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 [ambient air, low flow oxygen, nasal high-flow oxygen, non-invasive positive pressure ventilation (NIPPV), invasive mechanical ventilation, and extracorporeal membrane oxygenation (ECMO)]
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:

Not hospitalized
Hospitalized, not requiring supplemental oxygen
Hospitalized, requiring supplemental oxygen
Hospitalized, requiring high-flow nasal oxygen therapy, non-invasive mechanical ventilation or both
Hospitalized, requiring invasive mechanical ventilation, ECMO, or both
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.