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Authors: Wang et al.,

Link to paper: https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31022-9.pdf

Journal/ Pre-Print: Lancet

Tags: Diagnostics, Drug discovery/Drug repurpose, Statistics, Therapeutics, Virology

Research Highlights

1. Randomised, double-blind, placebo-controlled trial across 10 hospitals in Hubei, Chine investigating any benefit of treating COVID19 with the anti-viral Remdesivir

2. No significant difference between Remdesivir and placebo groups in terms of clinical improvement or viral load

3. Remdesivir was adequately tolerated, with no new safety concerns

Summary 

Remdesivir is a broad spectrum anti-viral that been shown to inhibit SARS-CoV2 in vitro and in rhesus macaques. This paper reports a randomised, double-blind, placebo-controlled trial into which SARSCoV2-positive adults from 10 hospitals in the Hubei province of China were recruited. No significant difference was observed in the time to clinical recovery (based on reduced requirement for ventilation/oxygen therapy) between the Remdesivir (n=155) and placebo (n=78) groups (hazard ratio 1·23 [95% CI 0·87–1·75]). There was also no difference in respiratory tract viral loads but Remdesivir was adequately tolerated. Unfortunately, this trial was underpowered leaving an open question as to the efficacy of Remdesivir in treating COVID19.

Impact for SARS-CoV2/COVID19 research efforts

Aimed to assess whether Resdesivir treatment can improve clinical outcomes in SARS-CoV2/COVID19 positive individuals, but the study was underpowered to make any definitive conclusions

Study Type

· Clinical Cohort study – randomised, double-blind, placebo-controlled, multicentre trial

Strengths and limitations of the paper

Novelty: First randomised controlled trial of Remdesivir in COVID19 patients

Standing in the field: The anti-viral Remdesivir has been shown to inhibit animal and human SARS-CoV2 in vitro (human nasal and bronchial airway epithelial cells) and in vivo (rhesus macaque), and case studies had reported benefit for COVID19 patients. Results from a phase 3 trial by Gilead published online on 29th April suggest that earlier treatment from Remdesivir (day 5 vs day 10 after symptom onset) had no benefit (https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19). Expansion studies are awaited.

Appropriate statistics: Yes, but power statistics were redundant due to premature study termination as a result of “control of the outbreak in Wuhan and on the basis of the termination criteria specified in the protocol”

Translatability: The study shows no significant effect of Remdesivir treatment on clinical outcomes or viral load in COVID19 patients. Larger validation cohorts are however required, alongside studies to test whether earlier initiation of treatment after symptom onset, a higher dose and/or combination therapies can be efficacious

Main limitations:

· Underpowered and start the treatment quite late in disease progression, both of which the authors acknowledge

· Relatively poor patient matching for age, gender & co-morbidities, but these variables are reported

· Only readouts are oxygen/ventilation requirements and RT-PCR; would have been good to assess changes in other clinical measures, infectious viral levels and/or immunological readouts for example

· Authors have used a 6 point scale for clinical severity, although this has not been validated. A two point decrease was considered improvement, again not validated. Sensitivity done with one point but again no significance found. This creates issues as patients who present as being 1 or 2.

· As the epidemic has been controlled in China there are no eligible patients to enrol.