Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial
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 3rd; 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
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 (Ã¢â€°Â¥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (Ã¢â€°Â¤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 Ã¢â€°Â¥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 (Ã¢â€°Â¤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/RESULTS: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 58Ã‚Â·3 years (SD 14Ã‚Â·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 87Ã‚Â·0% [95% CI 83Ã‚Â·7 to 89Ã‚Â·6] in the baricitinib plus remdesivir plus placebo group and 87Ã‚Â·6% [84Ã‚Â·2 to 90Ã‚Â·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0Ã‚Â·6 [95% CI -3Ã‚Â·6 to 4Ã‚Â·8]; p=0Ã‚Â·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 1Ã‚Â·01 (95% CI 0Ã‚Â·80 to 1Ã‚Â·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 7Ã‚Â·5% [1Ã‚Â·6 to 13Ã‚Â·3]; p=0Ã‚Â·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 6Ã‚Â·0% [2Ã‚Â·8 to 9Ã‚Â·3]; p=0Ã‚Â·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 7Ã‚Â·7% [1Ã‚Â·8 to 13Ã‚Â·4]; p=0Ã‚Â·012). INTERPRETATION/CONCLUSIONS: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/BACKGROUND:National Institute of Allergy and Infectious Diseases.
COVID-19 in solid organ transplant: A multi-center cohort study
Kates, Olivia S; Haydel, Brandy M; Florman, Sander S; Rana, Meenakshi M; Chaudhry, Zohra S; Ramesh, Mayur S; Safa, Kassem; Kotton, Camille Nelson; Blumberg, Emily A; Besharatian, Behdad D; Tanna, Sajal D; Ison, Michael G; Malinis, Maricar; Azar, Marwan M; Rakita, Robert M; Morillas, Jose A; Majeed, Aneela; Sait, Afrah S; Spaggiari, Mario; Hemmige, Vagish; Mehta, Sapna A; Neumann, Henry; Badami, Abbasali; Goldman, Jason D; Lala, Anuradha; Hemmersbach-Miller, Marion; McCort, Margaret E; Bajrovic, Valida; Ortiz-Bautista, Carlos; Friedman-Moraco, Rachel; Sehgal, Sameep; Lease, Erika D; Fisher, Cynthia E; Limaye, Ajit P
BACKGROUND:The COVID-19 pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well-described. METHODS:We performed a multi-center cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. RESULTS:Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (IQR 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had â‰¥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [aOR 3.0, 95%CI 1.7-5.5, p<0.001], congestive heart failure [aOR 3.2, 95%CI 1.4-7.0, p=0.004], chronic lung disease [aOR 2.5, 95%CI 1.2-5.2, p=0.018], obesity [aOR 1.9, 95% CI 1.0-3.4, p=0.039]) and presenting findings (lymphopenia [aOR 1.9, 95%CI 1.1-3.5, p=0.033], abnormal chest imaging [aOR 2.9, 95%CI 1.1-7.5, p=0.027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. CONCLUSIONS:Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality.