Remdesivir is the only therapy in the United States approved, under emergency use status, as a treatment for COVID-19 along with the just announced convalescent plasma. Referred to as not a ‘knockout drug’ by Dr. Anthony Fauci, Director of the National Institutes of Allergy and Infectious Diseases (NIAID), recently published outcomes from a multi-national and multi-academic medical center study had the potential to help turn what is frankly a question mark about the investigational drug into an exclamation point of confidence. The hope was that the antiviral offers a clear and compelling benefit to patients hospitalized with moderate COVID-19 pneumonia. Held at 105 hospitals, the study team treated 533 coronavirus patients with moderate pneumonia and randomized them to receive either remdesivir for 5 or 10 days or the standard of care from March 15 to April 18, 2020. While the drug showed a statistically significant benefit after a five-day course treatment, the group receiving the 10-day course of remdesivir received no statistically significant benefit in clinical status as compared with the standard of care at 11 days after onset of treatment. This drug now has produced mixed results in different randomized controlled studies, and although considerable real world data points to a regimen that can certainly help treat COVID-19 patients, Dr. Fauci’s declaration unfortunately was reaffirmed based on these outcomes.
Although after a five-day course, the patient group randomized to remdesivir had a statistically significant difference in clinical status as compared to standard of care; however, the authors report this difference was of uncertain clinical importance and frankly, perplexing if one considers that the whole point is to ensure improved clinical status by day 10 (that is to see progressive improvements)—which didn’t turn out to be the case. The investigative team, “GS-US-540-5774 Investigators” represented nations from three continents (North America, Europe and Asia). The study’s corresponding author was Diana M. Brainard, MD, Gilead Sciences.
Titled “A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734) in Participants with Moderate COVID-19 Compared to Standard of Care Treatment,” the sponsor (Gilead) and investigative team sought in this Phase 3 study to evaluate the efficacy of 2 remdesivir (RDV) regimens compared to standard of care with respect to clinical status assessed by a 7-point ordinal scale on Day 11.
The intervention included patients randomized in a 1:1:1 ration in order to receive a 10-day course of remdesivir (n=197), a 5-day course of remdesivir (n=199), or standard of care (n=200). The study drug was dosed intravenously at 200 mg on day 1 followed by 100mg/d.
The team’s established primary endpoint represented the odds of improvement in ordinal scale between the treatment groups. As described in the study disclosure, the ordinal scale is an assessment of the clinical status at a given day. During each day, the study team recorded the worst score from the previous day. The scale is as follows:
|2||Hospitalized, on invasive mechanical ventilation or ECMO|
|3||Hospitalized, on non-invasive ventilation or high flow oxygen devices|
|4||Hospitalized, requiring low flow supplemental oxygen|
|5||Hospitalized, non-requiring supplemental oxygen—requires ongoing medical care|
|6||Hospitalized, not requiring supplemental oxygen—no need for med care other than Remdesivir|
Again the study was conducted at 105 hospitals in three continents including North America (USA), Europe and Asia. Specific trial site organizations can be viewed here.
The study results were published in JAMA Network and the outcomes were overall perplexing at best and disappointing for some that would like to see, under controlled conditions, clear and compelling outcomes after a 10-day course of treatment. Of the 596 COVID-19 patients randomized, a total of 584 subjects started the study receiving the investigational drug or alternatively, the standard of care, and had a media age of 57 and a considerable number other diseases (e.g. cardiovascular disease, hypertension, diabetes, etc.). A total of 533 patients, 91% of the total actually completed the clinical trial. Showing promise at the five day mark, the patients given remdesivir had statistically significantly higher odds of a better clinical status distribution than the patients receiving the standard of care.
What matters in all of this is that patients progress and get better with the progression of time. The study that led to the U.S. Food and Drug Administration (FDA) approval for emergency use revealed that over a couple-week period, the use of remdesivir led to a shortening of hospitalization time—a benefit, albeit not a huge one. In this study, after 11 days the clinical status distribution for the 10-day remdesivir and standard of care groups was not significantly different (P=.18 by Wilcoxon rank sum test).
By the 28th day, a total of 9 patients died including 2 in the 5-day remdesivir group, 3 in the 10-day remdesivir group, and 4 in the standard of care group. As reported by the authors who used the Kaplan-Meier for death estimates from any cause at 28 days of treatment, these included 1% (95% CI, 0.0% to 2.6%) in the 5-day remdesivir group (log-rank P = 0.43 vs standard care), 2% (95% CI, 0.0% to 3.6%) in the 10-day remdesivir group (log-rank P = 0.72 vs standard care), and 2% (95% CI, 0.1% to 4.1%) in the group receiving standard care.
Here is a link for detailed review and analysis to the published study results and a deeper review.
Real World Data Points
During the pandemic, TrialSite covered several situations, including discussions with patient family members, where remdesivir appeared to have not only compressed COVID-19 infection period but also actually saved lives, such as the incident at Stanford Hospital. There are many real world accounts of the drug helping COVID-19 patients, however when the drug is studied under controlled conditions, it hasn’t produced consistent and compelling results. That doesn’t mean the drug can’t or doesn’t help. But it does reveal that the evidence is not strong for the antiviral to be classified as a true standard of care.
This study protocol was authored early on in the pandemic when a majority of the cases were limited to Asia and the overall understanding of the new disease was limited to a case series. Hence a primary endpoint change occurred while it was based on an open-label design, which potentially can lead to biases in patient care and reporting. Due to urgency of the moment, viral outcomes (e.g. effect of remdesivir on SARS-CoV-2 viral load) were not measured. The study team also reported that the study had limitations when factoring in laboratory parameters and the ordinal scale basis for endpoint wasn’t ideal for detecting difference in patients with moderate COVID-19.
Study Design Optimization?
Perhaps, positions some of the study investigators, such as Erin McCreary, Pharm D, and Derek Angus, MD, MPH, University of Pittsburgh School of Medicine, various results from differing randomized controlled studies could at least partially be correlated to actual study design. Maybe, authors suggest, more precision should be in order to better tailor the study drug to the optimal patient profile. That undoubtedly requires considerable more research and with other promising approaches to treating COVID-19, the value-added use of precious resources must be considered for such research endeavors. More on this topic can read in a JAMA commentary accompanying the study.