Covid-19: NIAID Unblinds Remdesivir Trial on Positive, Preliminary Results

Peer-reviewed results from the National Institute of Allergy and Infectious Diseases’ (NIAID) placebo-controlled trial of remdesivir in hospitalized Covid-19 patients appeared to confirm that treatment with this novel agent can shorten time to recovery.

However, the trial is ongoing, and the results are considered preliminary. Gilead Sciences, maker of the drug, released topline results from a similar trial in late April, which prompted the NIAID to go public with its results, but the May 22 publication in the New England Journal of Medicine offers the first peer-reviewed look at the data.

“This benefit was seen in the number of days to recovery (median, 11 days, as compared with 15; rate ratio for recovery, 1.32 [95% CI, 1.12 to 1.55]) and in recovery according to the ordinal scale score at day 15 (odds ratio, 1.50; 95% CI, 1.18 to 1.91),” John Beigel, MD, from NIAID, and colleagues wrote. “Given the strength of the results about remdesivir, these findings were deemed to be of immediate importance for the care of patients still participating in the trial as well as for those outside the trial who might benefit from treatment with remdesivir.”

The study authors’ Adaptive Covid-19 Trial (ACTT-1) is a double-blind, randomized, placebo-controlled trial that is looking at the treatment of hospitalized patients with Covid-19 who have evidence of lower respiratory tract involvement. They were randomized 1:1 to either intravenous remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days.

Time to recovery or hospitalization only for infection control was the defined primary outcome of the trial. The patients were assessed on an eight-category ordinal scale — 1, not hospitalized, no activity limitations; 2, not hospitalized, limitation of activities, home oxygen required, or both; 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (hospitalized for infection-control only); 4, hospitalized, not requiring supplemental oxygen (Covid-19-related or other medical conditions); 5, hospitalized with supplemental oxygen; 6, hospitalized with non-invasive ventilation or high-flow oxygen devices; 7, hospitalized, with invasive mechanical ventilation of ECMO; 8, death.

Patients were enrolled this year from Feb. 21 through April 19 at 60 trial sites and 13 subsites in the U.S., Denmark, U.K, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore.

There were 1,107 patients assessed for eligibility, and 1,063 patients were randomized — 541 to remdesivir and 522 to placebo. The preliminary results are for 1,059 of these patients.

“The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12),” Beigel and co-authors wrote. “Nine hundred forty-three (88.7%) patients had severe disease at enrollment…”

As mentioned above, the median time to recovery in the remdesivir group was 11 days compared with 15 days for those in the placebo group. “Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84); among patients with a baseline score of 4 (127 patients) and those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7; 272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42),” Beigel and colleagues wrote.

The study authors noted that remdesivir’s benefit was most notable in patients who had a baseline ordinal score of 5 (requiring oxygen), a finding they noted was “most likely due to the larger sample size in this category.” However, they noted that “[c]onfidence intervals for baseline ordinal scores of 4 (not receiving oxygen), 6 (receiving high-flow oxygen), and 7 (receiving ECMO or mechanical ventilation) are wide. We note that the median recovery time for patients in category 7 could not be estimated, which suggests that the follow-up time may have been too short to evaluate this subgroup.”

Most of the patients in the trial were white (53.2%), 20.6% were black, 12.6% were Asian, 23.4% were Hispanic of Latino, and 13.6% were either not reported or designated as other. Most patients (52.1%) had two or more comorbidities, and 27% had one. The most common co-exiting conditions were hypertension (49.6%), obesity (37%), and type 2 diabetes (29.7%).

There were serious adverse events in 114 (21.1%) of the patients in the remdesivir group and in 141 (27%) in the placebo group. One-hundred fifty-six (28.8%) patients in the remdesivir group had grade 3 or 4 adverse events.

“There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients). Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group,” the study authors wrote. “No deaths were considered to be related to treatment assignment, as judged by the site investigators.” At day 14, there were 32 deaths in the remdesivir group and 54 in the placebo group.

Beigel and colleagues noted that they will continue to conduct more analyses after all the patients have completed 28 days of follow-up, which may shed light on the critical subgroup.

“Our findings highlight the need to identify Covid-19 cases and start antiviral treatment before the pulmonary disease progresses to require mechanical ventilation,” they noted.

“The primary outcome of the current trial was changed with protocol version 3 on April 2, 2020, from a comparison of the eight-category ordinal scale scores on day 15 to a comparison of time to recovery up to day 29,” the study authors wrote.

They also noted several challenges encountered with the multi-nation trial — it was implemented when travel restrictions were in place as well as hospital restrictions concerning non-essential personnel. “Training, site initiation visits, and monitoring visits often were performed remotely,” they noted. “Research staff were often assigned other clinical duties and staff illnesses strained research resources.” Lack of PPE and trial related supplies were issues at some sites.

Remdesivir is currently available through an FDA emergency use authorization (EUA) for treatment of children and adults with severe Covid-19. And, while Beigel and colleagues write that these preliminary results support the use of remdesivir for the treatment of patients hospitalized with Covid-19, “…given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient,” they added.

1. Preliminary results of a randomized, double-blind, placebo-controlled trial by the NIAID shows that remdesivir resulted in a shorter time to recovery than placebo.

2. Be aware that this trial was unblinded and the results made public so those still participating in the trial as well as others might benefit from treatment.

Candace Hoffmann, Managing Editor, BreakingMED™

Cat ID: 190

Topic ID: 79,190,254,930,287,791,932,570,730,933,190,520,926,192,927,151,928,925,934