Randomized, Controlled Study of IFX-1 in Patients With Severe COVID-19 Pneumonia (PANAMO)

A Pragmatic Adaptive Randomized, Controlled Phase II/III Multicenter Study of IFX-1 in Patients With Severe COVID-19 Pneumonia

Phase II & Phase III: This is a pragmatic, adaptive, randomized, multicenter phase II/III study evaluating IFX-1 for the treatment of COVID-19 related severe pneumonia. The study consists of two parts: Phase II, an open-label, randomized, 2-arm phase evaluating best supportive care (BSC) + IFX-1 (Arm A) and BSC alone (Arm B); and Phase III, a double-blind, placebo-controlled, randomized phase comparing standard of care (SOC) + IFX-1 (Arm A) versus SOC + placebo-to-match (Arm B)

The phase II and Phase III portions enrolled patients subsequently. 1st patient was enrolled in the phase III portion on 1st October 2020.

Relative change (%) from baseline in Oxygenation Index (OI; partial pressure of oxygen in the arterial blood (PaO2) / fractional inspired oxygen (FiO2)) in supine position for ≥2 hours at day 5 (FAS)

Relative change (%) from baseline in Oxygenation Index (OI) in supine position for ≥2 hours at days 3, 7, 9, 11, and 15 (FAS)

Percentage of patients with an improvement in the 8-point ordinal scale (Day 15, Day 28), the scale ranges from 0 = 'No clinical or virological evidence of infection' to 8 = 'Death' with higher scores meaning greater limitation and ventilation/organ support

Percentage of patients developing acute kidney failure (estimated glomerular filtration rate [eGFR] < 15 mL/min/1.73m², assessed by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation requiring race information) until Day 28 (FAS)

Phase III: Percentage of Patients Free of Any Renal Replacement Therapy Within 28 Days Upon Randomization (FAS)

Percentage of patients free of any renal replacement therapy (RRT) within 28 days upon randomization (FAS), number of patients free of any RRT = number of patients - number of patients with RRT initiated after randomization until Day 28

Phase II Inclusion Criteria: At least 18 years of age or older Clinically evident or otherwise confirmed severe pneumonia SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization with locally available test system) Exclusion Criteria: Known history of progressed COPD as evidenced by use of daily maintenance treatment with long-acting bronchodilators or inhaled/oral corticosteroids for > 2 months Patient moribund or expected to die in next 24h according to the judgment of the investigator Known severe congestive heart failure (New York Heart Association [NYHA] Class III- IV) Received organ or bone marrow transplantation in past 3 months Known cardio-pulmonary mechanical resuscitation in past 14 days Phase III: Inclusion Criteria: At least 18 years of age or older Patient on invasive mechanical ventilation (but not more than 48h post intubation at time point of first IMP administration) Patients with a PaO2 / FiO2 ratio of < 200 and > 60 at randomization (one representative measurement within 6h before randomization) SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization with locally available test system) Exclusion Criteria: Intubated > 48 h at time point of first IMP administration Expected stop of invasive ventilation or expected extubation in the next 24h without additional intervention according to judgment of the investigator Known history of chronic dialysis OR received renal replacement therapy in past 14 days OR anticipated to receive renal replacement therapy within 24h after randomization Known history of progressed COPD as evidenced by use of daily maintenance treatment with long-acting bronchodilators or inhaled/oral corticosteroids for > 2 months Treatment of COVID-19 with investigational antibody treatment(s) which are not approved or not included in locally adopted treatment guidelines (e.g., WHO guidance, National Institutes of Health [NIH] COVID-19 treatment guidelines) for this indication in the past 7 days (Note: Antibody treatment[s] given within past 7 days for pre-existing diseases, other than COVID-19, are allowed.) At time point of randomization, treatment of COVID-19 with investigational treatments which are not approved or not included in locally adopted treatment guidelines for this indication (e.g., WHO guidance, NIH COVID-19 treatment guidelines), including SARS-CoV-2 multiplication inhibitor(s) or immunomodulator(s). (Note: If a locally adopted treatment guideline recommends drugs such as remdesivir, dexamethasone, or anticoagulation, this would be allowed. Adopted guidelines and updates must be documented at study initiation and throughout the conduct of the study.) Received cytokine adsorption therapy in past 3 days Known severe congestive heart failure (corresponding to e.g. NYHA Class III-IV, left ventricular ejection fraction <40%) Known history of chronic liver disease (Child-Pugh B or C)

Vlaar APJ, Witzenrath M, van Paassen P, Heunks LMA, Mourvillier B, de Bruin S, Lim EHT, Brouwer MC, Tuinman PR, Saraiva JFK, Marx G, Lobo SM, Boldo R, Simon-Campos JA, Cornet AD, Grebenyuk A, Engelbrecht JM, Mukansi M, Jorens PG, Zerbib R, Ruckinger S, Pilz K, Guo R, van de Beek D, Riedemann NC; 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. 2022 Dec;10(12):1137-1146. doi: 10.1016/S2213-2600(22)00297-1. Epub 2022 Sep 7.

Vlaar APJ, Lim EHT, de Bruin S, Ruckinger S, Pilz K, Brouwer MC, Guo RF, Heunks LMA, Busch MH, van Paassen P, Riedemann NC, van de Beek D. The anti-C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID-19. Clin Transl Sci. 2022 Apr;15(4):854-858. doi: 10.1111/cts.13213. Epub 2022 Jan 14.

Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Vlaar APJ, de Bruin S, Busch M, Timmermans SAMEG, van Zeggeren IE, Koning R, Ter Horst L, Bulle EB, van Baarle FEHP, van de Poll MCG, Kemper EM, van der Horst ICC, Schultz MJ, Horn J, Paulus F, Bos LD, Wiersinga WJ, Witzenrath M, Rueckinger S, Pilz K, Brouwer MC, Guo RF, Heunks L, van Paassen P, Riedemann NC, van de Beek D. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol. 2020 Dec;2(12):e764-e773. doi: 10.1016/S2665-9913(20)30341-6. Epub 2020 Sep 28.