In a large randomized, placebo-controlled study of hospitalized patients with COVID-19, patients who received remdesivir tended to recover days faster than those who received a placebo.
- In a well-designed, gold standard study, patients who received remdesivir recovered an average of four days sooner than patients who did not receive remdesivir.
- Recovering four days faster may seem like a relatively small benefit at the individual level. However, at the population level, this could be important for health systems which can be quickly overwhelmed if patients have to stay in the hospital for an extended period.
- Remdesivir increased the rate of recovery mainly for patients that did not need a ventilator. For sicker patients, the authors did not find a significant effect of remdesivir.
- The study was stopped earlier because of the promising results, so we don’t know whether remdesivir had a statistically significant effect in reducing the number of deaths.
Why is this important?
There is no confirmed treatment for COVID-19. In addition to creating new treatments (which will take many months to be tested and made widely available), the scientific community has turned to existing medicines in the hunt for treatments. Remdesivir has been widely discussed in general media, especially after being positively mentioned by Dr. Anthony Faucci, one of the principal advisors to President Trump on the coronavirus. This study is an important piece of evidence in the search for a treatment. Research Explained previously covered a study from China that did not show a beneficial effect to Remdesivir. Furthermore, the US Food and Drug Administration (FDA) has made remdesivir available under an emergency-use authorization for treatment of severe COVID-19. Since patients are already receiving remdesivir, there is greater importance and urgency in disseminating accurate and evidence-based information about its effects to the medical community.
What did the study do?
Enrolled patients with COVID-19 from over 60 hospitals
The project, called Adaptive COVID-19 Treatment Trial (ACTT-1) is a massive international endeavor, designed and led by the US National Institute of Allergy and Infectious Diseases (NIAID).
At over 60 locations (mostly in the US but also Europe and Asia), adult (≥ 18 years old) patients hospitalized with a lab-confirmed SARS-CoV-2 (COVID-19) infection and evidence of lung infection were considered for the study. Ultimately 1063 patients were enrolled and randomly assigned to either get remdesivir or a placebo (sugar pill, a substance that looks identical but has no effect). Of note, patients with kidney problems were excluded from the study because remdesivir may cause kidney damage.
Patients' health status was ranked on a scale of 1-8, with 1 being non-hospitalized with no limitations of activities, 3 being hospitalized, and 8 being death. At baseline, all patients were between status 4-7.
Large group of patients representing variety of backgrounds
The study population consisted of adult patients hospitalized with COVID-19 and exhibiting lung-related symptoms, with a range of healthcare systems, geographic regions, and co-existing conditions represented. Patients tended to be middle-aged (median: 58.9 years old), male (64.3% overall), and white (53.2%). Other ethnicities were also represented in the study population, with 20.6% African-American, 23.4% Hispanic/Latino, 12.6% Asian, and 0.7% American Indian/Alaska Native.
Possible other treatments used too
Although the study prohibited the use of other experimental treatments or medications, this was only if the participating hospital did not already have a written policy or guideline for existing COVID-19 treatments. What these other treatments were or what portion of the study population was affected by these exceptions is not mentioned in the text of the paper.
Patients received either remdesivir or placebo for 28 days
Researchers randomly assigned patients, taking care to maintain similar numbers of individuals, as well as how sick they were and where they were located, between the two treatment groups. Doses were administered intravenously, with 200 mg given on day 1 and then 100 mg daily on days 2-10 (or until hospital discharge or death). The study was double-blinded, meaning neither the staff nor the patients knew which treatment the patients were being given.
Patient status (on the 1-8 scale) was recorded each day for 28 days, as well as any serious reactions or suspected side effects of the medication. If a patient’s status improved to 3 or below, that patient was considered "recovered". The main research question was how many days it took for patients to reach a "recovered" status.
Double-blind randomized control study
Double-blind randomized controlled studies are considered a gold-standard in terms of testing the effect of a particular treatment, and great care appears to have been taken in the design and execution of this study.
Differences in group severity
A slightly greater percentage of patients placed in the placebo group were severely ill than those in the remdesivir group (28.3% vs. 23.1% of patients with status 7, meaning they were hospitalized and receiving invasive mechanical ventilation). This could have given a slight bias in favor of better outcomes for those in the remdesivir group. The researchers did control for this in their statistical analysis.
Compared improvement in remdesivir group with the placebo group
Researchers used a statistical test to see how remdesivir affected how quickly patient’s recovered while accounting for how sick patients were at their baseline. The days-to-recovery measure was a change from the original plan to use patient status change (i.e. how much a patient’s status on the 1-8 scale changed during the 28 day period), however we do not think this decision is problematic as they chose a reasonable outcome assessment.
Standard statistical approach
This is a standard statistical approach to looking at survival trends in clinical trials. As a metric, how long it takes to recover makes practical sense. Furthermore, the study was designed to achieve 85% statistical power to detect if a treatment is effective -- generally, 80% power is considered a minimum standard. For comparison, an earlier remdesivir study we reviewed only had a statistical power of 58%, casting some doubt onto that study’s ability to see an effect if one existed.
Limited follow up
One issue with this design is at the end of each patient’s 28-day trial period, unless that patient recovered, their final status (failure to recover, death) is unknown. Furthermore, not all patients had completed the study by the time the preliminary report was released.
Patients who received remdesivir recovered faster with similar side effects
Remdesivir Placebo Days to Recover 11 15 Mortality 7.1% 11.9% Adverse Events 21.1% 27.0%
This is good news for patients and potentially great news for hospitals and other systems whose resources can be quickly overwhelmed if a patients have to be hospitalized for an extended period. However, this was primarily for patients who required oxygen but not ventilation (status 5). Generally, it did not appear remdesivir carried a greater risk of side effects compared to the placebo.
There was not a statistically significant difference in the death rate between patients who received Remdesivir as compared to the placebo. This may be because the study was stopped early before it had recruited enough patients and because we still don’t know the final outcome after 28 days for some of the patients in the study.
The researchers arrived at a suitable conclusion based on the data they had obtained.
Trial stopped early
This study was stopped early because the researchers saw a significant benefit in how quickly patients were recovering in the remdesivir group and felt it would be unethical to keep giving the placebo to patients. This recommendation was made by the Data and Safety Monitoring Board (DSMB) which regularly reviews the data (independent of the research team) to ensure the study is running safely. Unfortunately, at the time the study was stopped, there was not a statistically significant difference in the death rate between the treatment and placebo group. This decision to stop the study early has been controversial.