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Remdesivir Reduces Time to Recovery in COVID-19 Patients
April 29, 2020 – An 800-patient randomized, double-blind, placebo-controlled trial conducted by the National Institute of Allergy and Infectious Diseases (NIAID) has apparently met its primary endpoint of reducing the time to recovery in COVID-19 patients, according to the drug’s manufacturer, Gilead Sciences.
The NIAID, part of the US National Institutes of Health, conducted the study at multiple centers around the US. The primary endpoint of time to recovery was predefined as the first day on which the patient satisfies one of the following three categories: 1) Hospitalized, not requiring supplemental oxygen—no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Not hospitalized, no limitations on activities (Adaptive COVID-19 Treatment Trial [ACTT]).
"The press release from Gilead previews data that is soon to be released regarding their drug remdesivir as a treatment option for COVID-19 patients. The announcement states that the primary endpoint of time to recovery was reached in a multisite, placebo-controlled, double-blinded control trial that included 800 COVID-19 patients randomized to 10 days of remdesivir versus placebo. We are awaiting the full data on this study,” said Virginia Brady, MD. Dr. Brady is associate editor for Respiratory Medicine for PracticeUpdate and is with Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center in Boston, MA.
The initial sample size was projected to be 572 subjects to achieve 400 subjects with a "recovered" status (per the primary objective). The primary analysis was to be based on 400 recoveries.
Remdesivir or placebo were administered as a 200-mg IV dose followed by a daily 100-mg dose for a total course of 10 days. No data on secondary endpoints such as specific treatment-related improvements or adverse effects are available at this time.
Gilead Sciences noted in a press release that “Remdesivir is not yet licensed or approved anywhere globally and has not yet been demonstrated to be safe or effective for the treatment of COVID-19.”(Gilead Sciences Statement on Positive Data Emerging From National Institute of Allergy and Infectious Diseases’ Study of Investigational Antiviral Remdesivir for COVID-19.)
In a separate press release, Gilead Sciences reported results from the phase III SIMPLE trial of approximately 400 patients which compared 5-day versus 10-day dosing of remdesivir (Gilead Announces Results From Phase 3 Trial of Investigational Antiviral Remdesivir in Patients With Severe COVID-19). The company reported similar improvement in clinical status for both doses (OR, 0.75; 95% CI, 0.51–1.12] on day 14) without any new safety signals in either arm.
“These study results complement data from the placebo-controlled study of remdesivir conducted by the National Institute for Allergy and Infectious Diseases and help to determine the optimal duration of treatment with remdesivir. The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with our current supply of remdesivir,” said Medad Parsey, MD, PhD, the Chief Medical Officer of Gilead Sciences, in a press release.
The company also reported that earlier treatment, within 10 days of symptom onset, resulted in 62% of patients being discharged from the hospital at 14 days compared with 49% of patients who were treated with remdesivir more than 10 days after symptom onset.
These potentially positive results from remdesivir in COVID-19 are in line with earlier data reported from an unpublished study conducted by the University of Chicago. The study of 125 patients, of whom 113 had severe disease, seemed to show earlier discharge and reduced mortality (Early peek at data on Gilead coronavirus drug suggests patients are responding to treatment, STATNews).
Meanwhile, researchers in China found no benefit in a study that ended early because of insufficient subjects.
Remdesivir is a nucleotide analog that is being investigated as a broad-spectrum antiviral agent against COVID-19 in multiple studies around the world as well as against viral pathogens such as Ebola, Marburg, MERS, and SARS.
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Primary Care
Remdesivir for COVID-19
“Oft expectation fails, and most oft there where most it promises; and oft it hits where hope is coldest, and despair most fits.” William Shakespeare was not a virologist or an expert in clinical trials; he was, however, an astute observer of human nature. As SARS-CoV-2 traverses the world, we are desperate for something that can provide hope. Amidst a wide variety of potential therapeutic agents, one—remdesivir—has finally emerged with some positive findings.
Remdesivir is a nucleotide analogue that inhibits RNA polymerases. It has been shown to be active across several families of viruses, including coronaviruses, and interferes with SARS-CoV-2 in vitro. This antiviral has been used on a compassionate basis for severe COVID-19.[1] In a cohort of 53 patients, with no control group, clinical improvement was noted in 68%.
A randomized, double blind, placebo-controlled trial (RCT) involving 237 patients with severe COVID-19 in Wuhan, China failed to demonstrate significant improvement with remdesivir as compared to placebo (hazard ratio = 1.23 [95% CI: 0.87-1.75]).[2] There was a trend for a more rapid improvement for those initiating treatment within 10 days of symptom onset (hazard ratio = 1.52 [95% CI: 0.95-2.43]).
We have now received results from an interim analysis of a RCT conducted by the National Institute of Allergy and Infectious Diseases. This trial compared remdesivir (200 mg IV on day one, followed by 100 mg IV for the following 9 days) to placebo. Information on the eligibility criteria within the Adaptive COVID-19 Treatment Trial news release is a bit confusing. Better clarity is available through clinicialtrails.gov.[3] Subjects were adults with laboratory-confirmed SAR-CoV-2 and admitted to the hospital with either pneumonia or reduced oxygenation (SpO2 ≤ 94% on room air, requiring supplemental oxygenation, or needing mechanical ventilation). The endpoints were a composite of outcomes demonstrating clinical improvement.
The results are encouraging. The median time to recovery was shortened from 15 days to 11 days (P<0.001) with a 31% reduction in the average time to recovery in those receiving remdesivir. Moreover, there was a non-significant trend for reduction in mortality (11.6% to 8.0%: P=0.059).
In an additional Phase III trial, the manufacturer compared a 10-day and 5-day course of remdesivir. There were no significant differences noted between the treatment times. In a post hoc analyses, however, there was an increase in the proportion (62% vs. 49%) of patients discharged from the hospital within 14 days, if treatment commenced within 10 days of symptom onset.
Some quick take home points for clinicians:
Remdesivir is not a panacea. It does tell us that SARS-CoV-2 can be inhibited and provides a pathway for other agents. It is a step that provides a bit of hope.
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