Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19
Andre C Kalil, Thomas F Patterson, Aneesh K Mehta, Kay M Tomashek, Cameron R Wolfe, Varduhi Ghazaryan, Vincent C Marconi, Guillermo M Ruiz-Palacios, Lanny Hsieh, Susan Kline, Victor Tapson, Nicole M Iovine, Mamta K Jain, Daniel A Sweeney, Hana M El Sahly, Angela R Branche, Justino Regalado Pineda, David C Lye, Uriel Sandkovsky, Anne F Luetkemeyer, Stuart H Cohen, Robert W Finberg, Patrick E H Jackson, Babafemi Taiwo, Catharine I Paules, Henry Arguinchona, Nathaniel Erdmann, Neera Ahuja, Maria Frank, Myoung-Don Oh, Eu-Suk Kim, Seow Y Tan, Richard A Mularski, Henrik Nielsen, Philip O Ponce, Barbara S Taylor, LuAnn Larson, Nadine G Rouphael, Youssef Saklawi, Valeria D Cantos, Emily R Ko, John J Engemann, Alpesh N Amin, Miki Watanabe, Joanne Billings, Marie-Carmelle Elie, Richard T Davey, Timothy H Burgess, Jennifer Ferreira, Michelle Green, Mat Makowski, Anabela Cardoso, Stephanie de Bono, Tyler Bonnett, Michael Proschan, Gregory A Deye, Walla Dempsey, Seema U Nayak, Lori E Dodd, John H Beigel, ACTT-2 Study Group Members, Thomas F Patterson, Philip O Ponce, Barbara S Taylor, Jan E Patterson, Jason E Bowling, Heta Javeri, Andre C Kalil, LuAnn Larson, Angela Hewlett, Aneesh K Mehta, Nadine G Rouphael, Youssef Saklawi, Nicholas Scanlon, Jessica J Traenkner, Ronald P Trible Jr, Emmanuel B Walter, Noel Ivey, Thomas L Holland, Guillermo M Ruiz-Palacios, Alfredo Ponce de León, Sandra Rajme, Lanny Hsieh, Alpesh N Amin, Miki Watanabe, Helen S Lee, Susan Kline, Joanne Billings, Brooke Noren, Hyun Kim, Tyler D Bold, Victor Tapson, Jonathan Grein, Fayyaz Sutterwala, Nicole Iovine, Lars K Beattie, Rebecca Murray Wakeman, Matthew Shaw, Mamta K Jain, Satish Mocherla, Jessica Meisner, Amneris Luque, Daniel A Sweeney, Constance A Benson, Farhana Ali, Robert L Atmar, Hana M El Sahly, Jennifer Whitaker, Ann R Falsey, Angela R Branche, Cheryl Rozario, Justino Regalado Pineda, José Arturo Martinez-Orozco, David Chien Lye, Sean W X Ong, Po Ying Chia, Barnaby E Young, Uriel Sandkovsky, Mezgebe Berhe, Clinton Haley, Emma Dishner, Valeria D Cantos, Colleen F Kelley, Paulina A Rebolledo Esteinou, Sheetal Kandiah, Sarah B Doernberg, Pierre-Cedric B Crouch, Hannah Jang, Anne F Luetkemeyer, Jay Dwyer, Stuart H Cohen, George R Thompson 3rd, Hien H Nguyen, Robert W Finberg, Jennifer P Wang, Juan Perez-Velazquez, Mireya Wessolossky, Patrick E H Jackson, Taison D Bell, Miranda J West, Babafemi Taiwo, Karen Krueger, Johnny Perez, Triniece Pearson, Catharine I Paules, Kathleen G Julian, Danish Ahmad, Alexander G Hajduczok, Henry Arguinchona, Christa Arguinchona, Nathaniel Erdmann, Paul Goepfert, Neera Ahuja, Maria G Frank, David Wyles, Heather Young, Myoung-Don Oh, Wan Beom Park, Chang Kyung Kang, Vincent Marconi, Abeer Moanna, Sushma Cribbs, Telisha Harrison, Eu Suk Kim, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Seow Yen Tan, Humaira Shafi, Jaime M F Chien, Raymond K C Fong, Daniel D Murray, Jens Lundgren, Henrik Nielsen, Tomas Jensen, Barry S Zingman, Robert Grossberg, Paul F Riska, Otto O Yang, Jenny Ahn, Rubi Arias, Rekha R Rapaka, Naomi Hauser, James D Campbell, William R Short, Pablo Tebas, Jillian T Baron, Susan L F McLellan, Lucas S Blanton, Justin B Seashore, C Buddy Creech, Todd W Rice, Shannon Walker, Isaac P Thomsen, Diego Lopez de Castilla, Jason W Van Winkle, Francis X Riedo, Surinder Kaur Pada, Alvin D Y Wang, Li Lin, Michelle Harkins, Gregory Mertz, Nestor Sosa, Louis Yi Ann Chai, Paul Anantharajah Tambyah, Sai Meng Tham, Sophia Archuleta, Gabriel Yan, David A Lindholm, Ana Elizabeth Markelz, Katrin Mende, Richard Mularski, Elizabeth Hohmann, Mariam Torres-Soto, Nikolaus Jilg, Ryan C Maves, Gregory C Utz, Sarah L George, Daniel F Hoft, James D Brien, Roger Paredes, Lourdes Mateu, Cora Loste, Princy Kumar, Sarah Thornton, Sharmila Mohanraj, Noreen A Hynes, Lauren M Sauer, Christopher J Colombo, Christina Schofield, Rhonda E Colombo, Susan E Chambers, Richard M Novak, Andrea Wendrow, Samir K Gupta, Tida Lee, Tahaniyat Lalani, Mark Holodniy, Aarthi Chary, Nikhil Huprikar, Anuradha Ganesan, Norio Ohmagari, Ayako Mikami, D Ashley Price, Christopher J A Duncan, Kerry Dierberg, Henry J Neumann, Stephanie N Taylor, Alisha Lacour, Najy Masri, Edwin Swiatlo, Kyle Widmer, James D Neaton, Mary Bessesen, David S Stephens, Timothy H Burgess, Timothy M Uyeki, Robert Walker, G Lynn Marks, Anu Osinusi, Huyen Cao, Anabela Cardoso, Stephanie de Bono, Douglas E Schlichting, Kevin K Chung, Jennifer L Ferreira, Michelle Green, Mat Makowski, Michael R Wierzbicki, Tom M Conrad, Jill Ann El-Khorazaty, Heather Hill, Tyler Bonnett, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, John H Beigel, Kay M Tomashek, Varduhi Ghazaryan, Tatiana Beresnev, Seema Nayak, Lori E Dodd, Walla Dempsey, Effie Nomicos, Marina Lee, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Tammy Yokum, Janice Arega, Ruth Florese, Jocelyn D Voell, Richard Davey, Andre C Kalil, Thomas F Patterson, Aneesh K Mehta, Kay M Tomashek, Cameron R Wolfe, Varduhi Ghazaryan, Vincent C Marconi, Guillermo M Ruiz-Palacios, Lanny Hsieh, Susan Kline, Victor Tapson, Nicole M Iovine, Mamta K Jain, Daniel A Sweeney, Hana M El Sahly, Angela R Branche, Justino Regalado Pineda, David C Lye, Uriel Sandkovsky, Anne F Luetkemeyer, Stuart H Cohen, Robert W Finberg, Patrick E H Jackson, Babafemi Taiwo, Catharine I Paules, Henry Arguinchona, Nathaniel Erdmann, Neera Ahuja, Maria Frank, Myoung-Don Oh, Eu-Suk Kim, Seow Y Tan, Richard A Mularski, Henrik Nielsen, Philip O Ponce, Barbara S Taylor, LuAnn Larson, Nadine G Rouphael, Youssef Saklawi, Valeria D Cantos, Emily R Ko, John J Engemann, Alpesh N Amin, Miki Watanabe, Joanne Billings, Marie-Carmelle Elie, Richard T Davey, Timothy H Burgess, Jennifer Ferreira, Michelle Green, Mat Makowski, Anabela Cardoso, Stephanie de Bono, Tyler Bonnett, Michael Proschan, Gregory A Deye, Walla Dempsey, Seema U Nayak, Lori E Dodd, John H Beigel, ACTT-2 Study Group Members, Thomas F Patterson, Philip O Ponce, Barbara S Taylor, Jan E Patterson, Jason E Bowling, Heta Javeri, Andre C Kalil, LuAnn Larson, Angela Hewlett, Aneesh K Mehta, Nadine G Rouphael, Youssef Saklawi, Nicholas Scanlon, Jessica J Traenkner, Ronald P Trible Jr, Emmanuel B Walter, Noel Ivey, Thomas L Holland, Guillermo M Ruiz-Palacios, Alfredo Ponce de León, Sandra Rajme, Lanny Hsieh, Alpesh N Amin, Miki Watanabe, Helen S Lee, Susan Kline, Joanne Billings, Brooke Noren, Hyun Kim, Tyler D Bold, Victor Tapson, Jonathan Grein, Fayyaz Sutterwala, Nicole Iovine, Lars K Beattie, Rebecca Murray Wakeman, Matthew Shaw, Mamta K Jain, Satish Mocherla, Jessica Meisner, Amneris Luque, Daniel A Sweeney, Constance A Benson, Farhana Ali, Robert L Atmar, Hana M El Sahly, Jennifer Whitaker, Ann R Falsey, Angela R Branche, Cheryl Rozario, Justino Regalado Pineda, José Arturo Martinez-Orozco, David Chien Lye, Sean W X Ong, Po Ying Chia, Barnaby E Young, Uriel Sandkovsky, Mezgebe Berhe, Clinton Haley, Emma Dishner, Valeria D Cantos, Colleen F Kelley, Paulina A Rebolledo Esteinou, Sheetal Kandiah, Sarah B Doernberg, Pierre-Cedric B Crouch, Hannah Jang, Anne F Luetkemeyer, Jay Dwyer, Stuart H Cohen, George R Thompson 3rd, Hien H Nguyen, Robert W Finberg, Jennifer P Wang, Juan Perez-Velazquez, Mireya Wessolossky, Patrick E H Jackson, Taison D Bell, Miranda J West, Babafemi Taiwo, Karen Krueger, Johnny Perez, Triniece Pearson, Catharine I Paules, Kathleen G Julian, Danish Ahmad, Alexander G Hajduczok, Henry Arguinchona, Christa Arguinchona, Nathaniel Erdmann, Paul Goepfert, Neera Ahuja, Maria G Frank, David Wyles, Heather Young, Myoung-Don Oh, Wan Beom Park, Chang Kyung Kang, Vincent Marconi, Abeer Moanna, Sushma Cribbs, Telisha Harrison, Eu Suk Kim, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Seow Yen Tan, Humaira Shafi, Jaime M F Chien, Raymond K C Fong, Daniel D Murray, Jens Lundgren, Henrik Nielsen, Tomas Jensen, Barry S Zingman, Robert Grossberg, Paul F Riska, Otto O Yang, Jenny Ahn, Rubi Arias, Rekha R Rapaka, Naomi Hauser, James D Campbell, William R Short, Pablo Tebas, Jillian T Baron, Susan L F McLellan, Lucas S Blanton, Justin B Seashore, C Buddy Creech, Todd W Rice, Shannon Walker, Isaac P Thomsen, Diego Lopez de Castilla, Jason W Van Winkle, Francis X Riedo, Surinder Kaur Pada, Alvin D Y Wang, Li Lin, Michelle Harkins, Gregory Mertz, Nestor Sosa, Louis Yi Ann Chai, Paul Anantharajah Tambyah, Sai Meng Tham, Sophia Archuleta, Gabriel Yan, David A Lindholm, Ana Elizabeth Markelz, Katrin Mende, Richard Mularski, Elizabeth Hohmann, Mariam Torres-Soto, Nikolaus Jilg, Ryan C Maves, Gregory C Utz, Sarah L George, Daniel F Hoft, James D Brien, Roger Paredes, Lourdes Mateu, Cora Loste, Princy Kumar, Sarah Thornton, Sharmila Mohanraj, Noreen A Hynes, Lauren M Sauer, Christopher J Colombo, Christina Schofield, Rhonda E Colombo, Susan E Chambers, Richard M Novak, Andrea Wendrow, Samir K Gupta, Tida Lee, Tahaniyat Lalani, Mark Holodniy, Aarthi Chary, Nikhil Huprikar, Anuradha Ganesan, Norio Ohmagari, Ayako Mikami, D Ashley Price, Christopher J A Duncan, Kerry Dierberg, Henry J Neumann, Stephanie N Taylor, Alisha Lacour, Najy Masri, Edwin Swiatlo, Kyle Widmer, James D Neaton, Mary Bessesen, David S Stephens, Timothy H Burgess, Timothy M Uyeki, Robert Walker, G Lynn Marks, Anu Osinusi, Huyen Cao, Anabela Cardoso, Stephanie de Bono, Douglas E Schlichting, Kevin K Chung, Jennifer L Ferreira, Michelle Green, Mat Makowski, Michael R Wierzbicki, Tom M Conrad, Jill Ann El-Khorazaty, Heather Hill, Tyler Bonnett, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, John H Beigel, Kay M Tomashek, Varduhi Ghazaryan, Tatiana Beresnev, Seema Nayak, Lori E Dodd, Walla Dempsey, Effie Nomicos, Marina Lee, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Tammy Yokum, Janice Arega, Ruth Florese, Jocelyn D Voell, Richard Davey
Abstract
Background: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.
Methods: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.
Results: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003).
Conclusions: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).
Copyright © 2020 Massachusetts Medical Society.
Figures
References
- Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 — final report. N Engl J Med 2020;383:1813-1826.
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-1034.
- Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis 2020;20:400-402.
- Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020;395(10223):e30-e31.
- Stebbing J, Krishnan V, de Bono S, et al. Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients. EMBO Mol Med 2020;12(8):e12697-e12697.
- Sims JT, Krishnan V, Chang C-Y, et al. Characterization of the cytokine storm reflects hyperinflammatory endothelial dysfunction in COVID-19. J Allergy Clin Immunol 2020. September 10 (Epub ahead of print).
- Cantini F, Niccoli L, Matarrese D, Nicastri E, Stobbione P, Goletti D. Baricitinib therapy in COVID-19: a pilot study on safety and clinical impact. J Infect 2020;81:318-356.
- Hoang TN, Pino M, Boddapati AK, et al. Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. September 16, 2020. (). preprint.
- Titanji BK, Farley MM, Mehta A, et al. Use of baricitinib in patients with moderate and severe COVID-19. Clin Infect Dis 2020. June 29 (Epub ahead of print).
- Cantini F, Niccoli L, Nannini C, et al. Beneficial impact of baricitinib in COVID-19 moderate pneumonia; multicentre study. J Infect 2020;81:647-679.
- Rodriguez-Garcia JL, Sanchez-Nievas G, Arevalo-Serrano J, Garcia-Gomez C, Jimenez-Vizuete JM, Martinez-Alfaro E. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study. Rheumatology (Oxford) 2020. October 6 (Epub ahead of print).
- Kalil AC. Treating COVID-19 — off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA 2020;323:1897-1898.
- Dodd LE, Follmann D, Wang J, et al. Endpoints for randomized controlled clinical trials for COVID-19 treatments. Clin Trials 2020;17:472-482.
- Ko JY, Danielson ML, Town M, et al. Risk factors for COVID-19-associated hospitalization: COVID-19-Associated Hospitalization Surveillance Network and Behavioral Risk Factor Surveillance System. Clin Infect Dis 2020. September 18 (Epub ahead of print).
- The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa2021436.
- Yao T-C, Huang Y-W, Chang S-M, Tsai S-Y, Chen Wu A, Tsai H-J. Association between oral corticosteroid bursts and severe adverse events: a nationwide population-based cohort study. Ann Intern Med 2020;173:325-330.
Source: PubMed