April 30, 2020

Remdesivir accelerates COVID-19 recovery in US randomised trial, results from another remdesivir trial from China

By Denise Baez

NEW YORK -- April 30, 2020 -- In this DG Alert, we look at results from the first 2 randomised controlled trials (RCTs) of remdesivir for coronavirus disease 2019 (COVID-19).

Preliminary data from the first RCT evaluating remdesivir for hospitalised patients with severe COVID-19 and lung involvement in the United States showed that those who received remdesivir recovered faster than placebo-treated patients. 

The Adaptive COVID-19 Treatment Trial (ACTT) began on February 21, 2020, and is sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

An independent data and safety monitoring board (DSMB) overseeing the trial met on April 27, 2020, to review data from 1,063 patients and share their interim analysis with the study team. Based upon their review of the data, they noted that remdesivir was better than placebo from the perspective of the primary endpoint, which is time to recovery -- defined as being well enough for hospital discharge or returning to normal activity level.

Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo.

Results also suggested a survival benefit, with a mortality rate of 8.0% in the remdesivir group compared with 11.6% in the placebo group (P = 0.059).

More detailed information about the trial results, including more comprehensive data, will be available in a forthcoming report.

Findings from another, but smaller RCT of remdesivir, published in The Lancet, arrived at different conclusions. 

The study, which involved 237 critically ill adults with COVID-19 from 10 hospitals in Wuhan, China, showed that treatment with remdesivir did not speed-up recovery compared with placebo. 

However, the authors cautioned that interpretation of their findings is limited because the study was stopped early by the DSMB because of difficulty recruiting patients after the outbreak in Wuhan was brought under control.

“Unfortunately, our trial found that while safe and adequately tolerated, remdesivir did not provide significant benefits over placebo”, said Bin Cao, MD, China-Japan Friendship Hospital, Beijing, China. “This is not the outcome we hoped for, but we are mindful that we were only able to enrol 237 of the target 453 patients because the COVID-19 outbreak was brought under control in Wuhan. What’s more, restrictions on bed availability resulted in most patients being enrolled later in the disease course, so we were unable to adequately assess whether earlier treatment with remdesivir might have provided clinical benefit.”

Between February 6, 2020, and March 12, 2020, the researchers enrolled 237 adults hospitalised with severe laboratory-confirmed severe COVID-19. To be eligible, patients had to enter the study within 12 days of symptom onset, have pneumonia confirmed by chest imaging, and oxygen saturation of ≤94%. Participants were randomised to daily infusions of remdesivir (n = 158; 200 mg on day 1 followed by 100 mg on days 2 to 10) or placebo infusions (n = 79) for 10 days. One patient in the placebo group withdrew before receiving treatment. Patients were permitted concomitant use of lopinavir/ritonavir, interferons, and corticosteroids.

The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of 2 levels on a 6-point ordinal scale of clinical status (from 1 = discharged to 6 = death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment.

Use of remdesivir was not associated with a difference in time to clinical improvement. Average time to clinical improvement was 21 days for the remdesivir group versus 23 days for the placebo group (hazard ratio [HR] = 1.23; 95% confidence interval [CI], 0.87-1.75). 

Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of ≤10 days (mean 18 days vs 23 days; HR = 1.52; 95% CI, 0.95-2.43). 

Death within 28 days of randomisation was similar between the remdesivir and placebo groups (14% vs 13). However, patients treated with remdesivir within 10 days of illness onset had a lower mortality rate (11% vs 15%), although the difference was not statistically significant. 

Duration of invasive mechanical ventilation was a mean 7 days in the remdesivir group compared with a mean 15.5 days in the placebo group, but the difference was not statistically significant.

Treatment with remdesivir did not result in significant reductions in viral load or detection of the virus in the upper or lower respiratory tract compared with placebo.

“Participants in our trial were less ill, and treated earlier in their disease course, compared with a recent observational study of patients with COVID-19, who received remdesivir on compassionate grounds,” said Ronghui Du, MD, Wuhan Lung Hospital. “Yet, remdesivir did not provide greater benefits in our study population as expected. Ongoing clinical trials of remdesivir will provide important additional information about whether and under what circumstances it may provide benefit.”

The authors noted several limitations to their study, including that stopping early gives insufficient power to detect differences in clinical outcomes, and it did not account for the possible emergence of reduced susceptibility to remdesivir because of a lack of data at the time. They pointed out that the frequent use of corticosteroids in patients in the study might have aided viral production. 

SOURCE: National Institutes of Health, The Lancet