Abstract and Introduction
Objectives: We 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.
Design: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial.
Setting: Five U.S. medical centers.
Patients: Adults inpatients with severe COVID-19 disease and hyperinflammation.
Interventions: Eighty-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 Results: The 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).
Conclusions: Clazakizumab 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.
The worldwide outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in greater than 5.7 million deaths. COVID-19 illness manifests across a spectrum ranging from no symptoms to overt acute respiratory distress syndrome (ARDS). Hyperinflammation or cytokine storm often accompanies COVID-19,[2–4] and this prompted use of the interleukin-6 receptor (IL-6R) antagonist tocilizumab at the pandemic outset.[5–8] Results from studies of tocilizumab in varied clinical populations have been mixed.[9–20]
Clazakizumab is a genetically engineered humanized monoclonal antibody with high affinity for human interleukin-6 (IL-6) that has been studied in disease states associated with hyperinflammation, including rheumatologic conditions.[21,22] Because clazakizumab is a direct ligand inhibitor not susceptible to sequestration by circulating soluble receptor, it might have greater potency than IL-6R inhibitors and may benefit patients with severe COVID-19 disease.
We report our multicenter seamless adaptive phase II/III randomized, placebo-controlled trial to assess the safety and efficacy of clazakizumab in severely or critically ill COVID-19 patients with hyperinflammation.
Crit Care Med. 2022;50(9):1348-1359. © 2022 Lippincott Williams & Wilkins