Avdoralimab (Anti-C5aR1 mAb) Versus Placebo in Patients With Severe COVID-19: Results From a Randomized Controlled Trial (FOR COVID Elimination [FORCE])

Abstract

Objectives: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19.

Design: FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study.

Setting: Twelve clinical sites in France (ICU and general hospitals).

Patients: Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3.

Interventions: Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2.

Measurements and main results: We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified.

Conclusions: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367).

Figure 1.

Flowchart. In cohort 1, 50 patients were assigned to receive avdoralimab (intention-to-treat [ITT] population), and 47 (94%) received the treatment as assigned (per-protocol [PP] population): three were on invasive mechanical ventilation (IMV) at first treatment administration. In cohort 1, 49 patients were assigned to receive placebo (ITT population), and 45 (92%) received placebo as assigned (PP population): one was assigned to placebo but switched treatment arms during the study, and three were on IMV at first treatment administration. In cohort 2, 24 patients were assigned to receive avdoralimab (ITT population), and 23 received the treatment as assigned. One patient was on conventional oxygen therapy at first treatment administration. In cohort 2, 25 patients were assigned to receive placebo (ITT population), and 24 (96%) received placebo as assigned: one was assigned to placebo but received avdoralimab. As this patient received only avdoralimab, he was switched to the avdoralimab group in the PP population. In cohort 3, 100% of patients received their assigned treatment in either arm; 29 patients received avdoralimab, and 30 patients received placebo (ITT and PP populations).

Figure 2.

Changes in clinical status according to the World Health Organization (WHO) ordinal scale (per-protocol [PP]-actual treatment). Categories on the WHO ordinal scale range from 0 to 10, with higher categories indicating a worse condition. Category 0 indicates that the patient was uninfected; 1, viral RNA but asymptomatic; 2, symptomatic, with no limitations on activities; 3, symptomatic needing assistance; 4, hospitalized with no need for oxygen therapy; 5, hospitalized receiving oxygen by mask or nasal prongs; 6, hospitalized receiving oxygen by noninvasive ventilation or high-flow oxygen; 7, intubated and receiving invasive mechanical ventilation (IMV) with Pao₂/Fio₂ ≥ 150; 8, receiving IMV with Pao₂/Fio₂ < 150 or vasopressors; 9, receiving IMV with Pao₂/Fio₂ < 150 and vasopressors, dialysis or extracorporeal membrane oxygenation; and 10, dead.