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 Sharpe; David Thickett; Julian Bion; Simon Gates; Duncan Richards; Pamela Kearns; Francis Mussai

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

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, Francis Mussai

Research output: Contribution to journal › Article › peer-review

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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% 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 language	English
Pages (from-to)	255-266
Journal	The Lancet Respiratory Medicine
Volume	10
Issue number	3
Early online date	16 Dec 2021
DOIs	https://doi.org/10.1016/S2213-2600(21)00460-4 https://doi.org/10.1016/s2213-2600(21)00460-4
Publication status	Published - Mar 2022

Bibliographical note

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

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FisherBA2021NamilumabAccepted author manuscript, 1.79 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

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CATALYST investigators, Fisher, B., Veenith, T., Slade, D., Gaskell, C., Rowland, M., Whitehouse, T., Scriven, J., Parekh, D., Balasubramaniam, M., Cooke, G., Morley, N., Gabriel, Z., Wise, M., Porter, J., McShane, H., Ho, L-P., Newsome, P., Rowe, A., ... Mussai, F. (2022). 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. The Lancet Respiratory Medicine, 10(3), 255-266. Advance online publication. https://doi.org/10.1016/S2213-2600(21)00460-4, https://doi.org/10.1016/s2213-2600(21)00460-4

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title = "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",

abstract = "BackgroundDysregulated 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.MethodsIn 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. FindingsBetween 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.InterpretationNamilumab, 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. FundingMedical Research Council.",

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

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pages = "255--266",

journal = "The Lancet Respiratory Medicine",

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CATALYST investigators, Fisher, B, Veenith, T, Slade, D, Gaskell, C, Rowland, M, Whitehouse, T , Scriven, J , Parekh, D, Balasubramaniam, M, Cooke, G, Morley, N, Gabriel, Z, Wise, M, Porter, J, McShane, H, Ho, L-P, Newsome, P , Rowe, A, Sharpe, R, Thickett, D , Bion, J , Gates, S, Richards, D, Kearns, P & Mussai, F 2022, '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', The Lancet Respiratory Medicine, vol. 10, no. 3, pp. 255-266. https://doi.org/10.1016/S2213-2600(21)00460-4, https://doi.org/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. / CATALYST investigators ; Fisher, Benjamin; Veenith, Tonny et al.
In: The Lancet Respiratory Medicine, Vol. 10, No. 3, 03.2022, p. 255-266.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST)

T2 - a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial

AU - CATALYST investigators

AU - Fisher, Benjamin

AU - Veenith, Tonny

AU - Slade, Daniel

AU - Gaskell, Charlotte

AU - Rowland, Matthew

AU - Whitehouse, Tony

AU - Scriven, James

AU - Parekh, Dhruv

AU - Balasubramaniam, Madhu

AU - Cooke, Graham

AU - Morley, Nick

AU - Gabriel, Zoe

AU - Wise, Matthew

AU - Porter, Joanna

AU - McShane, Helen

AU - Ho, Ling-Pei

AU - Newsome, Philip

AU - Rowe, Anna

AU - Sharpe, Rowena

AU - Thickett, David

AU - Bion, Julian

AU - Gates, Simon

AU - Richards, Duncan

AU - Kearns, Pamela

AU - Mussai, Francis

PY - 2022/3

Y1 - 2022/3

N2 - BackgroundDysregulated 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.MethodsIn 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. FindingsBetween 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.InterpretationNamilumab, 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. FundingMedical Research Council.

AB - BackgroundDysregulated 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.MethodsIn 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. FindingsBetween 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.InterpretationNamilumab, 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. FundingMedical Research Council.

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CATALYST investigators, Fisher B, Veenith T, Slade D, Gaskell C, Rowland M et al. 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. The Lancet Respiratory Medicine. 2022 Mar;10(3):255-266. Epub 2021 Dec 16. doi: 10.1016/S2213-2600(21)00460-4, 10.1016/s2213-2600(21)00460-4