Early Intervention with Remdesivir Associated with Clinical Improvement in Severe COVID-19 Patients

Table of Content

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.Remdesivir was well tolerated with no new safety concerns identified.

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.
Table 1. Outcomes in ITT population

 

Remdesivir group

Placebo group

Time to clinical improvement (days)

21

23

Time to clinical improvement among patients receiving treatment within 10 days of symptom onset (days)

18

23

28-day mortality rate

14%

13%

Incidence of TEAE

66%

64%

Discontinuations

12%

5%

Incidence of serious AEs

18%

26%

  • 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.