Convalescent plasma: randomised controlled study finds no benefit in moderate stage COVID-19

11 November 2020. Related: COVID-19: investigational drugs, COVID-19.

Simon Collins, HIV i-Base

Disappointing results from a randomised controlled study of convalescent plasma as a treatment for people hospitalised with COVID-19 unfortunately removes the early hopes, supported by smaller observational studies, that this might be a widely-used safe and effective option.  

The results, published on 23 October 2020 in the BMJ, reported no reduction of either progression to severe disease or mortality at 28 days. [1]

The PLACID study was an open label, parallel arm, phase 2 study at 39 public and private hospitals in India in 464 participants with moderate confirmed COVID-19 (defined as PaO/FiO ratio 200 to 300 mm/Hg or a respiratory rate >24/min with oxygen saturation 93% or less on room air). Participants were randomised to standard of care plus two doses of convalescent plasma (ideally from different donors), 24 hours apart (n=235) or a control arm of current standard of care only (n=229).

Standard of care was based on national guidelines and included antivirals (hydroxychloroquine, remdesivir, lopinavir/r, oseltamivir), broad spectrum antibiotics, immunomodulators (steroids, tocilizumab), and supportive management (oxygen through a nasal cannula, face mask, non-rebreathing face mask; non- invasive or invasive mechanical ventilation; awake proning).

Baseline characteristics were balanced between arms and included approximate median age 52 (IQR: 42 to 60), 76% men, mean BMI 26, with high rates of comorbidities including diabetes (38  – 48%) and hypertension (35 – 39%).

The primary composite endpoints of progression to severe disease or all cause mortality at 28 days occurred in 44 (19%) vs 41 (18%)
 in the active vs control group respectively. This was a risk difference of 0.008 (95% CI: −0.062 to 0.078) with a risk ratio 1.04 (95% CI: 0.71 to 1.54).

Overall, 34 participants (15%) died in the intervention arm and 31 participants (14%) in the control arm (RR: 1.04, 95%CI: 0.66 to 1.63). Progression to severe disease occurred in 17 participants in each arm.

For one of the secondary outcomes of improved symptoms by day 7, convalescent plasma was associated with earlier resolution of shortness of breath and fatigue and higher rates of negative conversion of SARS-CoV-2 RNA (supporting a virus neutralising effect). However, there was no evidence of immunomodulator functions and no differences in inflammatory markers.

Antibody titres of the donated plasma and from participants on days 0, 3 and 7, were only measured at the end of the study.

At enrolment, 348/418 participants with samples (83%) had detectable neutralising antibodies with median titre of 1:90 (interquartile range 1:30-1:240).

Donors were mostly men (n=247, 94%), with a mean age of 34.3 (SD 9.3) years, most (n=245, 94%) also reporting mild disease. The median disease duration was 6 days (IQR: 3 to 11 days). Nearly two thirds (n=161, 64%) of the donors had a neutralising antibody titre of more than 1:20, with a median titre of 1:40 (interquartile range 1:30-1:80). Plasma was donated after a median of 41 (IQR: 31 to 51) days from PCR confirmed diagnosis.

Study results were not affected by baseline levels of antibody in either participants or donors or from symptoms at enrolment.

Although future research could look at use in people who don’t already have neutralising antibodies or by using plasma with higher titres this would be more difficult to match donors and would limit use to a minority of patients and the researchers conclude that their results don’t support routine use of convalescent plasma as a treatment for COVID-19.

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Previous studies, include two RCTs that were stopped early, including one due to high levels of neutralising antibodies in participants at baseline. [2, 3]

An earlier Cochrane review, recently updated, is also unable to conclude on either safety or effectiveness. [4]

However, a very large open label US expanded access programme (n >35,000 transfused patients) in an adjusted analysis, reported reductions in both 7- and 30-day mortality with earlier use (within 3 vs >4 days) of diagnosis and greater IgG antibody levels in the transfused plasma. [5] 

This suggests that any benefit will need both early use and high antibody titres in the donated plasma, and that ongoing studies should review their design to improve the likelihood of more positive outcomes.

References

1. Agarwal A et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020;371:m3939.
   http://dx.doi.org/10.1136/bmj.m3939.
2. Li L et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe 
and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020;324(5):460-470. doi:10.1001/jama.2020.10044. (3 June 2020).
   http://10.0.3.233/jama.2020.10044
3. Gharbharan A et al. Convalescent Plasma for COVID-19. A randomized clinical trial. Ahead of peer review. medRxiv 2020; 2020.07.01.20139857. (3 July 2020).
   https://www.medrxiv.org/content/10.1101/2020.07.01.20139857v1
4. Piechotta V et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev 2020, 10:CD013600. doi: 10.1002/14651858.CD013600.pub3. (12 October 2020).
   https://pubmed.ncbi.nlm.nih.gov/33044747
5. Joyner MJ et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. Ahead of peer review. DOI: 10.1101/2020.08.12.20169359. (12 August 2020).
   https://www.medrxiv.org/content/10.1101/2020.08.12.20169359v1

This report was first published on 23 October 2020.