On February 25, the National Institutes of Health halted a clinical trial testing the use of convalescent plasma in non-hospitalized COVID-19 patients after an independent advisory board declared the treatment was no better than placebo at preventing severe disease or death.

“Even if enrollment continued, the trial was highly unlikely to demonstrate that convalescent plasma prevents progression from mild to severe disease,” says Simone Glynn, an epidemiologist at the NIH’s National Heart, Lung, and Blood Institute (NHLBI), which led the study. Data underlying the decision to stop the trial are not yet available, Glynn notes, because patients are being followed for up to 30 days after participating in the trial.

The cessation of the trial is the latest blow to an intervention that had been considered promising for preventing progression from mild to severe COVID-19 in people who contract the virus.

The principle behind infusing...

Convalescent plasma was a good treatment when we didn’t know how to make virus-specific antibodies. It was in the middle of the pandemic, and it served its purpose.

—Miriam Merad, Icahn School of Medicine at Mt. Sinai

Representatives of 47 emergency departments across the US took part in the Clinical Trial of COVID-19 Convalescent Plasma of Outpatients trial (C3PO), according to NIH, designed to test whether convalescent plasma is beneficial in an outpatient setting. The NHLBI had enrolled 511 of the 900 patients it had aimed to recruit by the time the trial ended.

The study participants were recruited for the trial when they went to emergency rooms after experiencing mild or moderate symptoms of COVID-19. All of them had been sick for a week or less and were not admitted to the hospital. Everyone had at least one risk factor, such as obesity or hypertension, for progressing to severe disease. Half of the participants were to receive a single infusion of plasma donated from COVID-19 survivors and the other half a placebo. 

While the monitoring board concluded that convalescent plasma was safe, they found that it was no better than placebo in changing the patients’ outcomes. Following that determination, NHLBI Director Gary Gibbons halted the study.

See “Indian Study Shows No Survival Benefit of Plasma in COVID-19

Although the data analysis continues, NHLBI officials are confident that the placebo and treatment groups were comparable to each other. “From what we’ve seen so far, all demographics were well balanced,” says Nahed El Kassar, who administered C3PO for the NHLBI.

The debate over convalescent plasma continues

The use of convalescent plasma quickly became politicized during the COVID-19 pandemic, with former President Donald Trump hyping the treatment long before randomized trials to determine its efficacy were conducted. Trump was at former FDA Commissioner Stephen Hahn’s side when Hahn announced the EUA for convalescent plasma at a press conference that led to calls for Hahn’s resignation for overstating the treatment’s benefits.

Against that fractious backdrop, several clinical trials have taken place around the world, some previously covered by The Scientist. They collectively appear to dampen hopes about the benefits of convalescent plasma, particularly in hospitalized patients. NIH’s decision to halt C3PO comes less than a week after a JAMA review of 10 clinical trials also found that plasma was no better than placebo at reducing death or improving clinical outcomes. Nine of these trials focused on hospitalized patients, the other looked at outpatients.

“Convalescent plasma was a good treatment when we didn’t know how to make virus-specific antibodies. It was in the middle of the pandemic, and it served its purpose. But right now, I think it’s the end [of convalescent plasma as a viable treatment], and I’m not surprised by the [NIH] results at all,” says Miriam Merad, an oncologist and immunologist at the Icahn School of Medicine at Mt. Sinai.

See “Two COVID-19 Clinical Trials Seek to Enroll Pregnant Women

Some physicians, such as Michael Joyner of the Mayo Clinic, maintain that convalescent plasma can be helpful for certain patients. Joyner was one of the leaders of the expanded access program for convalescent plasma in the US last year, which led the FDA to issue the EUA that ratified convalescent plasma’s use in hospitalized COVID-19 patients. He argues that emerging evidence shows a benefit of convalescent plasma if offered early in a hospital stay, at doses higher than those the NIH tested.

“I’m very comfortable saying if you have lymphoma, leukemia, some sort of inborn problem or are taking an immunosuppressant, that convalescent plasma is fantastic,” Joyner says. “I’m also very happy to tell people that if they’re symptomatic as outpatients, go get monoclonals,” Joyner adds. Monoclonal antibodies are tailored to attack the spike proteins of the virus that grab hold of receptors on human cells and initiate infection. Two monoclonal drugs from Regeneron and Eli Lilly have received EUA from the FDA.

Merad says that monoclonal antibodies are superior to convalescent plasma because they are purpose-built to target the SARS-CoV-2 virus. Convalescent plasma probably does contain some neutralizing antibodies to SARS-CoV-2, she says, but also will contain antibodies to other infections that have nothing to do with the virus. If the trouble is antibody production, she says, use the tool that’s best equipped to solve that challenge. Merad also notes that there is always a risk of contamination when a blood product is transfused from one person to another.

The debate over the use of convalescent plasma seems likely to continue as clinical trials proceed. NIH is sponsoring a study of the use of convalescent plasma in hospitalized COVID-19 patients, and Johns Hopkins University is sponsoring two trials of its use in outpatient settings.

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