=0.012): Of those ventilated including high-flow oxygen, 144/615 (23.4%) assigned to remdesivir died versus 146/630 (23.2%) assigned to no remdesivir (aOR 1.04 [0.79-1.38]; low certainty evidence). Of those receiving no or low flow oxygen, 85/1241 (6.8%) assigned to remdesivir died versus 122/1150 (10.6%) assigned to control (aOR 0.62 [0.46-0.83]; high certainty evidence). There was no evidence for a credible subgroup effect with respect to age, presence of comorbidities, time to start of remdesivir after symptom onset, C-reactive protein level, enrollment period, or presence of anti-SARS-CoV-2 antibodies. The frequency of severe or serious adverse events was not elevated with remdesivir.

Interpretation: This IPDMA showed reduced mortality with remdesivir in hospitalized COVID-19 patients requiring no or conventional oxygen support, but not in patients already ventilated.

Funding: EU-RESPONSE (grant number 101015736)

Declaration of Interest: Dominique Costagliola reports an HIV grant from Janssen (2019-2020), personal fees from Gilead (2020) and Pfizer (2022) for lectures outside the submitted work. Matthias Briel reports an unrestricted grant from Moderna (2022) for a study outside the submitted work. Todd C. Lee reports receiving salary support from the Fonds de Recherche du Québec Santé. Maya Hites reports personal fees from Gilead (2020) and Pfizer (2021) for lectures outside the submitted work, and congress/travel fees from Pfizer (2021), and Gilead (2022). Inge C. Olsen reports funding from BerGenBio for a study outside the submitted work. All other authors have declared that no competing interests exist.

Keywords: Remdesivir, COVID-19, systematic review, individual patient data meta analysis, randomized controlled trials, GS-5734

Suggested Citation

Amstutz, Alain and Speich, Benjamin and Mentré, France and Rueegg, Corina Silvia and Belhadi, Drifa and Assoumou, Lambert and Burdet, Charles and Murthy, Srinivas and Dodd, Lori Elizabeth and Wang, Yeming and Tikkinen, Kari and Ader, Florence and Hites, Maya and Bouscambert-Duchamp, Maude and Trabaud, Mary-Anne and Fralick, Mike and Lee, Todd Campbell and Pinto, Ruxandra and Barratt-Due, Andreas and Lund-Johansen, Fridtjof and Müller, Fredrik and Nevalainen, Olli and Cao, Bin and Bonnett, Tyler and Griessbach, Alexandra and Taji Heravi, Ala and Schönenberger, Christof and Janiaud, Perrine and Werlen, Laura and Aghlmandi, Soheila and Schandelmaier, Stefan and Yazdanpanah, Yazdan and Costagliola, Dominique and Olsen, Inge Christoffer and Briel, Matthias, Effects of Remdesivir in Hospitalized Patients with COVID-19: Systematic Review and Individual Patient Data Meta-Analysis of Randomized Clinical Trials. Available at SSRN: https://ssrn.com/abstract=4244759 or http://dx.doi.org/10.2139/ssrn.4244759

Alain Amstutz (Contact Author)

Basel University - CLEAR Methods Center ( email )

Benjamin Speich

University of Basel - University Hospital Basel ( email )

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland

France Mentré

Hôpital Bichat, APHP ( email )

France

Corina Silvia Rueegg

Oslo University Hospital ( email )

Oslo
Norway

Drifa Belhadi

University of Paris ( email )

Paris
France

Lambert Assoumou

Sorbonne University - Institut Pierre-Louis d'Epidémiologie et de Santé Publique ( email )

Charles Burdet

Hôpital Bichat, APHP ( email )

France

Srinivas Murthy

University of British Columbia (UBC) ( email )

Lori Elizabeth Dodd

University of North Carolina (UNC) at Chapel Hill - National Institute of Health ( email )

Chapel Hill, NC
United States

Yeming Wang

Government of the People's Republic of China - Department of Pulmonary and Critical Care Medicine ( email )

Kari Tikkinen

Helsinki University Hospital ( email )

Florence Ader

Hospices Civils de Lyon - Département des Maladies Infectieuses et Tropicales ( email )

103 Grande Rue de la Croix-Rousse
Lyon, F-69004
France
+33 (0)472 071 560 (Phone)
+33 (0)472 072 441 (Fax)

University of Claude Bernard Lyon 1 - ENS Lyon ( email )

Lyon, F-69372
France
+33 (0)472 071 560 (Phone)
+33 (0)472 072 441 (Fax)

Maya Hites

Université Libre de Bruxelles (ULB) ( email )

Maude Bouscambert-Duchamp

University of Claude Bernard Lyon 1 ( email )

43 Bl du 11 novembre 1918
Lyon, Villeurbanne cedex 69622
France

Mary-Anne Trabaud

Hospices Civils de Lyon - Laboratoire de Virologie ( email )

103 Grande Rue de la CroixRousse
Lyon, F-69317
France

Mike Fralick

University of Toronto ( email )

105 St George Street
Toronto, M5S 3G8
Canada

Todd Campbell Lee

McGill University - Division of Experimental Medicine ( email )

Ruxandra Pinto

Sunnybrook Health Sciences Centre ( email )

2075 Bayview Ave
Toronto, OR
Canada

Andreas Barratt-Due

Oslo University Hospital ( email )

Oslo
Norway

Fridtjof Lund-Johansen

University of Oslo - Department of Immunology and Transfusion Medicine ( email )

P. B. 4950 Nydalen
0424 Oslo
Norway

Fredrik Müller

Oslo University Hospital ( email )

Oslo
Norway

Olli Nevalainen

affiliation not provided to SSRN ( email )

No Address Available

Bin Cao

China-Japan Friendship Hospital - Department of Pulmonary and Critical Care Medicine ( email )

Beijing
China

Tyler Bonnett

University of North Carolina (UNC) at Chapel Hill - National Institute of Health ( email )

Chapel Hill, NC
United States

Alexandra Griessbach

University of Basel - University Hospital Basel ( email )

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland

Ala Taji Heravi

University of Basel - University Hospital Basel ( email )

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland

Christof Schönenberger

University of Basel - University Hospital Basel ( email )

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland

Perrine Janiaud

University of Basel - University Hospital Basel ( email )

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland

Laura Werlen

University of Basel - University Hospital Basel ( email )

Soheila Aghlmandi

University of Basel - Basel Institute for Clinical Epidemiology and Biostatistics ( email )

Stefan Schandelmaier

University of Basel - University Hospital Basel ( email )

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland

Yazdan Yazdanpanah

Hôpital Bichat - Claude-Bernard - INSERM, IAME Infectious Diseases Department ( email )

France

Dominique Costagliola

Sorbonne University - Institut Pierre Louis d'Épidémiologie et de Santé Publique IPLESP ( email )

Paris
France

Inge Christoffer Olsen

Oslo University Hospital ( email )

Oslo
Norway

Matthias Briel

University of Basel - University Hospital Basel ( email )

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland