Newly released data from the SIREN-C3PO trial show no benefit of convalescent plasma therapy in high-risk patients recently infected with COVID-19 in an outpatient setting as it failed to prevent progression to severe disease, when administered within a week of onset of symptoms. The final results of the trial were published in the New England Journal of Medicine (August 18, 2021, DOI: 10.1056/NEJMoa2103784).

The members of the Strategies to Innovate Emergency Care Clinical Trials Network (SIREN) conducted the Covid-19 Convalescent Plasma in Outpatients (C3PO) trial. The randomized, multicenter trial involved 511 patients aged ≥50 years, who had mild Covid-19 symptoms and who presented to the ED for treatment within a week after onset of symptoms. Patients were clinically stable and therefore could be managed as outpatients. Of these, 257 received one unit of convalescent plasma with a high titer of antibodies against SARS-CoV-2, while 254 were given a placebo. All study participants had at least one risk factor for progression to severe disease such as obesity, hypertension, diabetes, heart disease, or chronic lung disease.

Results showed that disease progression within 15 days was comparable between the treatment group and the placebo group, 30% (n=77) and 31.9% (n=81), respectively, a difference which is non-significant, thereby showing no advantage of convalescent plasma therapy in preventing progression of disease. There were five deaths in the convalescent plasma group and one death in the placebo group; but these were unrelated to plasma. The trial was stopped in February 2021 due to lack of efficacy based on a planned interim analysis.

We do know much more about the disease and how to manage it today than we did a year back when COVID-19 was still a new emerging disease caused by a novel Coronavirus. There were no specific treatments available and repurposed drugs were used to treat the infection.

Convalescent plasma was granted emergency use authorisation by the US FDA last year in August as a potential promising COVID-19 treatment for use in a hospital setting. In India also, high titer convalescent plasma was approved as an off-label therapy for patients with moderate disease who were not improving (progressive hypoxia) despite use of steroids. It was an experimental treatment for mild and moderate covid-19 patients; but it became a very popular treatment then. Delhi was the first state to use convalescent plasma therapy on compassionate grounds. The country’s first convalescent plasma bank also opened in Delhi in July.

Then came the ICMR’s PLACID (PLAsma Convalescent InDia) trial (BMJ. 2020 Oct 22;371:m3939), which investigated the effect of convalescent plasma in the management of moderate covid-19 in over 400 patients in India. While it was safe, the trial did not show any benefit of plasma in reducing progression of disease or all-cause mortality. This trial was conducted in 39 public and private hospitals across India. This trial led to questions about its effectiveness as treatment.

ICMR issued an advisory cautioning against inappropriate use of plasma therapy stating that convalescent plasma having low concentration of specific antibody against SARS-CoV-2 may be less beneficial for treating COVID-19. It also defined specific criteria for its use. Only those patients in the early stage of COVID-19 disease, 3-7 days from onset of symptoms, but not later than 10 days, or patients who had no IgG antibody against COVID-19 could be considered as plasma recipients after informed consent. Subsequently, the US FDA authorization was also revised allowing use of high titer COVID-19 convalescent plasma only for the treatment of hospitalized patients with COVID-19 early in the disease course and to those hospitalized patients who have impaired humoral immunity and cannot produce an adequate antibody response.

The PlasmAr Study from Argentina published in February this year did not show any significant clinical benefit of convalescent plasma in patients with severe Covid-19 pneumonia. Likewise, the UKs RECOVERY trial published in May showed no survival benefit in patients hospitalised with COVID-19.

Convalescent plasma has been left out of the latest version (24.05.21) of the national clinical management protocol for COVID-19 in adults. Besides its lack of efficacy in reducing progression to severe disease, another reason for this is a possible link with the emergence of more virulent variants with indiscriminate use of plasma therapy.

However, convalescent plasma continues to be studied in ongoing or forthcoming trials such as the PassItOn trial (Passive Immunity Trial for Our Nation to Treat COVID-19 in Hospitalized Adults). One trial is investigating the effect of Convalescent Plasma to Limit SARS-CoV-2 Associated Complications in outpatients (NCT04373460), while another trial is studying its effect as prophylaxis following exposure to COVID-19 (NCT04323800).

Results of these trials are awaited, but until then, convalescent plasma therapy seems to have fallen out of favour.