Ravulizumab as an add-on for best supportive care (BSC) for COVID-19 failed to improve survival or secondary outcomes in hospitalized adults with acute lung injury, severe pneumonia, or acute respiratory distress syndrome (ARDS) who were also receiving either invasive or noninvasive mechanical ventilation, according to study findings published in The Lancet Respiratory Medicine.
COVID-19 severity is correlated with increasing blood concentrations of proinflammatory complement components C5b-9 and C5a. Researchers sought to assess the efficacy and safety of ravulizumab, a terminal complement C5 inhibitor, in patients hospitalized with severe COVID-19 requiring invasive or noninvasive mechanical ventilation.
The researchers conducted an open-label, phase 3, randomized controlled trial (ClinicalTrials.gov Identifier: NCT04369469) of adult patients from 31 hospitals in the UK, Spain, Japan, France, and the US between May 2020 and January 2021. Eligible patients (body weight ≥40kg) required hospitalization and either invasive (intubation) or noninvasive (continuous or bilevel positive airway pressure) mechanical ventilation with a confirmed diagnosis (via polymerase chain reaction or antibody test) of SARS-CoV-2 with acute lung injury, severe pneumonia, or ARDS confirmed by x-ray or computed tomography scan.
The 201 patients included in the intention-to-treat (ITT) population were randomized 2:1 (stratified by intubation status) to receive ravulizumab plus BSC (n=135; 29% women; mean [SD] age, 63.2 [13.23] years) or BSC alone (n=66; 35% women; mean age, 63.5 [12.40] years). Ravulizumab was administered on days 1, 5, 10, and 15 in body-weight-based intravenous doses. Patients with at least 1 comorbidity accounted for 87% of the ravulizumab plus BSC group vs 94% of the BSC group. The most frequent comorbidities were hypertension (64% ravulizumab vs 74% BSC only), diabetes (52% vs 48%, respectively), and obesity (34% vs 38%, respectively). At baseline, 84% of patients in the ravulizumab plus BSC group were on invasive mechanical ventilation vs 80% of the BSC group.
We found no difference in overall survival at day 29 between patients receiving ravulizumab plus BSC and those receiving BSC, even though most patients who received ravulizumab achieved the target serum concentration for free C5 of less than 0.5µg/mL.
Overall survival estimates based on multiple imputation were 58% for patients receiving ravulizumab plus BSC and 60% for patients receiving BSC alone (Mantel-Haenszel analysis: risk difference, -0.0205; 95% CI, -0.1703 to 0.1293; one-sided P =.61).
In the safety assessment, 89% of patients in the ravulizumab group had a treatment-emergent adverse event vs 84% of patients in the BSC-only group. Infections and infestations were more frequent in the ravulizumab vs the BSC-only group (57% vs 36%, respectively) as were vascular disorders (31% vs 18%, respectively). Deaths occurred at day 29 in 41% of patients in the ravulizumab group vs 38% of those in the BSC-only group.
An analysis of a subset of 44 patients in the ravulizumab plus BSC group found at least 98% of patients had post-dose serum concentrations of ravulizumab at or greater than the target threshold of 175μg/mL. At least 96% of these patients had post-dose serum free C5 concentrations of less than 0.5µg/mL (the threshold for complete terminal complement inhibition) up to day 15. The researchers noted that 75% of these patients met this threshold at day 29.
Serious adverse events (pyrexia, cryptococcal pneumonia, esophageal hemorrhage, thrombocytopenia, bacteremia) related to ravulizumab occurred in 5 patients (1 event in each patient). This study was terminated at interim analysis due to futility.
Study limitations include open-label design, timing of intervention, and heterogeneity of BSC regimens across centers.
“We found no difference in overall survival at day 29 between patients receiving ravulizumab plus BSC and those receiving BSC, even though most patients who received ravulizumab achieved the target serum concentration for free C5 of less than 0.5µg/mL,” researchers concluded. “Despite the lack of efficacy, the study adds value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients,” the researchers added.
Disclosure: This research was supported by Alexion and AstraZeneca. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.