October 23, 2020

expert reaction to results from an open label phase II randomised control trial for convalescent plasma to treat moderate COVID-19

A trial, published in The BMJ, looked at convalescent plasma for the treatment of moderate COVID-19.

Prof Martin Landray, Professor of Medicine & Epidemiology, Nuffield Department of Population Health, University of Oxford and Co-lead, RECOVERY trial, said:

“There is substantial interest in convalescent plasma as a possible treatment for COVID-19. But there remains considerable uncertainty about whether it is effective in tackling the worst effects of the disease. Can it be used to shorten hospital stay, reduce the need for a mechanical ventilator, or improve a patient’s chances of survival. Even though over 100,000 patients have been given this treatment in the United States, only a tiny number have been enrolled in clinical trials and consequently we do not know if the theoretical benefits translate into reality.

“This paper by Dr Agarwal and colleagues reports the results of the largest randomized trial of convalescent plasma to complete so far. However, with just a few hundred patients, it is still much too small to give clear results. It would need to be substantially larger to pick up a meaningful sign of benefit and even then there would still be questions about whether different types of patient respond better or worse. For example, one could well imagine that the treatment might work particularly well in those earlier in the course of the disease or who have not been able to mount a good antibody response to the virus of their own. But such speculation needs to be tested – we can’t just rely on an educated guess.

“There is a further caveat. Convalescent plasma is, quite literally, a mixed bag. It contains lots of different antibodies some of which will bind very well to the coronavirus and others less so – and some donors have higher levels of the relevant antibodies than others. In this particular study, one third of the donors had very low levels of the neutralising antibody – when plasma from those people is used as a treatment, one would not expect that to be as effective as would be the case if the plasma contained higher levels of the relevant antibodies.

“Here in the UK, the RECOVERY trial is studying this important question at over 120 NHS hospitals across the country. The NHS Blood Transfusion Service is collecting convalescent plasma from people who have had coronavirus. The convalescent plasma is then tested and those units with the highest levels of antibodies are then used as part of the trial. Over 1900 patients have taken part in this particular part of the study so far and we continue to enrol patients in order to ensure that we get clear answers that will give doctors the information they need to treat future patients. We anticipate answers will become available within the next few months.”

Dr Simon Clarke, Associate Professor in Cellular Microbiology, said:

“Use of someone’s blood plasma that contains antibodies against a virus or bacteria to treat an infection in someone else, is not a new technology and although usually safe, is not entirely without risk.  There has been a lot of renewed interest in the use of plasma therapy as doctors scrambles to find ways to treat Covid-19.  The PLACID trial was able to show a small effect on the rate at which patients were able rid themselves of the virus, but this was not enough to improve their recovery from the disease.  In simple terms, there were no clinical benefits to the patients.  While this is a blow to the use of plasma therapy for Covid-19, it should not be abandoned, there may be ways to refine it as a treatment and deliver solid, demonstrable benefits.”

Prof Ian Jones, Professor of Virology, University of Reading, said:

“The poor performance of convalescent plasma in this trial is disappointing but not entirely surprising. The treatment, which delivers antibodies from Covid survivors to infected persons is, in essence, intended as an anti-viral treatment and like all antivirals the window of opportunity to stop an acute infection is very short. The treatment has to be given soon after infection, by the time of hospitalisation it is too late. The sera used here did help clear residual virus but the damage was already done and there was no benefit to patient outcome. What is really needed is a robust predictor of those likely to need hospital support and those not. We should trial this treatment as an intervention much sooner in the disease progression for those at risk of severe disease and see if the outcome improves. We still do not have enough treatments for the early stage of disease to prevent severe disease and until this becomes an option, avoiding being infected with the virus remains the key message.”       

A NHS Blood and Transplant spokesperson said:

“This was a trial which used donations with antibody levels around 6 to 10 times lower than we are using. There is other promising evidence that convalescent plasma transfusions with high antibody levels could improve patient outcomes. We are carrying out two world leading full randomised control trials using only high antibody donations (we are only using donations with a EUROImmun score of 6 or greater), with several thousand patients, which should provide clear answers.”

‘Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomized controlled trial (PLACID Trial)’ by Anup Agarwal et al. was published in the BMJ at 00:01 UK time on Friday 23 October.

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

Prof Martin Landray:

– Co-chief investigator of the RECOVERY trial of potential treatments for COVID-19 (funded by UKRI and NIHR; contributions to supply of study treatment from Abbvie, Roche, and Regeneron).

– Research funding to University of Oxford received from Novartis, Boehringer Ingelheim, and Merck Sharp & Dohme.-

– Infrastructure and core funding received from Health Data Research UK, NIHR Oxford Biomedical Research Centre, UK Biobank Ltd, MRC Population Health Research Unit, and British Heart Foundation Centre for Research Excellence.

– Employee of University of Oxford with salary supported by Li Ka Shing Foundation, Health Data Research UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, and National Health Service.

– I do not accept personal honoraria payments directly or indirectly from the pharmaceutical, biotechnology, or food industries although reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings may be accepted. I hold no shares in and receive no consultancy payments directly or indirectly from tobacco, pharmaceutical, biotechnology, or food companies. I comply with the Independence of Research Policy of the Nuffield Department of Population Health, University of Oxford. For details see: https://www.ndph.ox.ac.uk/files/about/ndph-independence-of-research-policy-jun-20.pdf/@@download

Prof Ian Jones: No conflicts of interest

NHS Blood and Transplant is leading a programme to collect plasma for clinical trials (https://www.nhsbt.nhs.uk/covid-19-research/plasma-programme/).

None others received.