Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial

CATALYST investigators, Benjamin Fisher, Tonny Veenith, Daniel Slade, Charlotte Gaskell, Matthew Rowland, Tony Whitehouse, James Scriven, Dhruv Parekh, Madhu Balasubramaniam, Graham Cooke, Nick Morley, Zoe Gabriel, Matthew Wise, Joanna Porter, Helen McShane, Ling-Pei Ho, Philip Newsome, Anna Rowe, Rowena SharpeDavid Thickett, Julian Bion, Simon Gates, Duncan Richards, Pamela Kearns

Research output: Contribution to journalArticlepeer-review

Abstract

Background
Dysregulated inflammation is associated with poor outcomes in Coronavirus disease 2019 (COVID-19). We assessed the efficacy of namilumab, a granulocyte-macrophage colony-stimulating factor inhibitor and infliximab, a tumour necrosis factor inhibitor in hospitalised patients with COVID-19 in order to prioritise agents for phase 3 trials.

Methods
In this randomised, multi-arm, parallel group, open label, adaptive phase 2 proof-of-concept trial (CATALYST) we recruited hospitalised patients ≥16 years with COVID-19 pneumonia and C-reactive protein (CRP) ≥40mg/L in nine UK hospitals. Participants were randomly allocated with equal probability to usual care, or usual care plus a single 150mg intravenous dose of namilumab (150mg) or infliximab (5mg/kg). Randomisation was stratified for ward versus ICU. The primary endpoint was improvement in inflammation in intervention arms compared to control as measured by CRP over time, analysed using Bayesian multi-level models. ISRCTN registry number 40580903.

Findings
Between 15th June 2020 and 18th February 2021 we randomised 146 participants: 54 to usual care, 57 to namilumab and 35 to infliximab. The probabilities that namilumab and infliximab were superior to usual care in reducing CRP over time were 97% and 15% with point estimates for treatment-time interactions of -0.09 (-0.19, 0.00) and 0.06 (-0.05, 0.17) respectively. Consistent effects were seen in ward and ICU patients and aligned with clinical outcomes, such that the probability of discharge (WHO levels 1-3) at day 28 was 47% and 64% for ICU and ward patients on usual care, versus 66% and 77% for patients treated with namilumab. Death occurred in 6 (11%) and 10 (19%) namilumab and usual care patients respectively, and 4 (14%) and 5 (15%) infliximab and usual care patients respectively. 134 adverse events occurred in 30/55 (55%) namilumab patients compared to 145 in 29/54 (54%) usual care patients. 102 events occurred in 20/29 (69%) infliximab patients versus 112 events in 17/34 (50%) usual care patients.

Interpretation
Namilumab, but not infliximab, demonstrated proof-of-concept evidence for reduction in inflammation in hospitalised patients with COVID-19 pneumonia which was consistent with secondary clinical outcomes. Namilumab should be prioritised for further investigation in COVID-19.

Funding
Medical Research Council.
Original languageEnglish
JournalThe Lancet Respiratory Medicine
Early online date16 Dec 2021
DOIs
Publication statusE-pub ahead of print - 16 Dec 2021

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