TY - JOUR
T1 - Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO)
T2 - an exploratory, open-label, phase 2 randomised controlled trial
AU - Vlaar, Alexander P. J.
AU - de Bruin, Sanne
AU - Busch, Matthias
AU - Timmermans, Sjoerd A. M. E. G.
AU - van Zeggeren, Ingeborg E.
AU - Koning, Rutger
AU - ter Horst, Liora
AU - Bulle, Esther B.
AU - van Baarle, Frank E. H. P.
AU - van de Poll, Marcel C. G.
AU - Kemper, E. Marleen
AU - van der Horst, Iwan C. C.
AU - Schultz, Marcus J.
AU - Horn, Janneke
AU - Paulus, Frederique
AU - Bos, Lieuwe D.
AU - Wiersinga, W. Joost
AU - Witzenrath, Martin
AU - Rueckinger, Simon
AU - Pilz, Korinna
AU - Brouwer, Matthijs C.
AU - Guo, Ren-Feng
AU - Heunks, Leo
AU - van Paassen, Pieter
AU - Riedemann, Niels C.
AU - van de Beek, Diederik
N1 - Funding Information:
We would like to thank all medical, paramedical, and nursing staff involved in the care of the patients with COVID-19 for making it possible to perform this trial in the middle of the COVID-19 outbreak in the Netherlands. The trial is funded by InflaRx. It was designed by InflaRx representatives and academic advisors. Data were collected by investigators and associated site personnel, analysed by statisticians employed by Metronomia, and interpreted by academic authors and InflaRx representatives. APJV, SR, NCR, KP, and DvdB take responsibility for the integrity of the data and the accuracy of the data analysis. All authors had full access to the data, vouch for the completeness and accuracy of the data, and attest that the trial was done in accordance with the protocol and all amendments. The first draft of the manuscript was written by APJV and DvdB with input from authors employed by InflaRx. As part of the site agreement signed before trial participation, investigators agreed to keep all aspects of the trial, including the resulting data, confidential.
Funding Information:
APJV reports personal fees from InflaRx, paid to Amsterdam UMC, during the conduct of the study. NCR and R-FG are founders, active officers, and executive directors of InflaRx and hold shares and stock options in InflaRx. KP is Global Head of Clinical Development of InflaRx and holds stock options in InflaRx. SR is an employee at Metronomia, a contracted statistical service provider for InflaRx. MW is supported by grants from the German Research Foundation ( SFB-TR84 C6 and C9 ) and by the German Ministry of Education and Research in the framework of the CAPSyS (01ZX1304B) and the PROVID project (FKZ 01KI20160A). DvdB reports receiving departmental honoraria for serving on a scientific advisory board for InflaRx in 2017, paid to Amsterdam UMC. All other authors declare no competing interests.
Funding Information:
APJV reports personal fees from InflaRx, paid to Amsterdam UMC, during the conduct of the study. NCR and R-FG are founders, active officers, and executive directors of InflaRx and hold shares and stock options in InflaRx. KP is Global Head of Clinical Development of InflaRx and holds stock options in InflaRx. SR is an employee at Metronomia, a contracted statistical service provider for InflaRx. MW is supported by grants from the German Research Foundation (SFB-TR84 C6 and C9) and by the German Ministry of Education and Research in the framework of the CAPSyS (01ZX1304B) and the PROVID project (FKZ 01KI20160A). DvdB reports receiving departmental honoraria for serving on a scientific advisory board for InflaRx in 2017, paid to Amsterdam UMC. All other authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/12
Y1 - 2020/12
N2 - Background: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19. Methods: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO
2/FiO
2) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO
2/FiO
2 in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420). Findings: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO
2/FiO
2 assessments (irrespective of position). At day 5 after randomisation, the mean PaO
2/FiO
2 (irrespective of position) was 158 mm Hg (SD 63; range 84–265) in the IFX-1 group and 189 mm Hg (89; 71–329) in the control group. Analyses of the least squares mean relative change in PaO
2/FiO
2 at day 5 showed no differences between treatment groups (17% change in the IFX-1 group vs 41% in the control group; difference −24% [95% CI −58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0–31) for the IFX-1 group and 27% (4–49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10–4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group vs seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group. Interpretation: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint. Funding: InflaRx.
AB - Background: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19. Methods: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO
2/FiO
2) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO
2/FiO
2 in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420). Findings: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO
2/FiO
2 assessments (irrespective of position). At day 5 after randomisation, the mean PaO
2/FiO
2 (irrespective of position) was 158 mm Hg (SD 63; range 84–265) in the IFX-1 group and 189 mm Hg (89; 71–329) in the control group. Analyses of the least squares mean relative change in PaO
2/FiO
2 at day 5 showed no differences between treatment groups (17% change in the IFX-1 group vs 41% in the control group; difference −24% [95% CI −58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0–31) for the IFX-1 group and 27% (4–49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10–4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group vs seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group. Interpretation: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint. Funding: InflaRx.
KW - C5A
KW - COMPLEMENT ACTIVATION
KW - NEUTROPHILS
KW - TISSUE FACTOR
U2 - 10.1016/s2665-9913(20)30341-6
DO - 10.1016/s2665-9913(20)30341-6
M3 - Article
SN - 2665-9913
VL - 2
SP - E764-E773
JO - The Lancet Rheumatology
JF - The Lancet Rheumatology
IS - 12
ER -