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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% 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. 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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BackgroundAspirin has been proposed as a treatment for COVID-19 on the basis of its antithrombotic properties. MethodsIn this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care plus 150mg aspirin once daily until discharge or usual standard of care alone using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 01 November 2020 and 21 March 2021, 7351 patients were randomly allocated to receive aspirin and 7541 patients to receive usual care alone. Overall, 1222 (17%) patients allocated to aspirin and 1299 (17%) patients allocated to usual care died within 28 days (rate ratio 0{middle dot}96; 95% confidence interval [CI] 0{middle dot}89-1{middle dot}04; p=0{middle dot}35). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to aspirin had a slightly shorter duration of hospitalisation (median 8 vs. 9 days) and a higher proportion were discharged from hospital alive within 28 days (75% vs. 74%; rate ratio 1{middle dot}06; 95% CI 1{middle dot}02-1{middle dot}10; p=0{middle dot}0062). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0{middle dot}96; 95% CI 0{middle dot}90-1{middle dot}03; p=0{middle dot}23). Aspirin use was associated with an absolute reduction in thrombotic events of 0.6% (SE 0.4%) and an absolute increase in major bleeding events of 0.6% (SE 0.2%). InterpretationIn patients hospitalised with COVID-19, aspirin was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death but was associated with a small increase in the rate of being discharged alive within 28 days. FundingUK Research and Innovation (Medical Research Council), National Institute of Health Research (Grant ref: MC_PC_19056), and the Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator.
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IntroductionSevere SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, pro-inflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs. Methods and analysisThe CATALYST trial is a multi-arm, open-label, multi-centre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription polymerase chain reaction (RT-PCR) assay) and a C-Reactive Protein (CRP) [≥]40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment. Ethics and disseminationThe protocol was approved by the East Midlands - Nottingham 2 Research Ethics Committee (20/EM/0115) and given Urgent Public Health status; initial approval was received on 05-May-2020, current protocol version (v6.0) approval on 12-Oct-2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. Trial registration numberEudraCT Number: 2020-001684-89 ISRCTN Number: 40580903 Strengths and limitations of this trialO_LICATALYST will provide a rapid readout on the safety and proof-of-concept of candidate novel treatments C_LIO_LICATALYST will enable phase III trial resources to be focussed and allocated for agents with a high likelihood of success C_LIO_LICATALYST uses Bayesian multi-level models to allow for nesting of repeated measures data, with factors for each individual patient and treatment arm, and allowing for non-linear responses C_LIO_LICATALYST is not designed to provide a definitive signal on clinical outcomes C_LI
