The RECOVERY trial independent Data Monitoring Committee (DMC) held a routine meeting on Thursday 14 January to review the available safety and efficacy data.
On the advice of the DMC, recruitment to the convalescent plasma arm of the RECOVERY trial has now closed. The DMC saw no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any pre-specified subgroup.
The DMC reviewed data on patients randomised to convalescent plasma vs. usual care. The preliminary analysis based on 1873 reported deaths among 10,406 randomised patients shows no significant difference in the primary endpoint of 28-day mortality (18% convalescent plasma vs. 18% usual care alone; risk ratio 1.04 [95% confidence interval 0.95-1.14]; p=0.34). Follow-up of patients is ongoing and final results will be published as soon as possible.
Recruitment to all other treatment arms – tocilizumab, aspirin, colchicine, and Regeneron’s antibody cocktail – continues as planned.
It seems for the moment that steroids are your best bet once you’re admitted.
The monoclonal infusion should work but it’s not given during a hospital admission because it’s been shown to work best early on when the virus load within you is low. Plus it may not work as well against the mutated strains. Hopefully the brightest minds are already at work on this.
Everyone just needs to roll up their sleeves and get the vaccine now.
Although this outcome puts the kibosh on convalescent plasma as a treatment for Covid, one should make the point that it has no implications for monoclonal antibodies synthesised from convalescent plasma, like Regeneron's and AZ's. It's not that the antibodies in convalescent plasma don't work, more that plasma has negative effects that cancel out the positive.
The earlier, smaller PLACID trial of convalescent plasma given to moderately ill Covid-19 patients in India was equally unsuccessful: "The composite primary outcome (progression to severe disease or all cause mortality at 28 days) occurred in 19% (44/235) of patients in the intervention arm and 18% (41/229) of patients in the control arm (risk ratio 1.04, 95% confidence interval 0.71 to 1.54). Restricting the comparison to the subset of patients who received plasma with detectable antibody titers did not change the outcome".
This article bmj.com/content/371/bmj.m4072 tried to explain why what appeared to be a sound concept didn't work in practice.
"The primary hypothesized mechanism of benefit from convalescent plasma is through direct antiviral action of neutralizing antibodies on SARS-CoV-2 RNA. In the PLACID Trial, a statistically significant 20% higher rate of conversion to a negative result for SARS-CoV-2 RNA occurred on day 7 among patients in the intervention arm" ..." In plain English, this means that convalescent plasma did exactly what the investigators hoped it would do, yet there was no net clinical benefit to patients. Why might this be the case?
The most common use of therapeutic plasma, which contains more than 1000 different proteins,1 is for the management of acute bleeding and complex coagulopathies. Despite the presence in plasma of anticoagulation factors such as antithrombin and protein C, the net effect of plasma is prothrombotic.
An excellent recent pathophysiology synthesis concluded that “SARS-CoV-2 not only produces an inflammatory and hypercoagulable state, but also a hypofibrinolytic state not seen with most other types of coagulopathy.” Most recently, plasma from convalescent covid-19 patients has been shown to directly cause endothelial cell damage in vitro".
Great reply bennevisplace and this all sounds entirely plausible. The hypofibrinlytic state that you mention is somewhat contradicted by uniquely, massively elevated d-dimer levels which are a product of fibrinolysis. However, d-dimers are known to be elevated in inflammatory states, which is of course is exactly what occurs in covid infection. Hard to know how much d-dimer can be attributed to each cause.In the UK, the infusion of donor plasma is a standard of care treatment for people with coagulopathies and it's interesting that the damage to the vascular endothelium (in vitro in this report) has not been reported in other hyper coagulable states.
Despite the fact that covid is recognised as a thrombotic disorder, thrombotic events were not a prespecified outcome in the PLACID Trial and were not reported. "Adjudication of the “relatedness” of serious adverse thrombotic and cardiac events was conducted by the treating physician, with no defined protocol and no independent review. Most of the 677 cardiac events (88.2%) and 113 thrombotic events (66.3%) were judged not to be related to transfusion, and these events were therefore excluded from the reported adverse event rates."
From this report it seems that some opportunities to evaluated effectiveness were omitted and others poorly defined. However, the trial still showed no benefit in outcomes for convalescent plasma, whatever the reason, which is a pity as the antibodies appeared to be doing their job.
You're right that this report has no implications for the Regeneron monoclonal antibodies and others like them so they remain an important and hopeful therapeutic intervention.
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