Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial

Abstract

Purpose: Trials of tocilizumab in patients with severe COVID-19 pneumonia have demonstrated mixed results, and the role of tocilizumab in combination with other treatments is uncertain. Here we evaluated whether tocilizumab plus remdesivir provides greater benefit than remdesivir alone in patients with severe COVID-19 pneumonia.

Methods: This randomized, double-blind, placebo-controlled, multicenter trial included patients hospitalized with severe COVID-19 pneumonia requiring > 6 L/min supplemental oxygen. Patients were randomly assigned (2:1 ratio) to receive tocilizumab 8 mg/kg or placebo intravenously plus ≤ 10 days of remdesivir. The primary outcome was time from randomization to hospital discharge or "ready for discharge" (defined as category 1, assessed by the investigator on a 7-category ordinal scale of clinical status) to day 28. Patients were followed for 60 days.

Results: Among 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. 566 patients (88.2%) received corticosteroids during the trial to day 28. Median time from randomization to hospital discharge or "ready for discharge" was 14 (95% CI 12-15) days with tocilizumab plus remdesivir and 14 (95% CI 11-16) days with placebo plus remdesivir [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78-1.19)]. Serious adverse events occurred in 128 (29.8%) tocilizumab plus remdesivir and 72 (33.8%) placebo plus remdesivir patients; 78 (18.2%) and 42 (19.7%) patients, respectively, died by day 28.

Conclusions: Tocilizumab plus remdesivir did not shorten time to hospital discharge or "ready for discharge" to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.

Keywords: COVID-19; Pneumonia; Remdesivir; Tocilizumab.

Fig. 1

The safety population was defined as all patients who received any amount of study medication (remdesivir, tocilizumab/placebo) with patients grouped according to treatment received. ^aIncludes 1 patient who was randomly assigned to the tocilizumab plus remdesivir arm but received placebo plus remdesivir. ^bDoes not include 1 patient who was randomly assigned to the tocilizumab plus remdesivir arm but received placebo plus remdesivir; this patient was included in the placebo plus remdesivir arm of the safety population. ^cIncludes the patient who was randomly assigned to the tocilizumab plus remdesivir arm but received placebo plus remdesivir and 2 patients (1 from each treatment arm) who received remdesivir but not tocilizumab or placebo. ALT alanine aminotransferase, AST aspartate aminotransferase, eGFR estimated glomerular filtration rate, PCR, polymerase chain reaction, ULN upper limit of normal

Fig. 2

Time to (a) hospital discharge or “ready for discharge” (primary outcome), (b) mechanical ventilation or death, (c) death. Data are shown as (a) 1 minus the Kaplan–Meier curve, (b) Kaplan–Meier curve for time to mechanical ventilation or death, and (c) Kaplan–Meier curve for time to death (modified intention-to-treat population). Panel a shows time to hospital discharge or “ready for discharge” defined as days from randomization to hospital discharge or “ready for discharge” not followed by ordinal scale category > 1, hospital readmission, or death. Patients who discontinued or were lost to follow-up for any reason before hospital discharge or “ready for discharge” criteria were met were censored at their last recorded ordinal scale assessment. Panel b shows time to mechanical ventilation or death defined as the time from randomization to the first occurrence of death or mechanical ventilation. For patients already receiving mechanical ventilation at baseline, only death was counted as an event. One patient had a missing baseline mechanical ventilation record; therefore, the baseline ordinal scale category (category 3: non-ICU hospital ward or “ready for hospital ward” requiring supplemental oxygen) was used to impute baseline mechanical ventilation status as not receiving mechanical ventilation. Patients who withdrew or were lost to follow-up before discharge (not followed by death) were censored at their last assessment of vital signs. Patients who withdrew or who were lost to follow-up on or after the day of discharge (not followed by death or hospital readmission) were censored at day 28. Panel c shows time to death defined as the time from randomization to death. Patients who withdrew or were lost to follow-up before discharge (not followed by death) were censored at the last known date they were alive. Patients who withdrew or were lost to follow-up on or after the day of discharge (not followed by death or hospital readmission) were censored at day 28. ICU intensive care unit