Randomized Controlled Trial

. 2022 Sep;10(9):888-899.

doi: 10.1016/S2213-2600(22)00088-1. Epub 2022 May 23.

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial

Cameron R Wolfe¹, Kay M Tomashek², Thomas F Patterson³, Carlos A Gomez⁴, Vincent C Marconi⁵, Mamta K Jain⁶, Otto O Yang⁷, Catharine I Paules⁸, Guillermo M Ruiz Palacios⁹, Robert Grossberg¹⁰, Michelle S Harkins¹¹, Richard A Mularski¹², Nathaniel Erdmann¹³, Uriel Sandkovsky¹⁴, Eyad Almasri¹⁵, Justino Regalado Pineda¹⁶, Alexandra W Dretler¹⁷, Diego Lopez de Castilla¹⁸, Angela R Branche¹⁹, Pauline K Park²⁰, Aneesh K Mehta⁵, William R Short²¹, Susan L F McLellan²², Susan Kline²³, Nicole M Iovine²⁴, Hana M El Sahly²⁵, Sarah B Doernberg¹⁵, Myoung-Don Oh²⁶, Nikhil Huprikar²⁷, Elizabeth Hohmann²⁸, Colleen F Kelley²⁹, Mark Holodniy³⁰, Eu Suk Kim³¹, Daniel A Sweeney³², Robert W Finberg³³, Kevin A Grimes³⁴, Ryan C Maves³⁵, Emily R Ko¹, John J Engemann¹, Barbara S Taylor³, Philip O Ponce³, LuAnn Larson³⁶, Dante Paolo Melendez⁴, Allan M Seibert⁴, Nadine G Rouphael⁵, Joslyn Strebe⁶, Jesse L Clark⁷, Kathleen G Julian⁸, Alfredo Ponce de Leon⁹, Anabela Cardoso³⁷, Stephanie de Bono³⁷, Robert L Atmar²⁵, Anuradha Ganesan²⁷, Jennifer L Ferreira³⁸, Michelle Green³⁸, Mat Makowski³⁸, Tyler Bonnett³⁹, Tatiana Beresnev², Varduhi Ghazaryan², Walla Dempsey², Seema U Nayak², Lori E Dodd², John H Beigel², Andre C Kalil⁴⁰; ACTT-4 Study Group

Collaborators, Affiliations

Collaborators

ACTT-4 Study Group:
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 3rd, 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

Affiliations

¹ Duke University, Durham, NC, USA.
² The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³ University of Texas Health San Antonio, University Health, and the South Texas Veterans Health Care System, San Antonio, TX, USA.
⁴ University of Utah, Salt Lake City, UT, USA.
⁵ Emory University, Atlanta, GA, USA.
⁶ University of Texas Southwestern and Parkland Health and Hospital System, Dallas, TX, USA.
⁷ University of California, Los Angeles, CA, USA.
⁸ Pennsylvania State Health Milton S Hershey Medical Center, Hershey, PA, USA.
⁹ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
¹⁰ Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
¹¹ University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
¹² Kaiser Permanente Northwest, Portland, OR, USA.
¹³ University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁴ Baylor University Medical Center, Dallas, TX, USA.
¹⁵ University of California, San Francisco, CA, USA.
¹⁶ Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
¹⁷ Infectious Disease Specialists of Atlanta and Emory Decatur Hospital, Decatur, GA, USA.
¹⁸ Evergreen Health Medical Center, Kirkland, WA, USA.
¹⁹ University of Rochester Medical Center, Rochester, NY, USA.
²⁰ University of Michigan, Ann Arbor, MI, USA.
²¹ The University of Pennsylvania, Philadelphia, PA, USA.
²² The University of Texas Medical Branch, Galveston, TX, USA.
²³ The University of Minnesota Medical School, Minneapolis, MN, USA.
²⁴ University of Florida Health, Shands Hospital, Gainesville, FL, USA.
²⁵ Baylor College of Medicine, Houston, TX, USA.
²⁶ Seoul National University Hospital, Seoul, South Korea.
²⁷ Walter Reed National Military Medical Center, Bethesda, MD, USA.
²⁸ Massachusetts General Hospital, Boston, MA, USA.
²⁹ Grady Memorial Hospital, Atlanta, GA, USA.
³⁰ VA Palo Alto Health Care System, Palo Alto, CA, USA.
³¹ Seoul National University Bundang Hospital, Seongnam, South Korea.
³² University of California, San Diego, La Jolla, CA, USA.
³³ University of Massachusetts Medical School, Worcester, MA, USA.
³⁴ Houston Methodist Hospital, Houston, TX, USA.
³⁵ Naval Medical Center, San Diego, CA, USA.
³⁶ University of Nebraska Medical Center, Omaha, NE, USA.
³⁷ Eli Lilly, Indianapolis, IN, USA.
³⁸ The Emmes Company, LLC, Rockville, MD, USA.
³⁹ Clinical Monitoring Research Program Directorate, Frederick National Laboratory, Frederick, MD, USA.
⁴⁰ University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: akalil@unmc.edu.

PMID: 35617986
PMCID: PMC9126560
DOI: 10.1016/S2213-2600(22)00088-1

Randomized Controlled Trial

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial

Cameron R Wolfe et al. Lancet Respir Med. 2022 Sep.

. 2022 Sep;10(9):888-899.

doi: 10.1016/S2213-2600(22)00088-1. Epub 2022 May 23.

Authors

Collaborators

ACTT-4 Study Group:
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 3rd, 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

Affiliations

¹ Duke University, Durham, NC, USA.
² The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³ University of Texas Health San Antonio, University Health, and the South Texas Veterans Health Care System, San Antonio, TX, USA.
⁴ University of Utah, Salt Lake City, UT, USA.
⁵ Emory University, Atlanta, GA, USA.
⁶ University of Texas Southwestern and Parkland Health and Hospital System, Dallas, TX, USA.
⁷ University of California, Los Angeles, CA, USA.
⁸ Pennsylvania State Health Milton S Hershey Medical Center, Hershey, PA, USA.
⁹ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
¹⁰ Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
¹¹ University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
¹² Kaiser Permanente Northwest, Portland, OR, USA.
¹³ University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁴ Baylor University Medical Center, Dallas, TX, USA.
¹⁵ University of California, San Francisco, CA, USA.
¹⁶ Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
¹⁷ Infectious Disease Specialists of Atlanta and Emory Decatur Hospital, Decatur, GA, USA.
¹⁸ Evergreen Health Medical Center, Kirkland, WA, USA.
¹⁹ University of Rochester Medical Center, Rochester, NY, USA.
²⁰ University of Michigan, Ann Arbor, MI, USA.
²¹ The University of Pennsylvania, Philadelphia, PA, USA.
²² The University of Texas Medical Branch, Galveston, TX, USA.
²³ The University of Minnesota Medical School, Minneapolis, MN, USA.
²⁴ University of Florida Health, Shands Hospital, Gainesville, FL, USA.
²⁵ Baylor College of Medicine, Houston, TX, USA.
²⁶ Seoul National University Hospital, Seoul, South Korea.
²⁷ Walter Reed National Military Medical Center, Bethesda, MD, USA.
²⁸ Massachusetts General Hospital, Boston, MA, USA.
²⁹ Grady Memorial Hospital, Atlanta, GA, USA.
³⁰ VA Palo Alto Health Care System, Palo Alto, CA, USA.
³¹ Seoul National University Bundang Hospital, Seongnam, South Korea.
³² University of California, San Diego, La Jolla, CA, USA.
³³ University of Massachusetts Medical School, Worcester, MA, USA.
³⁴ Houston Methodist Hospital, Houston, TX, USA.
³⁵ Naval Medical Center, San Diego, CA, USA.
³⁶ University of Nebraska Medical Center, Omaha, NE, USA.
³⁷ Eli Lilly, Indianapolis, IN, USA.
³⁸ The Emmes Company, LLC, Rockville, MD, USA.
³⁹ Clinical Monitoring Research Program Directorate, Frederick National Laboratory, Frederick, MD, USA.
⁴⁰ University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: akalil@unmc.edu.

PMID: 35617986
PMCID: PMC9126560
DOI: 10.1016/S2213-2600(22)00088-1

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests We declare no competing interests.

Figures

**Figure 1**
Trial profile *13 patients excluded from as-treated population as they did not receive at least one dose of baricitinib plus remdesivir plus placebo. †12 patients excluded from as-treated population as they did not receive at least one dose of dexamethasone plus remdesivir plus placebo.

**Figure 2**
Mechanical ventilation-free survival at day 29 by subgroup Each datapoint represents the difference in mechanical ventilation-free survival at day 29 between groups and 95% CI.

See this image and copyright information in PMC

Comment in

In adults hospitalized with COVID-19, adding baricitinib vs. dexamethasone to remdesivir did not differ for MV-free survival.
Tran A, Rochwerg B. Tran A, et al. Ann Intern Med. 2022 Oct;175(10):JC115. doi: 10.7326/J22-0074. Epub 2022 Oct 4. Ann Intern Med. 2022. PMID: 36191322

References

1. Tahaghoghi-Hajghorbani S, Zafari P, Masoumi E, et al. The role of dysregulated immune responses in COVID-19 pathogenesis. Virus Res. 2020;290 - PMC - PubMed
1. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N Engl J Med. 2021;384:795–807. - PMC - PubMed
1. Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384:693–704. - PMC - PubMed
1. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9:1407–1418. - PMC - PubMed
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Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial

Collaborators

Affiliations

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial

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Conflict of interest statement

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