In patients with severe COVID-19 receiving invasive mechanical ventilation, adding vilobelimab treatment to standard care reduces mortality in the short term (28 days) and longer term (60 days), according to phase 3 clinical trial findings published in Lancet Respiratory Medicine.
A phase 2 clinical trial found that vilobelimab, an anti-C5a monoclonal antibody, was safe when added to standard care in patients with COVID-19 receiving invasive mechanical ventilation. Researchers therefore conducted a phase 3 trial to assess whether vilobelimab improved survival outcomes in these patients.
The researchers conducted the multicenter, placebo-controlled, double-blind, randomized phase 3 PANAMO trial (ClinicalTrials.gov Identifier: NCT04333420) at 46 hospitals in South Africa, Mexico, Peru, Brazil, Belgium, Germany, France, Netherlands, and Russia from October 2020 until October 2021. The trial’s primary outcome was all-cause mortality at 28 days. The secondary outcome was mortality at 60 days.
At its inception, the trial included 368 adult patients (median age, 58 years; 32% female) who received invasive mechanical ventilation within 48 hours of intubation, had a confirmed diagnosis of SARS-CoV-2 infection within the previous 14 days, and had a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2)of 60 to 200mm Hg. All participants received standard care, with 177 randomized to receive intravenous vilobelimab 800mg for a maximum of 6 doses (days 1, 2, 4, 8, 15, 22), while 191 participants received matching placebo.
The treatment and placebo cohorts were well matched for baseline characteristics, demographics (ie, nationality, race/ethnicity, sex, age, and BMI), estimated glomerular filtration rate, and most comorbidities (except for diabetes, which was 19% higher in the placebo group). At baseline, the mean PaO2/FiO2 ratio was 131.9±39.2 in the vilobelimab group and 130.6±44.8 in the placebo group. Before and following randomization, 17% of patients received anti-interleukin-6 treatment. There was concomitant use of glucocorticosteroids in 97% of patients, antithrombotic agents in 98%, and anti-interleukin-6 in 3%.
The investigators found 59% of patients in the vilobelimab group and 63% in the placebo group reported serious treatment-emergent adverse events (TEAEs), the most common of which were acute kidney injury (20% in the vilobelimab group vs 21% in the placebo group), pneumonia (22% vs 14%, respectively), and septic shock (14% vs 16%, respectively).
Researchers found 31% of patients in the treatment group and 40% of patients in the placebo group died within the first 28 days. At 28 days, all-cause mortality rate was 32% in the vilobelimab group (95% CI, 25-39) and 42% in the placebo group (95% CI, 35-49) (hazard ratio [HR] 0.73; 95% CI, 0.50-1.06; P =.094).
Predefined analysis without site-stratification showed that all-cause mortality was significantly reduced by vilobelimab at 28 days (HR 0.67; 95% CI, 0.48-0.96; P =.027). The all-cause mortality rate at 60 days was 35% of patients in the vilobelimab group and 46% of patients in the placebo group, with mortality rates of 37% in the vilobelimab group (95% CI, 30-44) and 47% in the placebo group (95% CI, 40-55) (HR 0.74; 95% CI, 0.52-1.04; P =.082).
Trial limitations include a considerable proportion of patients likely infected with the Delta variant of SARS-CoV-2 when Omicron is currently more dominant; lack of COVID-19 vaccination, which was just becoming available, among most patients in the study; and a lack of statistical significance in the stratified analysis.
Researchers concluded that the trial “showed a consistent reduction of all-cause mortality at 28 days in patients with COVID-19 who receive invasive mechanical ventilation in addition to standard of care.” The study authors concluded that vilobelimab could be considered as additional therapy for patients with severe COVID-19 receiving invasive mechanical ventilation.
Disclosure: This research was supported by InflaRx. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Vlaar APJ, Witzenrath M, van Paassen P, et al.; PANAMO study group. Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. Published online September 7, 2022. doi:10.1016/S2213-2600(22)00297-1