麻豆传媒

Remdesivir, an investigational antiviral treatment for COVID-19, showed clinical benefit in a randomized trial conducted by the National Institute of Allergy and Infectious Diseases (NIAID), manufacturer .

An interim analysis of the Adaptive COVID-19 Treatment Trial (ACTT) found the drug had a 31% faster time to recovery versus placebo (median 11 days vs 15 days, respectively, P<0.001). It also trended toward a survival benefit (8.0% mortality rate in remdesivir group vs 11.6% in placebo, P=0.059), the NIAID said in a statement.

Time to recovery is a metric often used in influenza trials, the agency noted, and was defined as hospital discharge or returning to normal activity level. An independent data and safety monitoring board performed this interim analysis on April 27.

NIAID director Anthony Fauci, MD, and added, "this will be the standard of care," according to CNBC.

White House pool reports of additional comments by Fauci indicated full results have been submitted to a peer-reviewed journal.

The trial included repatriated citizens from the Diamond Princess cruise ship, the when announcing the study, and the study ultimately was comprised of 68 sites, including 47 in the U.S. and 21 in Europe and Asia. Hospitalized patients with COVID-19 and evidence of lung involvement would receive either 200 mg of remdesivir on the first day, followed by 100 mg for up to 10 days total, or placebo treatment in equal amounts.

Participants were scheduled to be evaluated at day 15 from both groups for clinical benefit, according to the release, and scored on a seven-point scale that ranged from "fully recovered" to "death." This scale would be re-evaluated after reviewing data from the first 100 patients, the agency said.

In a separate statement on Wednesday, Gilead also , an international study comparing a 5-day to a 10-day course of remdesivir in severe COVID-19 but without a no-remdesivir control group. It found no significant difference in clinical improvement between the 5-day and the 10-day group (OR 0.75, 95% CI 0.51-1.12) on day 14, the company said.

A shorter regimen could enable more patients to be treated with the drug, Gilead explained.

Clinical improvement was defined as an improvement of two or more points on a pre-determined seven-point scale. Eligible patients had evidence of pneumonia and reduced oxygen levels, but did not require mechanical ventilation, the manufacturer added. Clinical recovery was defined as patients no longer needing oxygen support and medical care or being discharged from the hospital.

No significant differences were observed in time to clinical improvement between groups (10 days for 5-day group vs 11 days for 10-day group), and more than half of patients in both groups were discharged from the hospital by day 14, the manufacturer said. By day 14, about 65% of the 5-day group and 54% of the 10-day group achieved clinical recovery.

An exploratory analysis found improved outcomes for patients receiving the treatment within 10 days of symptom onset compared with those treated more than 10 days after symptom onset.

"While additional data are still needed, these results help to bring a clearer understanding of how treatment with remdesivir may be optimized, if proven safe and effective," said one of the study's lead investigators, Aruna Subramanian, MD, of Stanford University School of Medicine, in Gilead's statement.

The manufacturer also noted no new safety signals with either treatment group. Nausea and acute respiratory failure were the most common adverse events occurring in more than 10% of patients. Notably, about 7% of patients had grade 3 or higher alanine aminotransferase elevations, and 3% discontinued treatment due to elevated liver enzymes.

Gilead noted a second SIMPLE trial is evaluating remdesivir dosing in patients with moderate COVID-19 versus standard of care, with results from the first 600 patients expected at the end of May.

Full Results of Chinese Trial Show 'Inconclusive Findings'

Hopes for remdesivir had dimmed somewhat last week, when data released accidentally by the World Health Organization from a study of severe COVID-19 patients in China indicated no clinical benefit with the drug, though with important methodological caveats.

Now, were published on Wednesday by Bin Cao, MD, of the National Clinical Research Center for Respiratory Diseases in China, and colleagues in The Lancet.

Because it was underpowered, argued John David Norrie, PhD, of Edinburgh Clinical Trials Unit in Scotland, in an accompanying editorial.

"The study has not shown a statistically significant finding that confirms a remdesivir treatment benefit of at least the minimally clinically important difference, nor has it ruled such a benefit out," he wrote. "The minimally clinically important difference ... will depend on a complex reckoning of evidence for effectiveness, safety, acceptability, access, and cost."

As previously noted, the trial intended to enroll 453 patients beginning on February 6, but was stopped early because patients meeting eligibility criteria became too difficult to find after March 12. Cao and colleagues managed to enroll just 237 adult patients from Wuhan with severe COVID-19 infection.

Patients were assigned 2:1 to remdesivir or placebo for 10 days. The primary endpoint was time to clinical improvement within 28 days of randomization, defined as a two-point decline on a six-point ordinal scale of clinical status, from "discharged" to "death," the authors said.

They noted more patients with hypertension, diabetes, or coronary heart disease in the remdesivir group, and more patients in the control group had been symptomatic for 10 days or less. More remdesivir patients reported a respiratory rate of more than 24 breaths per minute.

Hypertension was the most common comorbidity in both groups, followed by diabetes and coronary heart disease. Median time from symptom onset to treatment was 10 days.

As previously reported, an intention-to-treat analysis found no significant difference in time to clinical improvement (HR 1.23, 95% CI 0.87-1.75). Norrie pointed out that the researchers had hoped to show a treatment effect hazard ratio of 1.40, or a median time to clinical improvement of 15 days versus 21 days for placebo.

Similar to the SIMPLE trial, Cao and colleagues did find a "numerically faster" time to symptom improvement in the remdesivir group over controls when the drug was administered within 10 days of symptom onset, though this was not statistically significant (median 23 days vs 18 days, respectively, HR 1.52, 95% CI 0.95-2.43).

Norrie seized upon that point, writing that "the authors give prominence to the 10 days or less subgroup," but that these hypotheses require further research.

"As well as being vigilant against overinterpretation, we need to ensure that hypotheses generated in efficacy-based trials, even in subgroups, are confirmed or refuted in subsequent adequately powered trials or meta-analyses," he wrote.

Cao and colleagues found no difference in 28-day mortality rates between groups (14% vs 13%), differences in duration of invasive mechanical ventilation, hospital length of stay, or time to viral clearance.

Two-thirds of patients experienced adverse events, with constipation, hypoalbuminemia, hypokalemia, and anemia common in both groups. The control group had a higher proportion of serious adverse events compared with remdesivir, although more patients in the remdesivir group discontinued treatment due to adverse events. Seven of 18 patients in the remdesivir group who discontinued treatment did so because of respiratory failure or acute respiratory distress syndrome, i.e., continued or worsening COVID-19 symptoms.

Ultimately, Norrie emphasized "pandemic trials" will often be underpowered, with "each individual study at heightened risk of being incomplete," and suggested pooling data across "several underpowered, but high quality" studies to potentially tease out the best results.

Comment