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

Abstract

Background: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population.

Methods: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO2/FiO2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420.

Findings: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group.

Interpretation: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections.

Funding: InflaRx and the German Federal Government.

Conflict of interest statement

Declaration of interests NCR and RG are founders, active officers, and executive directors of the board, and hold shares and stock options in InflaRx. KP is the chief clinical development officer and holds stock options in InflaRx. RZ is the program director and holds stock options in InflaRx. SR is an employee of Metronomia Clinical Research and a contracted statistical service provider for InflaRx. MW receives grants from the German Research Foundation (SFB-TR84 C6, SFB-TR84 C9, and SFB 1449 B02) and German Ministry of Education and Research (e:Med CAPSyS [01ZX1304B], SYMPATH [01ZX1906A], NUM-NAPKON [01KX2021], and PROVID [01KI20160A]). APJV received consulting fees from InflaRx for advisory work, paid to the institution. GM received honoraria for lecturing and consulting from B Braun, 4TEEN4, Adrenomed, and Philips. All other authors declare no competing interests.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial profile 12 additional patients who discontinued due to transfer to another hospital but completed survival follow-up until day 60 are not shown separately and are included in the number of patients with complete survival follow-up. Patients who discontinued before or after day 28 are not shown separately.

Figure 2

Kaplan-Meier curves for mortality (full analysis set) (A) All-cause mortality at day 28 (primary endpoint). (B) All-cause mortality at day 60 (secondary endpoint).

Figure 3

Cumulative incidence for first renal replacement therapy (full analysis set) ???

Figure 4

Prespecified subgroup analysis for all-cause mortality at 28 days in patients with higher disease severity Moderate and severe ARDS was defined using BERLIN criteria. ARDS=acute respiratory distress syndrome. eGFR=estimated glomerular filtration rate.