A new randomized controlled trial (RCT) of COVID-19 convalescent plasma (CCP) treatment for moderately ill COVID-19 patients run at 39 Indian hospitals found no association between CCP therapy and reduced mortality or progression to severe disease. Results of the study appear to fit with a recent Cochrane review conclusion of high uncertainty over whether CCP is beneficial for people admitted to the hospital with COVID‐19, but they contribute to a growing body of evidence about the approach, a form of passive immunization.

CCP, the liquid part of blood collected from COVID-19 survivors, is one of just two therapeutics with an emergency use authorization (EUA) from the FDA, alongside Veklury (remdesivir, Gilead Sciences Inc.). But while clinical evidence for Veklury's benefit has been building, evidence has amassed more slowly around the value of CCP, a factor that has made its EUA controversial in some quarters.

So far, just two randomized controlled trials on CCP use in COVID-19 have been published, one in China and the other from the Netherlands. Some benefits appeared, though neither study found a mortality benefit, and more importantly, both were halted prematurely, limiting their utility. The Indian study, called Placid, generated new evidence that's not only complete, but also strengthened by virtue of its status of the largest RCT to date to test CCP in hospitalized COVID-19 patients, as well as its inclusion of a control arm and a multicenter design.

Sponsored by the Indian Council of Medical Research, the trial assigned 464 patients to receive either two doses of CCP plus best supportive care (BSC) or BSC alone. Results, published online on the Medrxiv preprints server, indicated no difference in 28-day mortality or progression to severe disease among moderately ill COVID-19 patients treated with CCP plus BSC vs. BSC alone. The conclusion seems clear, but elements of the study also raised interesting new questions.

For one, CCP donors in the Indian study appeared to have, at the median, low titers of detectable neutralizing antibody (NAb) relative to the higher titers that the FDA has recommended in its guidance on the matter, possibly impacting efficacy, said Todd Rice, an associate professor of medicine and director of Vanderbilt University Medical Center's (VUMC) intensive care unit. Rice is co-leader of Passive Immunity Trial for Our Nation (PassItOn), one of the two high-profile U.S. clinical trials currently underway with the funding of the federal government's Operation Warp Speed.

Another stand-out aspect of the study, Rice told BioWorld, is that a large proportion of the patients who received CCP in the study already had their own antibodies against SARS-CoV-2. In some case, the patients even had higher antibody levels than were present in the CCP they received. "If that bears out in other studies, it would be concerning that the patient's response is early enough and robust enough that we might not be able to help them by giving them convalescent plasma in the hospital," he said.

Currently, patients in the U.S. come into hospitals with an average of five days of symptoms. However, VUMC is getting patients earlier, with an average of two days of symptoms, Rice said. "We've always assumed that the timing matters – that the earlier we give people plasma, the better the chance that it's going to work," but the Indian study really highlights that question, he said.

Further questions around the use of CCP (which the authors call CP) remain, too, the researchers, wrote. "Questionable practices such as calls for donors on social media, and the sale of CP on the black market with exorbitant price tags in India" have paralleled India's authorization of CCP for off-label use, they wrote.

"Additionally, although CP is a safe therapeutic modality, plasmapheresis, plasma storage and NAb measurement are all resource-intensive processes, with limited number of institutes in the country having the capacity to undertake these activities in a quality-assured manner," they said.

Anup Agarwal is the primary author of the study. Aparna Mukherjee, part of the Indian Council of Medical Research's clinical trial and health systems research unit, is the corresponding author.