Evaluation of the effectiveness of remdesivir in treating severe COVID-19 using data from the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, national cohort study

Abstract

AbstractBackgroundRemdesivir was given UK early-access approval for use in COVID-19 in people aged 12 years and older on 26th May 2020 on the basis of unmet clinical need. Evidence on the side effects, complications of therapy and effectiveness of this therapy is lacking or conflicting.MethodsAdults with severe COVID-19 treated with remdesivir were compared with propensity-score matched controls, identified from the ISARIC WHO Clinical Characterisation Protocol study of UK hospitalised patients with COVID-19. Remdesivir patients were matched to controls according to baseline underlying 14-day mortality risk. The effect of remdesivir on short-term outcomes was investigated (primary outcome: 14-day mortality). Effect sizes were estimated and adjusted for potential confounders using multivariable modelling.Results1,549 patients given remdesivir and 4,964 matched controls were identified satisfying inclusion and exclusion criteria. The balance diagnostic threshold was achieved. Patients had symptoms for a median of 6 days prior to baseline; 62% were male, with mean (SD) age 63.1 (15.6) years, and 80% categorised as ‘White’ ethnicity. Fourteen-day mortality was not statistically significantly associated with treatment (9.3 % remdesivir vs. 11.9% controls, odds-ratio 0.80, [95% CI 0.60-1.07], p=0.116, adjusted for age, sex, number of key comorbidities, dexamethasone use, and diagnosis of viral pneumonia.FindingsTreatment with remdesivir was not associated with a reduction in mortality in our primary endpoint at 14 days.InterpretationRemdesivir did not significantly improve mortality in this study. The findings are subject to the limitations of an observational study. Balance was achieved for measured baseline factors, but unmeasured confounders may account for observed treatment effect sizes.FundingMedical Research Council UK & National Institute of Health ResearchResearch in contextEvidence before this studyAt the time of designing this study, two clinical trials measuring the efficacy of remdesivir as a therapeutic in treating SARS COV-2 had published results: ACTT-1 and SOLIDARITY. ACTT-1 suggested that for those who required supplemental oxygen but not ventilation at baseline, remdesivir reduced time-to-recovery (rate ratio 1.45, [95% CI: 1.19-1.79]), improved clinical status at 15 days (proportional odds ratio 1.6 [1.2-2.3]), and improved mortality by both 15 days (hazard ratio 0.28 [0.12-0.66]) and 29 days (0.30 [0.14-0.64]) compared with a placebo. SOLIDARITY did not find any evidence of benefit for remdesivir in these same types of patients – it reported on time-to-recovery, and 28-day mortality, compared with the local standard of care.Added value of this studyThis study presents real-world data on the effectiveness of remdesivir use during a non-surge phase of the pandemic in the UK, specifically looking at patients for whom the ACTT-1 trial suggested would be most likely to benefit from remdesivir.Implications of all the available evidenceWe show that during the pandemic, remdesivir was given to a wide demographic of patients in the UK (on average older than those in clinical trials). At 14-days post baseline no reduction in absolute mortality was observed. Propensity score matching achieved balance for measured baseline variables. However as with all observational studies, differences between the groups in unmeasured variables that may influence clinicians but were not recorded in our study, are plausible.