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

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

doi:10.1016/S2213-2600(21)00460-4

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

Lancet Respir Med. 2022 Mar;10(3):255-266. doi: 10.1016/S2213-2600(21)00460-4. Epub 2021 Dec 16.

Authors

Benjamin A Fisher¹, Tonny Veenith², Daniel Slade³, Charlotte Gaskell³, Matthew Rowland⁴, Tony Whitehouse², James Scriven⁵, Dhruv Parekh⁶, Madhu S Balasubramaniam⁷, Graham Cooke⁸, Nick Morley⁹, Zoe Gabriel¹⁰, Matthew P Wise¹¹, Joanna Porter¹², Helen McShane¹³, Ling-Pei Ho¹⁴, Philip N Newsome¹⁵, Anna Rowe¹⁶, Rowena Sharpe³, David R Thickett¹⁷, Julian Bion², Simon Gates³, Duncan Richards¹⁸, Pamela Kearns¹⁶; CATALYST investigators

Affiliations

¹ Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. Electronic address: [email protected].
² Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Department of Critical Care Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
³ Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁴ Kadoorie Centre for Critical Care Research, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁵ Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK; Department of Infectious Diseases, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
⁶ Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Department of Critical Care Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Department of Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
⁷ Department of Critical Care Medicine, Royal Bolton Hospital, Bolton, UK.
⁸ Department of Infectious Disease, Imperial College London, London, UK.
⁹ Department of Haematology, Royal Hallamshire Hospital, Sheffield, UK.
¹⁰ Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
¹¹ Department of Critical Care Medicine, University Hospital of Wales, Cardiff, UK.
¹² Department of Respiratory Medicine, University College Hospital, London, UK.
¹³ Jenner Institute, University of Oxford, Oxford, UK.
¹⁴ Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Oxford Interstitial Lung Disease Service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁵ Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹⁶ Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹⁷ Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Department of Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹⁸ Oxford Clinical Trials Research Unit, Botnar Research Centre, University of Oxford, Oxford, UK.

Abstract

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

Methods: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903.

Findings: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment-time interactions were -0·09 (95% CI -0·19 to 0·00) for namilumab and 0·06 (-0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group.

Interpretation: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation-as measured by CRP concentration-in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19.

Funding: Medical Research Council.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Antibodies, Monoclonal, Humanized
Bayes Theorem
COVID-19 Drug Treatment*
Humans
Infliximab / therapeutic use
SARS-CoV-2
Standard of Care
Treatment Outcome

Substances

Antibodies, Monoclonal, Humanized
Infliximab
namilumab

Grants and funding

MC_PC_20007/MRC_/Medical Research Council/United Kingdom