No Survival or Other Benefit for Remdesivir in COVID-19

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

Death rates at 28 days barely differed (rate ratio 0.95, 95% CI 0.81-1.11, P=0.50), reported the WHO Solidarity Trial Consortium investigators in a preprint published on medRxiv.

Moreover, no advantage in secondary outcomes — initiation of ventilation and duration of hospital stay — was seen for remdesivir either.

“A pragmatic approach to doing research in a crisis. Lots 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 first-line treatment in NIH clinical guidelines for hospitalized COVID-19 patients who require supplemental oxygen.

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

“I do think the guidelines will need to be revised to take Solidarity into account given its size and primary finding, particularly when additional detail is available on the analysis,” he told MedPage Today.

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

“It is unclear if any conclusive findings can be drawn from the study results,” the company added in a statement. It pointed to the randomized trials results that did document certain benefits from remdesivir, although no significant survival advantage was ever shown.

Interestingly, WHO investigators noted the previous research on remdesivir, including ACTT-1 from the NIH, and two smaller trials. They combined the four findings for a death rate ratio of 0.91 (95% CI 0.79-1.05).

From March 22 to October 4, WHO investigators compiled data from 405 hospitals in 30 countries, in a trial that comprised 11,266 adults: 2,750 receiving remdesivir, 954 hydroxychloroquine (HCQ), 1,411 lopinavir, 651 interferon plus lopinavir, 1,412 only interferon, and 4,088 standard care without any of the above. Adults hospitalized with COVID-19 who did not receive any study drug, had no known contraindications to any study drug, with no transfer anticipated within 72 hours were eligible.

Within the study, HCQ was discontinued for futility on June 18 and lopinavir on July 4. Interferon was discontinued on October 16. The NIH currently recommends against the use of interferons (alpha or beta) for severe or critical patients with COVID-19, except in the context of a clinical trial. The agency made similar recommendations for HCQ and lopinavir.

About 81% of Solidarity patients were older than age 70, 62% were men, a quarter had diabetes and 8% were already ventilated.

There was also no significant difference 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), both of which had previously shown no benefit in other randomized trials.

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

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

WHO investigators also found that no study drug reduced initiation of ventilation in those not already ventilated (295 with remdesivir vs 284 for controls), and found “a lack of material difference” in proportion of patients still hospitalized at day 7 (69% with remdesivir vs 59% for controls).

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

“The unpromising overall findings from the regimens tested suffice to refute early hopes, based on smaller or non-randomized studies, that any will substantially reduce inpatient mortality, initiation of ventilation or [hospitalization] duration.”

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

“When adding Solidarity to the trials we have to date, I think it is likely that a large mortality benefit does not exist, and in this context, the cost is too high,” he said.

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    Molly Walker is an associate editor, who covers infectious diseases for MedPage Today. She has a passion for evidence, data and public health. Follow

Disclosures

The views expressed are those of the Writing Group, not necessarily those of WHO.

This study was supported by the WHO.

The authors disclosed no conflicts of interest.