Compassionate Use of Remdesivir for Patients with Severe Covid-19

Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19 [published online ahead of print, 2020 Apr 10]. N Engl J Med. 2020;NEJMoa2007016. doi:10.1056/NEJMoa2007016

Review written by:

Robert Parry, edited by Naomi Ali

Yellow - A well-known study published in NEJM with some of the first positive results for treating COVID-19, but the study is limited in its validity and generalizability.

Remdesivir, a prodrug for an analogue of ATP, has broad spectrum antiviral activity, including in vitro success against SARS-CoV-2.  Remdesivir has previously been demonstrated  to have a favorable treatment safety profile in 500 patients.


Type of Study: Single-arm prospective open-label study


Patient Inclusion Criteria:

  • confirmed SARS-CoV-2 infection by RT-PCR

  • Receiving oxygen support or SaO2 < 94% on room air

  • eGFR > 30 mL / minute

  • AST and ALT < 5 times the upper limit of normal

  • an agreement to not use other investigational agents for COVID-19

Treatment Regimen: A 10-day remdesivir course, with a 200 mg IV loading dose on day 1 followed by 100 mg IV for the next 9 days. Of the 53 patients enrolled, 40 received the full course while 13 received only a partial course for various reasons. Supportive care was left to the discretion of the clinician, and patients were followed for 28 days, until discharge, or until death.


Baseline Characteristics: Patients were enrolled from 9 different countries. The median age was 64 years and 75% of patients were men. Patients showed symptoms for a median of 12 days before beginning remdesivir. At baseline, 64% were previously receiving mechanical ventilation for a median of 2 days before beginning remdesivir treatment.


Improvement in Patient Status: With a median follow up of 18 days after initiating remdesivir, 68% showed improvement in oxygen support category while only 15% showed worsening (O2 support categories were death, invasive ventilation, non-invasive ventilation, low-flow oxygen, ambient air, and discharged).

Cumulative incidence of clinical improvement was assessed at 28 days of follow-up using a WHO-based six-point ordinal scale (1, not hospitalized; 2, hospitalized, not requiring supplemental oxygen; 3, hospitalized, requiring supplemental oxygen; 4, hospitalized, requiring nasal high-flow oxy- gen therapy, noninvasive mechanical ventila- tion, or both; 5, hospitalized, requiring invasive mechanical ventilation, ECMO, or both; and 6, death). For study purposes clinical improvement was defined as hospital discharge or a reduction of at least 2 points in the ordinal scale. At 28 days of follow-up, 84% of patients achieved clinical improvement. Clinical improvement was less frequent in patients receiving invasive ventilation and those 70 years of age or older.


Mortality: There was 13% mortality overall. Patients receiving invasive ventilation, patients who were 70 years of age or older, and patients with higher baseline creatinine had a greater risk of death. With no control cohort, the authors compare mortality rates from other studies. In a recent RCT for lopinavir-ritonavir by Cao et al., the 28-day mortality was 22% with a smaller fraction (0.5%) of patients receiving invasive ventilation at baseline. In other case series and cohort studies mostly conducted in China, mortality rates  range from 17-78%. Baseline patient characteristics, among other important factors for comparison, are not mentioned for these referenced studies.


Safety: 60% of patients reported an adverse event, with the most common being increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. 23% of patients reported a serious adverse event, which included acute kidney injury, septic shock, hypotension, and multiple-organ-dysfunction syndrome. Adverse events were more common in patients receiving invasive ventilation.

Review Notes
 

Strengths:

  • While a direct comparison should not be made, and certainly nothing conclusive can be said, the mortality rate of 13% associated with remdesivir compared to higher mortality rates in other COVID-19 studies does provide hope for future success with remdesivir in randomized controlled clinical trials

  • Expands information on the clinical safety profile of remdesivir

Limitations:

  • This is a one-arm study:

  • Endpoints of clinical improvement and reduction in oxygen support  have no control group for a reference point, and thus very little can be inferred about remdesivir’s true efficacy.

  • The authors mention mortality rates from other studies as a reference point. However, many factors can differ between studies (supportive care given, inclusion and exclusion criteria, patient baseline characteristics, duration of follow-up for the enrolled patients, etc.). More methodologically rigorous clinical trials are needed to draw definitive conclusions of remdesivir’s efficacy.

  • The trial is not only open-label, but physicians had to submit a request to Gilead Sciences to use remdesivir. The clinician must have had some underlying reason initially to seek out remdesivir specifically, indicating that selection bias and confirmation bias could confound the results.

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