Key Trials

Introduction

The ongoing pandemic of acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infections has been a significant cause of mortality worldwide. Although most of the infections are self-limiting, 15% develop pneumonia requiring supplemental oxygen treatment and additional 5% may progress to critical illness requiring ventilatory support for weeks. Data shows that mortality rate of COVID-19 patients requiring invasive mechanical ventilation is 50%. Remdesivir (GS-5734), a nucleoside analogue prodrug, inhibits all human and animal coronaviruses, including SARS-CoV-2 in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. However, the clinical and antiviral efficacy of remdesivir in COVID-19 needs to be explored.

Aim

This study assessed the efficacy and safety of intravenous remdesivir in patients with severe COVID-19.

Methods

Study Design

• Multicenter, randomized, placebo-controlled, double-blind trial

Inclusion Criteria

• Adults aged ≥18 years admitted to hospital with laboratory-confirmed SARS-CoV-2 infection 
• An interval from symptom onset to enrolment of 12 days or less
• Oxygen saturation of 94% or less on room air or
• Ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less
• Radiologically confirmed pneumonia

Exclusion Criteria

• Pregnancy or breast feeding
• Hepatic cirrhosis
• Alanine aminotransferase or aspartate aminotransferase more than five times the upper limit of normal
• Known severe renal impairment (estimated glomerular filtration rate <30 mL/min per 1·73 m²) or receipt of continuous renal replacement therapy
• Haemodialysis, or peritoneal dialysis

Treatment Strategy

• Patients were randomized in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days
• Concomitant use of lopinavir–ritonavir, interferons, and corticosteroids was permitted 
• Primary efficacy analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who initiated treatment.

Endpoints

• Time to clinical improvement up to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first
• The six-point scale was as follows
  
  • Death=6
  • Hospital admission for extracorporeal membrane oxygenation or mechanical ventilation=5
  • Hospital admission for non-invasive ventilation or high-flow oxygen therapy=4
  • Hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)=3
  • Hospital admission but not requiring oxygen therapy=2
  • Discharged or having reached discharge criteria (defined as clinical recovery—ie, normalisation of pyrexia, respiratory rate <24 breaths per minute, saturation of peripheral oxygen >94% on room air, and relief of cough, all maintained for at least 72 h)=1
• Proportions of patients in each category of the six-point scale at day 7, 14, and 28 after randomization
• All-cause mortality at day 28
• Frequency of invasive mechanical ventilation
• Duration of oxygen therapy
• Duration of hospital admission
• Proportion of patients with nosocomial infection
• Proportions of patients with viral RNA detected and viral RNA load
• Incidence of treatment-emergent adverse events, serious adverse events, and premature discontinuations of study drug

Results

• The remdesivir and placebo groups included 158 and 79 patients respectively; 1 patient in the placebo group who withdrew after randomization was not included in the ITT population
• Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23) as seen in table 1.
• Remdesivir group demonstrated a numerically faster time to clinical improvement among patients receiving treatment within 10 days of symptom onset (hazard ratio 1·52), although statistically insignificant as seen in table 1.
• 28-day mortality rate was similar in both groups (difference 1.1%)
• The incidence of adverse events was 66% and 64% in the remdesivir and placebo groups respectively
• Discontinuations due to adverse events were 12% vs 5% in the remdesivir and placebo recipients.

• The viral load decreased similarly in both the groups
• Cumulative rate of undetectable viral RNA by day 28 was 78% and the negative proportion was similar in both groups
• The most common adverse events (AEs) in the remdesivir group were constipation, hypoalbuminaemia, hypokalaemia, anaemia, thrombocytopenia, and increased total bilirubin
• The most common AEs in the placebo group were hypoalbuminaemia, constipation, anaemia, hypokalaemia, increased aspartate aminotransferase, increased blood lipids, and increased total bilirubin

Conclusion

• The results did not show statistically significant clinical benefits with the use of remdesivir in patients hospitalized for severe COVID-19
• Nevertheless, there was a numerical reduction in time to clinical improvement in patients treated earlier with remdesivir, confirmation of these findings in large populations is warranted
• Remdesivir was well tolerated with no new safety concerns identified.

Lancet. 2020 May 16;395(10236):1569-1578. Doi: 10.1016/S0140-6736(20)31022-9.