Compassionate Use of Remdesivir to Treat Patients with Severe Covid-19

Table of Content

The results of this small-scale study demonstrated a significant clinical improvement amongst patients hospitalized for COVID-19 when they were treated with compassionate use remdesivir for 10 days.

Background

Covid-19; the illness caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) is already overwhelming the health care system globally. In absence of a proven effective therapy, the current management of COVID-19 relies completely on supportive care, including invasive and noninvasive oxygen support and treatment with antibiotics. Many patients have also received off-label or compassionate-use therapies such as; antiretrovirals, antiparasitic agents, antiinflammatory compounds, and convalescent plasma.  Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2.

Aim

To describe clinical outcomes in a cohort of patients hospitalized for severe Covid-19 while being treated with remdesivir on a compassionate-use basis.

Patient Profile

  • Patients with confirmed SARS-CoV-2 infection with an oxygen saturation ≤ 94% while they were breathing ambient air or receiving oxygen support (n=61, age 23-82 years)
  • All patients also had creatinine clearance >30 ml/min and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels less than 5 times the upper limit of the normal range

Methods

Study Design

  • Open-label, multinational (conducted in the US, Europe and Japan) study

Treatment Strategy

  • Patients were treated with a 10-day course of remdesivir as follows:
    • Day 1: Loading dose- 200 mg administered intravenously
    • Day 2-10: 100 mg/day

Assessments

  • Daily assessment of serum creatinine, ALT, AST from day 1 of treatment initiation through day 10

Follow-up

  • At least 28 days after initiating remdesivir treatment or until discharge or death

Outcomes

Primary Outcomes

  • Changes in oxygen support requirement
  • Hospital discharge
  • Adverse events (AEs; including those leading to treatment discontinuation)
  • Serious adverse events (SAE)
  • Death

Secondary Outcomes

  • Proportion of patients with clinical improvement, defined as; live discharge from hospital, a minimum of 2 point decrease from baseline on a modified ordinal scale. This six-point scale consists of the following categories:
  1. Not hospitalized
  2. Hospitalized, not requiring supplemental oxygen
  3. Hospitalized, requiring supplemental oxygen
  4. Hospitalized, requiring high-flow nasal oxygen therapy, non-invasive mechanical ventilation or both
  5. Hospitalized, requiring invasive mechanical ventilation, ECMO, or both
  6. Death

Results

  • Eight out of 61 patients were excluded from the trial due to lack of data or dosing error (n=1). Of the 53 patients included in this analysis, 75% (n=40) received the full ten-day course of remdesivir, 19% (n=19) received 5 to 9 days of treatment and 6% (n=3) received less than 5 days of treatment.
  • Median age of the study population was 64 years and three-quarters of them were men (n=40)
  • Of the patients included in the analysis, 57% (n=30) were receiving mechanical ventilation and 8% (n=4) were receiving ECMO.
  • Patients receiving invasive ventilation, rather than those receiving non-invasive oxygen support at baseline, were older (median age; 67 vs. 53 years), were more likely to be men (79% vs. 68%), had a higher median serum ALT (48 U/L vs. 27 U/L) and creatinine (0.90 mg/dL vs. 0.79 mg/dL).
  • Patients receiving invasive ventilation vs. those receiving non-invasive oxygen support, also had a higher prevalence of comorbid conditions including hypertension (26% vs. 21%), hyperlipidemia (18% vs. 0%) and asthma (15% vs. 5%).
  • The median duration of symptoms before initiating remdesivir treatment was 12 days and did not differ significantly amongst the patients receiving invasive or non-invasive ventilation
  • Median follow-up period of the study was 18 days. After receiving the first dose of remdesivir, 68% patients (n=36) experienced an improvement in oxygen-support class, while 15% (n=8) exhibited worsening.
  • Notably, 17/30 (57%) who were receiving mechanical ventilation were extubated and 3/4 (75%) receiving ECMO stopped receiving it all (all of them were alive at the last follow-up).
  • Of the entire study population, 47% (n=25) were discharged, while 13% (n=7) died.
  • As per a Kaplan Meier analysis, the cumulative incidence of clinical improvement at 28 days was 84%.
  • Fewer patients receiving invasive ventilation exhibited clinical improvement when compared with patients receiving non-invasive support [hazard ratio (HR) for improvement; 0.33, 95% confidence interval (CI). 0.16-0.68).
  • Fewer patients aged ≥70 years exhibited clinical improvement as compared with those younger than 50 years (HR, 0.29; 95% CI, 0.11 to 0.74).
  • Gender, region of enrollment, presence of comorbidity and duration of symptoms before initiation of remdesivir treatment were not associated with clinical improvement.
  • Overall, 13% patients died, with 18% (6/34) deaths amongst patients receiving invasive ventilation vs. 5% (1/9) deaths amongst those receiving non-invasive oxygen support. The median interval between remdesivir initiation and death was 15 days.
  • Patients aged ≥70 years had a higher risk of death as compared with patients younger than 70 years (HR, 11.34; 95% CI, 1.36 to 94.17). Patients with higher serum creatinine at baseline also had higher risk of death (HR per mg/dL, 1.91; 95% CI, 1.22 to 2.99). Patients receiving invasive ventilation also had a higher risk of death as compared with those receiving noninvasive oxygen support (HR, 2.78; 95% CI, 0.33 to 23.19).
  • Adverse events during follow-up were reported by 60% of the study population (n=32), the most common AEs were; increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. In general, the incidence of AEs was more common in patients receiving invasive ventilation.
  • Serious adverse events were reported by 23% patients, the most common SAEs were; multiple organ dysfunction syndrome, septic shock, acute kidney injury, and hypotension.

Conclusions

  • Amongst patients hospitalized for severe Covid-19 and being treated with compassionate-use remdesivir for 10 days, 68% patients exhibited clinical improvement, while 13% patients died during a median follow-up of 18 days.
  • Results from ongoing randomized, placebo controlled trials on remdesivir therapy would enhance the current understanding on the efficacy of remdesivir.

New Engl J Med. Apr 10, 2020 (Published Online); DOI: 10.1056/NEJMoa2007016.