Clinical Trials Find No Increase in Mortality Among COVID-19 Patients Treated with Remdesivir, Contrary to Viral Claim

There are no cures for COVID-19, but an increasing number of evidence-based treatments have been identified. Most of these have emergency use authorization, rather than full approval, from the Food and Drug Administration.

At the end of December 2021, the FDA authorized for emergency use the first oral antivirals for COVID-19, Pfizer’s Paxlovid and Merck’s molnupiravir. Both drugs are authorized for patients with mild-to-moderate COVID-19 who are at high risk of severe disease. The pills should be given as early as possible and no later than five days after symptoms begin.

Paxlovid consists of nirmatrelvir, a protease inhibitor that prevents replication of the coronavirus, or SARS-CoV-2; and ritonavir, a drug that slows breakdown of nirmatrelvir. Paxlovid was found in a randomized, double-blind, placebo-controlled clinical trial to reduce COVID-19-related hospitalization or death from any cause by 88% compared with a placebo after 28 days of follow-up.

Molnupiravir also prevents viral replication of SARS-CoV-2, but works in a different way, by introducing errors into the virus’s genetic code. It was shown in a randomized, double-blind, placebo-controlled clinical trial to reduce hospitalization or death from any cause by 30% compared with a placebo after 29 days.

While potentially revolutionary for COVID-19 treatment, the pills are not a substitute for vaccination and come with some risks. Paxlovid, for example, may not be suitable in people with kidney disease or those taking certain other drugs, while molnupiravir is not recommended for pregnant people. Also, initial availability is expected to be very limited. 

The only FDA-approved treatment for COVID-19 is remdesivir, an intravenous antiviral drug. It was approved in October 2020 for hospitalized patients based on randomized, controlled clinical trials that found faster recovery times and statistically significant odds of improving conditions among hospitalized patients with mild to severe COVID-19 who received the drug, compared with those who got a placebo plus standard care.

On Jan. 21, as part of the agency’s response to the omicron variant, the FDA expanded the approved use of remdesivir to high-risk patients who are not hospitalized. That decision was based on a clinical trial that demonstrated that nonhospitalized patients with mild to moderate COVID-19 can benefit from early treatment with the drug. High-risk patients who received three days of IV remdesivir within a week of symptom onset were 87% less likely to be hospitalized or die compared with those receiving placebo.

Other important therapies include several monoclonal antibodies that target SARS-CoV-2, which the FDA has authorized for patients with mild to moderate disease who are at high risk for developing severe COVID-19. These drugs are synthetic antibodies that are designed to prevent the virus from entering cells, although some may not be effective against all variants of the coronavirus. Only two antibodies, Vir Biotechnology and GlaxoSmithKline’s sotrovimab and Eli Lilly’s bebtelovimab, are thought to have activity against the omicron variant, and only bebtelovimab is thought to work against the omicron subvariant BA.2.

Another key drug in the arsenal is the steroid dexamethasone, which was found in a large randomized controlled trial in the U.K. to provide a mortality benefit in hospitalized COVID-19 patients who were ventilated or receiving supplemental oxygen. The finding was announced in June 2020. Dexamethasone, however, did not help patients who weren’t receiving respiratory support, and may have harmed them.

A large randomized controlled trial conducted in Brazil and published in the Lancet Global Health in late October also found fluvoxamine, a cheap antidepressant and obsessive-compulsive disorder drug, reduced the risk of hospitalization and prolonged ER visits by 32% when given early to high-risk outpatients. When the analysis was limited to the people who actually took fluvoxamine regularly, the results were even more impressive, showing a 66% drop in hospitalization or a prolonged ER stay and a 91% reduction in death.

Another very small clinical trial found a benefit of taking fluvoxamine for COVID-19, but a larger subsequent trial was stopped prematurely because few people in the trial became very ill and it did not appear that the drug was having an effect. For now, the NIH’s treatment guidelines neither endorse nor recommend against use of the drug.

The FDA has also issued EUAs for two immune modulating drugs, tocilizumab and baricitinib, for use in certain patients who are hospitalized, in combination with other drugs. Both drugs are used to treat rheumatoid arthritis and are thought to help by tamping down an overactive immune system later in the disease progression.

Baricitinib was authorized in combination with remdesivir for hospitalized patients who require ventilation or supplemental oxygen; that decision was based on a randomized, controlled clinical trial that found faster recovery times and better odds of improvement with the drug combination. Tocilizumab was authorized for patients taking systemic corticosteroids, such as dexamethasone, who need supplemental oxygen or ventilation.

Convalescent plasma, or the part of the blood that contains antibodies from people who have recovered from COVID-19, has also been studied as a potential treatment. In February 2021, the FDA modified its EUA to include only plasma with a high concentration of antibodies “for the treatment of hospitalized patients early in the disease course,” following studies that found no benefit with lower antibody amounts. In a March 9 letter, the FDA noted that “the clinical evidence supporting this EUA remains limited” and encouraged health care providers to enroll patients in ongoing clinical trials. The NIH’s COVID-19 treatment guidelines do not currently recommend convalescent plasma for any patient group and recommend against its use in hospitalized patients without impaired humoral immunity.

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