A national multi-site clinical trial in India, funded by the Indian Council of Medical Research (ICMR), found that the use of convalescent plasma fails to reduce mortality or even stop progression of severe COVID-19. Conducted at 39 trial site organizations (primarily hospitals and health centers) around the nation, the PLACID Trial was conducted between April 22 and July 14 to investigate the efficacy of convalescent plasma (CP) for the treatment of COVID-19. The prominent Indian study team suggests a prior measurement of neutralizing antibody titers in convalescent plasma donors and participating patients could likely contribute clarity and clarification to the role of CP in the ongoing management of SARS-CoV-2, the virus behind COVID-19.
The PLACID Trial, results for which were recently uploaded to the preprint server medRxiv, involved 464 moderately ill COVID-19 patients who were admitted to Indian hospitals. The study is yet to be peer reviewed. This therapy, of course, involves the donation of blood (which includes the plasma) from recovered COVID-19 patients and is then used to process and prepare the convalescent plasma. Approved controversially in the United States for emergency use authorization, this Indian national study generated a significantly different outcome.
Recently, India’s The Tribune reported on this important study and its implication. During the pandemic onset, ICMR launched the National Task Force for COVID-19 to respond to the pandemic; this body reviewed and approved the PLACID Trial.
Off-Label Convalescent Plasma Use in India
The Tribune reports that by June 27, 2020, the Indian Union Health Ministry issued Clinical Management Protocols for COVID-19 that supported the off label use of convalescent plasma for treating moderate stage COVID-19 under the “investigational therapies” category.
Challenges in India
However, TrialSite reported that often due to protocols, at least for studies, sponsors found it difficult to secure sufficient amounts of convalescent plasma. Moreover, The Tribune reports that unfortunately, the use of the therapy has been associated with ethical to potentially criminal practices in the world’s second most populated nation and seventh largest economy as measured by GPD (soon to pass France for the sixth slot). For example, a black market economy around the investigational product has pushed up prices, in some cases to “exorbitant” levels.
Moreover, convalescent plasma involves resource-intensive process challenges (plasmapheresis, plasma storage and Nab measurement) coupled with capacity limitations rendering the management of such a program across the nation a more difficult undertaking.
This clinical trial involved 464 moderately ill patients infected and hospitalized with SARS-CoV-2; 235 were administered convalescent plasma coupled with standard of care while 229 received just the standard of care, per the study protocol.
Patients in the intervention arm received two doses of 200 ml of CP, transfused 24 hours apart, in addition to the best standard of care. Each of the two plasma units originate from ideally differing donors, contingent on not only availability but also ABO compatibility, all in the quest to boost the probability of convalescent plasma with sufficient levels of neutralizing antibody (Nab).
Unfortunately, the results of the study precluded any benefit to patients, the whole point of this yet-to-be-proven therapy approach. In the United States, the Mayo Clinic-led National Convalescent Plasma Program has produced some positive results but that expanded access endeavor wasn’t a randomized controlled study like The Placid Trial.
The Tribune quoted the study comments: “The Placid trial results indicate that were was no difference in 28-day mortality or progression to severe disease among moderately ill COVID-19 patients treated with CP along with BSC compared to BSC alone.” TrialSite includes the non-peer reviewed, preprint server uploaded report here. The study team also reported, “The CP was not associated with reduction in mortality or progression to severe COVID-19.” They added that the study design ensured “high generalizability” while approximating “real-life setting of CP therapy in settings with limited laboratory capacity.”
This study was funded by ICMR.
Quality of Convalescent Plasma
Ensuring a steady supply of consistently high quality, sufficiently antibody enriched convalescent plasma could represent a problem for many studies including this one. The Tribune commented, “A prior measurement of neutralizing antibody titers in donors and participants may further clarify the role of CP in management of COVID-19.”
Other Studies with Problems
The ICMR study reported to the press in India that most recently two randomized controlled trials involving use of CP on COVID-19 patients were published recently in both China and Holland. Unfortunately, both studies had to end early: in China, this was due to a lack of sufficient patient participation, while in the Netherlands, it was due to a trial redesign based on interim findings. The data that was available from both studies pointed to a lack of benefit for CP. The Dutch study concluded the importance of systematically and methodically determining, with specificity, the quality and richness of the antibody involved with the CP.
ICMR is the apex biomedical research body for the nation of India. It also happens to be one of the oldest of national research bodies worldwide.
The Tribune was founded in 1881 by philanthropist Sardar Dyal Singh Majithia, and is a prominent English-language daily in Northern India. The outfit is run by a trust comprising five persons as trustees and produces most of its income via advertising rather than subscriptions. This media is not in the top 10 of India.
Call to Action: Check out the preprint server for the quantitative results. Note, this study hasn’t yet been peer reviewed.