Avdoralimab (anti-C5aR1 mAb) Versus Placebo in Patients With Severe COVID-19: Results From a Randomized Controlled Trial (FORCE)

Background: 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.Methods: FORCE was a double-blind, placebo-controlled study. Patients receiving oxygen support ≥5 L/min to maintain SpO2 > 93% (WHO scale ≥ 5) were randomly assigned, in a 1:1 ratio to the avdoralimab and placebo arms. Avdoralimab (500 mg loading dose followed by a 200 mg maintenance dose) or placebo (normal saline) was administered intravenously every 48 h until oxygen therapy was no longer needed, and for a maximum of 14 days. Patients received conventional oxygen therapy or high-flow oxygen (HFO)/non-invasive ventilation (NIV) in cohort 1; HFO, NIV or invasive mechanical ventilation (IMV) in cohort 2 and IMV in cohort 3. The primary outcome was clinical status on the WHO 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.Findings: Between May 2020 and January 2021, we randomized 207 patients: 99 in cohort 1, 49 in cohort 2 and 59 in cohort 3. Glucocorticoids were administered to 95% of patients during hospitalization. Avdoralimab did not improve WHO 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.Interpretation: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 or 28.Trial Registration Details: This trial was registered with ClinicalTrials.gov, NCT04371367. Funding Information: Innate Pharma. Declaration of Interests: JK, SC, ABC, EV, JV, LB, OD, and others in the FORCE Study group are Innate Pharma employees and might hold stock. All other authors declare no competing interests.Ethics Approval Statement: The trial protocol was approved by the French National Agency for the Safety of Medicines and Health Products (ANSM, MEDAECNAT-2020-04-00043_2020-001686-36), and the competent ethics committee (Comité de Protection des Personnes Ouest II CPP #2020/34/Covid-19, EudraCT2020- 26 001686-36), and was overseen by an independent data and safety monitoring board (DSMB). Data were analyzed by independent statisticians at the International Drug Development Institute (IDDI). Written informed consent was obtained from all patients or their legal representatives (if the patient was unable to provide consent).