Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial
Cameron R. Wolfe
,
Kay M. Tomashek
,
Thomas F Patterson
,
Carlos A. Gomez
,
Vincent C. Marconi
,
Mamta K. Jain
,
Otto O Yang
,
Catharine I Paules
,
Guillermo M Ruiz Palacios
,
Robert Grossberg
,
Michelle S. Harkins
,
Richard A. Mularski
,
Nathaniel Erdmann
,
Uriel Sandkovsky
,
Eyad Almasri
,
Justino Regalado Pineda
,
Alexandra W. Dretler
,
Diego Lopez de Castilla
,
Angela R. Branche
,
Pauline K. Park
,
Aneesh K. Mehta
,
William R. Short
,
Susan L.F. McLellan
,
SUSAN KLINE
,
Nicole M. Iovine
,
Hana M. El Sahly
,
Sarah B. Doernberg
,
Myoung-don Oh
,
Nikhil Huprikar
,
Elizabeth Hohmann
,
Colleen F. Kelley
,
Mark Holodniy
,
Eu Suk Kim
,
Daniel A. Sweeney
,
Robert W. Finberg
,
Kevin A. Grimes
,
Ryan C. Maves
,
Emily R. Ko
,
John J. Engemann
,
Barbara S. Taylor
,
Philip O. Ponce
,
LuAnn Larson
,
Dante Paolo Melendez
,
Allan M Seibert
,
Nadine G. Rouphael
,
Joslyn Strebe
,
Jesse L. Clark
,
Kathleen G. Julian
,
Alfredo Ponce De Leon
,
Anabela Cardoso
,
Stephanie de Bono
,
Robert L. Atmar
,
Anuradha Ganesan
,
Jennifer L Ferreira
,
Michelle Green
,
Mat Makowski
,
Tyler Bonnett
,
Tatiana Beresnev
,
Varduhi Ghazaryan
,
Walla Dempsey
,
Seema U. Nayak
,
Lori E. Dodd
,
John H Beigel
,
Andre C. Kalil
,
Lana Wahid
,
Emmanuel B. Walter
,
Akhila G. Belur
,
Grace Dreyer
,
JAN E. PATTERSON
,
Jason E Bowling
,
Danielle O Dixon
,
Angela Hewlett
,
Robert Odrobina
,
Jakrapun Pupaibool
,
Satish Mocherla
,
Suzana Lazarte
,
Meilani Cayabyab
,
Rezhan H Hussein
,
Reshma R. Golamari
,
Kaleigh L Krill
,
Sandra Rajme
,
PAUL F. RISKA
,
Barry S. Zingman
,
Gregory Mertz
,
Nestor Sosa
,
Paul A. Goepfert
,
Mezgebe Berhe
,
Emma Dishner
,
MOHAMED FAYED
,
Kinsley Hubel
,
José Arturo Martinez-Orozco
,
Nora Bautista Felix
,
Sammy T Elmor
,
Amer Ryan Bechnak
,
Youssef Saklawi
,
Jason W Van Winkle
,
Diego F Zea
,
Maryrose Laguio-Vila
,
Edward E. Walsh
,
Ann R. Falsey
,
Karen Carvajal
,
Robert C. Hyzy
,
Sinan Hanna
,
Norman Olbrich
,
Jessica J Traenkner
,
Colleen S. Kraft
,
Pablo Tebas
,
Jillian T Baron
,
Corri Levine
,
Joy Nock
,
Joanne Billings
,
Hyun Kim
,
Marie-Carmelle Elie-Turenne
,
Jennifer A Whitaker
,
Anne F. Luetkemeyer
,
Jay Dwyer
,
Emma Bainbridge
,
Pyoeng Gyun Choe
,
Chang Kyung Kang
,
Nikolaus Jilg
,
Valeria D. Cantos
,
Divya R. Bhamidipati
,
Srinivasa Nithin Gopalsamy
,
Aarthi Chary
,
Jongtak Jung
,
Kyoung-Ho Song
,
Hong Bin Kim
,
Constance A. Benson
,
Kimberly McConnell
,
Jennifer P. Wang
,
Mireya Wessolossky
,
Katherine Perez
,
Taryn A Eubank
,
Catherine Berjohn
,
Gregory C Utz
,
Patrick E H Jackson
,
Taison D. Bell
,
Heather M Haughey
,
Abeer Moanna
,
Sushma Cribbs
,
Telisha Harrison
,
Christopher J. Colombo
,
Christina Schofield
,
Rhonda E. Colombo
,
Victor F. Tapson
,
Jonathan Grein
,
Fayyaz Sutterwala
,
Dilek Ince
,
Patricia L Winokur
,
Monica Fung
,
Hannah Jang
,
David Wyles
,
Maria G. Frank
,
Ellen Sarcone
,
Henry Neumann
,
Anand Viswanathan
,
Sarah Hochman
,
Mark Mulligan
,
Benjamin Eckhardt
,
Ellie Carmody
,
Neera Ahuja
,
Kari Nadeau
,
David Svec
,
Jeffrey C Macaraeg
,
Lee Morrow
,
Dave Quimby
,
Mary Bessesen
,
Lindsay Nicholson
,
Jill Adams
,
Princy Kumar
,
Allison A. Lambert
,
Henry Arguinchona
,
Radica Z. Alicic
,
Sho Saito
,
Norio Ohmagari
,
Ayako Mikami
,
David Chien Lye
,
Tau Hong Lee
,
Po Ying Chia
,
Lanny Hsieh
,
Alpesh N Amin
,
Miki Watanabe
,
Keith A. Candiotti
,
Jose G. Castro
,
Maria A Antor
,
Tida Lee
,
Tahaniyat Lalani
,
Richard M. Novak
,
Andrea Wendrow
,
Scott A. Borgetti
,
Sarah L. George
,
Daniel F. Hoft
,
James D Brien
,
Stuart H. Cohen
,
George R. Thompson
,
Melony Chakrabarty
,
Faheem Guirgis
,
Richard T. Davey
,
Jocelyn Voell
,
Jeffrey R. Strich
,
David A. Lindholm
,
Katrin Mende
,
Trevor R. Wellington
,
Rekha R. Rapaka
,
Jennifer S. Husson
,
Andrea R. Levine
,
Seow Yen Tan
,
Humaira Shafi
,
Jaime M F Chien
,
David C Hostler
,
Jordanna M. Hostler
,
Brian T Shahan
,
David H. Adams
,
Anu Osinusi
,
Huyen Cao
,
Timothy H. Burgess
,
Julia Rozman
,
Kevin K. Chung
,
Christina Nieuwoudt
,
Jill A. El-Khorazaty
,
Heather Hill
,
Stephanie Pettibone
,
Nikki Gettinger
,
Theresa Engel
,
Teri Lewis
,
Jing Wang
,
Gregory A. Deye
,
Effie Nomicos
,
Rhonda Pikaart-Tautges
,
Mohamed Elsafy
,
Robert Jurao
,
Hyung Koo
,
Michael Proschan
,
Tammy Yokum
,
Janice Arega
,
Ruth Florese
Publication type: Journal Article
Publication date: 2022-09-01
scimago Q1
wos Q1
SJR: 6.788
CiteScore: 53.2
Impact factor: 32.8
ISSN: 22132600, 22132619
PubMed ID:
35617986
Pulmonary and Respiratory Medicine
Abstract
Summary
Background
Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.Methods
In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.Findings
Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI −3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).Interpretation
In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.Funding
National Institute of Allergy and Infectious Diseases.Found
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GOST
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Wolfe C. R. et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial // The Lancet Respiratory Medicine. 2022. Vol. 10. No. 9. pp. 888-899.
GOST all authors (up to 50)
Copy
Wolfe C. R. et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial // The Lancet Respiratory Medicine. 2022. Vol. 10. No. 9. pp. 888-899.
Cite this
RIS
Cite this
BibTex (up to 50 authors)
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@article{2022_Wolfe,
author = {Cameron R. Wolfe and Kay M. Tomashek and Thomas F Patterson and Carlos A. Gomez and Vincent C. Marconi and Mamta K. Jain and Otto O Yang and Catharine I Paules and Guillermo M Ruiz Palacios and Robert Grossberg and Michelle S. Harkins and Richard A. Mularski and Nathaniel Erdmann and Uriel Sandkovsky and Eyad Almasri and Justino Regalado Pineda and Alexandra W. Dretler and Diego Lopez de Castilla and Angela R. Branche and Pauline K. Park and Aneesh K. Mehta and William R. Short and Susan L.F. McLellan and SUSAN KLINE and Nicole M. Iovine and Hana M. El Sahly and Sarah B. Doernberg and Myoung-don Oh and Nikhil Huprikar and Elizabeth Hohmann and Colleen F. Kelley and Mark Holodniy and Eu Suk Kim and Daniel A. Sweeney and Robert W. Finberg and Kevin A. Grimes and Ryan C. Maves and Emily R. Ko and John J. Engemann and Barbara S. Taylor and Philip O. Ponce and LuAnn Larson and Dante Paolo Melendez and Allan M Seibert and Nadine G. Rouphael and Joslyn Strebe and Jesse L. Clark and Kathleen G. Julian and Alfredo Ponce De Leon and Anabela Cardoso and others},
title = {Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial},
journal = {The Lancet Respiratory Medicine},
year = {2022},
volume = {10},
publisher = {Elsevier},
month = {sep},
url = {https://doi.org/10.1016/S2213-2600(22)00088-1},
number = {9},
pages = {888--899},
doi = {10.1016/S2213-2600(22)00088-1}
}
Cite this
MLA
Copy
Wolfe, Cameron R., et al. “Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.” The Lancet Respiratory Medicine, vol. 10, no. 9, Sep. 2022, pp. 888-899. https://doi.org/10.1016/S2213-2600(22)00088-1.