• Bonnie E Lonze, Peter Spiegler, Russell N Wesson, Nada Alachkar, Eva Petkova, Elaina P Weldon, Rebecca A Dieter, Yi Li, Max Quinn, Aprajita Mattoo, Irfana Soomro, Steven M Cohen, Sherry Leung, Cecilia L Deterville, B Mark Landrum, Muhammad Imran Ali, David J Cohen, Andrew L Singer, Ayan Sen, Edward Chong, Judith S Hochman, Andrea B Troxel, and Robert A Montgomery.
• NYU Langone Health, New York, NY.
• Crit. Care Med. 2022 Sep 1; 50 (9): 134813591348-1359.

ObjectivesWe designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation.DesignMulticenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial.SettingFive U.S. medical centers.PatientsAdults inpatients with severe COVID-19 disease and hyperinflammation.InterventionsEighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo.Measurements And Main ResultsThe primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival, frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively).ConclusionsClazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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