No benefit from convalescent plasma in UK RECOVERY study: limited results restrict implications for COVID-19

Simon Collins, HIV i-Base

On 15 January 2021, the UK RECOVERY study reported top-line results showing no benefit from using convalescent plasma as a treatment for COVID-19. Also, that further enrollment to this arm was stopped based on a recommendation from the Data Monitoring Committee (DMC) the day before. [1]

However, only three days earlier, the investigators had issued a statement that “strongly encouraged continuing recruitment” for low risk participant – based on the DMC review a week earlier. The suggests that either significant changes occurred during one week or a disconnect between the investigators and the DMC. [2]

Now, more than a month later, no further details have been released and the pre-review paper is still not published. Also, although the press statement refers to the protocol for the RECOVERY study being available online, the only reference to convalescent plasma is a listing as a new treatment (in May 2020). [3]

The press release reported 1873 deaths among 10,406 participants. There was no difference in the primary endpoint of 28-day mortality with 18% mortality in each arm: risk ratio 1.04 (95%CI: 0.95 to 1.14), p=0.34. 

No details were given on the participants, time to treatment, antibody titre, numbers included in the analysis or how many were still in follow-up.

Dosing information from the trial register includes that a single unit of convalescent plasma (275 mls +/– 75 mls IV) was given on day one (as soon as possible after randomisation) and another on day two (with a minimum of 12 hour interval between the first and second units). [4]

As background, although other early studies reported conflicting results from using convalescent plasma, [5] several larger studies highlighted the importance of perhaps only using high-titre plasma in early infection.

In August 2020, a large open label US expanded access programme with more than 35,000 participants reported reductions in both 7- and 30-day mortality with early use (within 3 days vs >4 days after diagnosis) and greater IgG antibody levels in the transfused plasma. In this study, 52% of participants were in ICU and 27% were on mechanical ventilation. [6] 

Shortly afterwards, in October 2020, a large randomised study (PLACID) reported no benefit from convalescent plasma, but included the possibility that using a high-titre plasma earlier in infection might be more effective. [7]

More recently, a study published in January in the NEJM reported that early use of high-titre convalescent plasma was associated with a 48% reduction in the risk of developing severe respiratory disease. [8]

This double-blind, placebo-controlled study randomised 160 participants at high risk of progression due to age and/or comorbidities at multiple sites in Argentina. The primary endpoint was defined as developing a respiratory rate >30 breaths per minute, oxygen saturation <93% on ambient air, or both.

The primary endpoint was reached in 16% vs 31% participants (n=13 vs 25) in the active vs placebo arms respectively: relative risk 0.52 (95%CI: 0.29 to 0.94), p=0.03). This study used a single 250 mL infusion with an IgG titer greater than 1:1000 against SARS-CoV-2 spike (S) protein.

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The results from this high-profile study have received minimal press coverage, certainly compared to results with other repurposed drugs.

As well as being disappointing, withholding further details in the press release complicates use of the results in current clinical practice and in ongoing studies – and a paper in CID last July criticised the RECOVERY study for doing this previously. [9]

In this case, however, further details are particularly important to understand whether the study design was adapted to only use high-titre plasma in early infection – also recently recommended by the US FDA. [10]

If not, then in addition to potentially contributing to poor outcomes for the participants, it might be premature to conclude that the question of using convalescent plasma has been answered.

References

1. Statement from the RECOVERY trial chief investigators. RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19. (15 January 2021).
   https://www.recoverytrial.net/news/statement-from-the-recovery-trial-chief-investigators-15-january-2021-recovery-trial-closes-recruitment-to-convalescent-plasma-treatment-for-patients-hospitalised-with-covid-19
2. Statement from the RECOVERY trial chief investigators. Update on recruitment to convalescent plasma and tocilizumab treatment arms.
   https://www.recoverytrial.net/news/update-on-recruitment-to-convalescent-plasma-and-tocilizumab-treatment-arms-statement-from-the-recovery-trial-chief-investigators
3. Study Protocol. Randomised Evaluation of COVID-19 Therapy (RECOVERY) study.
   https://www.recoverytrial.net
4. clinicaltrials.gov. Randomised Evaluation of COVID-19 Therapy (RECOVERY) study. NCT04381936.
   https://clinicaltrials.gov/ct2/show/NCT04381936
5. Convalescent plasma therapy for COVID-19. HTB (1 June 2020).
   https://i-base.info/htb/38022
6. Convalescent plasma: randomised controlled study finds no benefit in moderate stage COVID-19. HTB (11 November 2020).
   https://i-base.info/htb/39247
7. 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
8. Libster R et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. NEJM. DOI: 10.1056/NEJMoa2033700. (6 January 2021).
   https://www.nejm.org/doi/full/10.1056/NEJMoa2033700
9. Siedner MJ and Gandhi RT. Proposing minimum requirements for announcing clinical trial results during the COVID-19 pandemic. Clinical Infectious Diseases, ciaa945. DOI: 10.1093/cid/ciaa945. (8 July 2020).
   https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa945/5868929
10. FDA. Investigational covid-19 convalescent plasma—emergency INDs. (4 February 2021).
    https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds
    https://www.fda.gov/media/141477/download (PDF letter)

This article was first posted on 6 February 2021.