No survival or other benefit for Remdesivir in COVID-19

There were no significant differences in mortality for hospitalized COVID-19 patients who received the antiviral agent remdesivir (Veklury) compared to regular care, an interim analysis of a large World Health Organization (WHO) study found.

Mortality rates at 28 days hardly differed (rate ratio 0.95, 95% CI 0.81-1.11, P= 0.50), the researchers from the WHO Solidarity Trials Consortium reported in a preprint published in medRxiv.

Furthermore, no advantages were seen with remdesivir on secondary outcomes (onset of ventilation and length of hospital stay).

“A pragmatic approach to doing research in a crisis. There’s a lot to learn about how they did it,” medRxiv co-founder Harlan Krumholz, MD, of Yale University, tweeted about the study.

Remdesivir is currently recommended as a first-line treatment in the NIH clinical guidelines for hospitalized patients with COVID-19 requiring supplemental oxygen.

When asked for his opinion, Matthew Spinelli, MD, of the University of California, San Francisco, cautioned that Solidarity involved many different settings around the world, with “heterogeneous approaches to inpatient care for COVID-19” and Therefore, trials conducted by the NIH may have more “external validity” for their guidelines.

“I think the guidelines will need to be revised to take Solidaridad into account given its size and main finding, particularly when additional details on the analysis are available,” he said. MedPage today.

The manufacturer Gilead Sciences commented that “we are concerned that the data from this global open-label trial has not undergone the rigorous review necessary to allow for constructive scientific discussion, particularly given the limitations of the trial design.”

“It is not clear whether conclusive findings can be drawn from the study results,” the company added in a statement. He noted the results of randomized trials that documented certain benefits of remdesivir, although a significant survival advantage was never demonstrated.

Interestingly, the WHO researchers pointed to previous research on remdesivir, including the NIH’s ACTT-1, and two smaller trials. They combined the four findings for a mortality rate of 0.91 (95% CI 0.79 to 1.05).

From March 22 to October 4, WHO researchers collected data from 405 hospitals in 30 countries, in a trial that included 11,266 adults: 2,750 received remdesivir, 954 hydroxychloroquine (HCQ), 1,411 lopinavir, 651 interferon plus lopinavir , 1412 only interferon and 4088 standard care without any of the above. Hospitalized adults with COVID-19 who did not receive any study drug, who had no known contraindications to any study drug, and who did not have an anticipated transfer within 72 hours were eligible.

Within the study, HCQ was suspended for futility on June 18 and lopinavir on July 4. Interferon was discontinued on October 16. The NIH currently recommends not using interferons (alpha or beta) for severely or critically ill patients with COVID-19, except in the context of a clinical trial. The agency made similar recommendations for HCQ and lopinavir.

Approximately 81% of Solidarity patients were over 70 years old, 62% were male, a quarter had diabetes, and 8% were already ventilated.

There were also no significant differences in mortality for interferon-β1 (RR 1.16, 95% CI 0.96-1.39; P= 0.11), nor HCQ (RR 1.19, 95% CI: 0.89-1.59, P= 0.23) and lopinavir (RR 1.00, 95% CI 0.79-1.25, P= 0.97), which had previously shown no benefit in other randomized trials.

“The in-hospital mortality outcome is imperfect because, of course, deaths can occur outside of the hospital,” Spinelli said, adding that remdesivir requires participants to stay in hospital for 10 days of treatment.

He added that he expected some questions about the trial to be resolved in a preprint review or when the results appear in a peer-reviewed journal.

The WHO researchers also found that no study drug reduced the initiation of ventilation in those who were not yet ventilated (295 with remdesivir versus 284 for controls), and found “a lack of material difference” in the proportion of patients who were still hospitalized on day 7 (69% with remdesivir vs 59% for controls).

On Twitter, Krumholz specifically cited this quote from the researchers:

“The unpromising overall results of the tested regimens are enough to refute initial hopes, based on smaller or non-randomized studies, that any of them will substantially reduce in-hospital mortality, initiation of ventilation, or [hospitalization] duration.”

Spinelli said it will be important to look at the trials examining both remdesivir and dexamethasone to fully understand what recovery time, mortality and duration of infectivity look like when both therapies are used together.

“By adding Solidarity to the trials that we have to date, I think there is probably not a big mortality benefit and in this context the cost is too high,” he said.