Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST): a phase 2 randomised adaptive 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

doi:10.1101/2021.06.02.21258204

Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST): a phase 2 randomised adaptive 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. ThickettJulian Bion, Simon Gates, Duncan Richards, Pamela Kearns

Research output: Working paper/Preprint › Preprint

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% 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. 134 adverse events occurred in 30/55 (54.5%) namilumab patients compared to 145 in 29/54 (53.7%) usual care patients. 102 events occurred in 20/29 (69.0%) infliximab patients versus 112 events in 17/34 (50.0%) 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 language	English
Publisher	medRxiv
Pages	1-26
Number of pages	26
DOIs	https://doi.org/10.1101/2021.06.02.21258204
Publication status	Published - 9 Jun 2021

Keywords

intensive care and critical care medicine

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Fisher, B. A., Veenith, T., Slade, D., Gaskell, C., Rowland, M., Whitehouse, T., Scriven, J., Parekh, D., Balasubramaniam, M. S., Cooke, G., Morley, N., Gabriel, Z., Wise, M. P., Porter, J., McShane, H., Ho, L-P., Newsome, P. N., Rowe, A., Sharpe, R., ... Kearns, P. (2021). Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST): a phase 2 randomised adaptive trial. (pp. 1-26). medRxiv. https://doi.org/10.1101/2021.06.02.21258204

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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% 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. 134 adverse events occurred in 30/55 (54.5%) namilumab patients compared to 145 in 29/54 (53.7%) usual care patients. 102 events occurred in 20/29 (69.0%) infliximab patients versus 112 events in 17/34 (50.0%) 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.",

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

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Fisher, BA, Veenith, T, Slade, D, Gaskell, C, Rowland, M, Whitehouse, T , Scriven, J , Parekh, D, Balasubramaniam, MS, Cooke, G, Morley, N, Gabriel, Z, Wise, MP, Porter, J, McShane, H, Ho, L-P, Newsome, PN , Rowe, A, Sharpe, R, Thickett, DR , Bion, J , Gates, S, Richards, D & Kearns, P 2021 'Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST): a phase 2 randomised adaptive trial' medRxiv, pp. 1-26. https://doi.org/10.1101/2021.06.02.21258204

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AU - Gaskell, Charlotte

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AB - 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% 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. 134 adverse events occurred in 30/55 (54.5%) namilumab patients compared to 145 in 29/54 (53.7%) usual care patients. 102 events occurred in 20/29 (69.0%) infliximab patients versus 112 events in 17/34 (50.0%) 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.

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BT - Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST)

PB - medRxiv

ER -

Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST): a phase 2 randomised adaptive trial

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Keywords

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