Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Issue 9 (September 2022)

• Record Type: Journal Article
• Authors: Wolfe, Cameron R; Tomashek, Kay M; Patterson, Thomas F; Gomez, Carlos A; Marconi, Vincent C; Jain, Mamta K; Yang, Otto O; Paules, Catharine I; Palacios, Guillermo M Ruiz; Grossberg, Robert; Harkins, Michelle S; Mularski, Richard A; Erdmann, Nathaniel; Sandkovsky, Uriel; Almasri, Eyad; Pineda, Justino Regalado; Dretler, Alexandra W; de Castilla, Diego Lopez; Branche, Angela R; Park, Pauline K; Mehta, Aneesh K; Short, William R; McLellan, Susan L F; Kline, Susan; Iovine, Nicole M; El Sahly, Hana M; Doernberg, Sarah B; Oh, Myoung-don; Huprikar, Nikhil; Hohmann, Elizabeth; Kelley, Colleen F; Holodniy, Mark; Kim, Eu Suk; Sweeney, Daniel A; Finberg, Robert W; Grimes, Kevin A; Maves, Ryan C; Ko, Emily R; Engemann, John J; Taylor, Barbara S; Ponce, Philip O; Larson, LuAnn; Melendez, Dante Paolo; Seibert, Allan M; Rouphael, Nadine G; Strebe, Joslyn; Clark, Jesse L; Julian, Kathleen G; de Leon, Alfredo Ponce; Cardoso, Anabela; de Bono, Stephanie; Atmar, Robert L; Ganesan, Anuradha; Ferreira, Jennifer L; Green, Michelle; Makowski, Mat; Bonnett, Tyler; Beresnev, Tatiana; Ghazaryan, Varduhi; Dempsey, Walla; Nayak, Seema U; Dodd, Lori E; Beigel, John H; Kalil, Andre C; Wahid, Lana; Walter, Emmanuel B.; Belur, Akhila G.; Dreyer, Grace; Patterson, Jan E.; Bowling, Jason E.; Dixon, Danielle O.; Hewlett, Angela; Odrobina, Robert; Pupaibool, Jakrapun; Mocherla, Satish; Lazarte, Suzana; Cayabyab, Meilani; Hussein, Rezhan H.; Golamari, Reshma R.; Krill, Kaleigh L.; Rajme, Sandra; Riska, Paul F.; Zingman, Barry S.; Mertz, Gregory; Sosa, Nestor; Goepfert, Paul A.; Berhe, Mezgebe; Dishner, Emma; Fayed, Mohamed; Hubel, Kinsley; Martinez-Orozco, José Arturo; Bautista Felix, Nora; Elmor, Sammy T.; Bechnak, Amer Ryan; Saklawi, Youssef; Van Winkle, Jason W.; Zea, Diego F.; Laguio-Vila, Maryrose; Walsh, Edward E.; Falsey, Ann R.; Carvajal, Karen; Hyzy, Robert C.; Hanna, Sinan; Olbrich, Norman; Traenkner, Jessica J.; Kraft, Colleen S.; Tebas, Pablo; Baron, Jillian T; Levine, Corri; Nock, Joy; Billings, Joanne; Kim, Hyun; Elie-Turenne, Marie-Carmelle; Whitaker, Jennifer A.; Luetkemeyer, Anne F.; Dwyer, Jay; Bainbridge, Emma; Gyun Choe, Pyoeng; Kyung Kang, Chang; Jilg, Nikolaus; Cantos, Valeria D; Bhamidipati, Divya R.; Nithin Gopalsamy, Srinivasa; Chary, Aarthi; Jung, Jongtak; Song, Kyoung-Ho; Kim, Hong Bin; Benson, Constance A.; McConnell, Kimberly; Wang, Jennifer P.; Wessolossky, Mireya; Perez, Katherine; Eubank, Taryn A; Berjohn, Catherine; Utz, Gregory C.; Jackson, Patrick E.H.; Bell, Taison D.; Haughey, Heather M.; Moanna, Abeer; Cribbs, Sushma; Harrison, Telisha; Colombo, Christopher J.; Schofield, Christina; Colombo, Rhonda E.; Tapson, Victor F.; Grein, Jonathan; Sutterwala, Fayyaz; Ince, Dilek; Winokur, Patricia L.; Fung, Monica; Jang, Hannah; Wyles, David; Frank, Maria G.; Sarcone, Ellen; Neumann, Henry; Viswanathan, Anand; Hochman, Sarah; Mulligan, Mark; Eckhardt, Benjamin; Carmody, Ellie; Ahuja, Neera; Nadeau, Kari; Svec, David; Macaraeg, Jeffrey C.; Morrow, Lee; Quimby, Dave; Bessesen, Mary; Nicholson, Lindsay; Adams, Jill; Kumar, Princy; Lambert, Allison A.; Arguinchona, Henry; Alicic, Radica Z.; Saito, Sho; Ohmagari, Norio; Mikami, Ayako; Chien Lye, David; Hong Lee, Tau; Ying Chia, Po; Hsieh, Lanny; Amin, Alpesh N.; Watanabe, Miki; Candiotti, Keith A.; Castro, Jose G.; Antor, Maria A.; Lee, Tida; Lalani, Tahaniyat; Novak, Richard M.; Wendrow, Andrea; Borgetti, Scott A.; George, Sarah L.; Hoft, Daniel F.; Brien, James D.; Cohen, Stuart H.; Thompson, George R.; Chakrabarty, Melony; Guirgis, Faheem; Davey, Richard T.; Voell, Jocelyn; Strich, Jeffrey R.; Lindholm, David A.; Mende, Katrin; Wellington, Trevor R.; Rapaka, Rekha R.; Husson, Jennifer S.; Levine, Andrea R.; Yen Tan, Seow; Shafi, Humaira; Chien, Jaime M F; Hostler, David C.; Hostler, Jordanna M.; Shahan, Brian T.; Adams, David H.; Osinusi, Anu; Cao, Huyen; Burgess, Timothy H.; Rozman, Julia; Chung, Kevin K.; Nieuwoudt, Christina; El-Khorazaty, Jill A.; Hill, Heather; Pettibone, Stephanie; Gettinger, Nikki; Engel, Theresa; Lewis, Teri; Wang, Jing; Deye, Gregory A.; Nomicos, Effie; Pikaart-Tautges, Rhonda; Elsafy, Mohamed; Jurao, Robert; Koo, Hyung; Proschan, Michael; Yokum, Tammy; Arega, Janice; Florese, Ruth;
• Is Part Of: Lancet. Volume 10:Issue 9(2022)
• Page Start: 888
• Page End: 899
• Publication Date: 2022-09
• Subjects: Respiratory organs -- Diseases -- Periodicals; 616.2005
• DOI: 10.1016/S2213-2600(22)00088-1
• Languages: English
• ISSNs: 2213-2600

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.