BREAKING! India’s Randomized Controlled PLACID Trial Shows Convalescent Plasma Does Not Improve Outcome Of Moderate COVID-19 Patients

COVID-19 Convalescent Plasma: An open-label, parallel-arm, phase II, multicentre, randomized controlled trial (PLACID) in India has shown that the use of convalescent plasma as a therapeutic for moderate COVID-19 patients showed no positive effects and did not improve the outcome of the patients.


 
The study findings are published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2020.09.03.20187252v1
 
This is the first completed controlled trial of convalescent plasma unlike the studies in America that had no controls and where researchers with political agendas were spewing out arbitrary statistical data that had nothing to compare against.
 
Convalescent Plasma (CP) is often used on the physiological basis that its contains specific neutralizing antibodies (Nabs) in the plasma. Also it might embrace antibody-dependent cellular cytotoxicity, complement activation, or phagocytosis. In addition it may also contain anti-inflammatory cytokines and other immunomodulatory proteins, which may regulate systemic inflammation.
 
Significantly however a recent systematic review showed that CP did not reduce the mortality rate in severe respiratory viral infections. Despite some evidence that convalescent plasma does contain specific anti-receptor binding domain (RBD) antibodies that have potent neutralizing activity, much remains to be done to establish the right timing, dosage, and patient characteristics for the optimal use of CP. https://www.cmaj.ca/content/192/27/E745
 
Although many non-proper observational studies have appeared which support the role of CP on mortality, hospital stay, and the viral load in COVID-19 patients, only two randomized controlled trials were ever reported, but both were stopped before the endpoint. One was stopped because of the lack of a sufficient number of patients, the other because preliminary findings made it necessary to change the trial design. https://jamanetwork.com/journals/jama/article-abstract/2766943 and https://www.medrxiv.org/content/10.1101/2020.07.01.20139857v1
 
In the United States, the U.S. FDA under political pressure from the White House had granted EUA status for convalescent plasma therapy in the country despite lack of any proper supporting studies on its therapeutic role specifically in the COVID-19 disease.
 
India’s PLACID trial involved thirty-nine public and private hospitals across India. A total of 464 moderate COVID-19 participants were enrolled; 235 and 229 in intervention and control arms between 22nd April to 14th July 2020.
 
The trial focused on evaluating the efficacy of convalescent plasma in hospitalized patients with moderate COVID-19 across India. The outcomes assessed were whether it could prevent the progression of the condition to severe disease, and its short-term adverse effects.
 
All participants in the multi-center study were above 18 years, had a co nfirmed reverse transcriptase-polymerase chain reaction (RT PCR), and met the criteria for moderate COVID-19 based on their ability to maintain arterial blood oxygenation. (PaO2/FiO2: 200-300 or respiratory rate > 24/min and SpO2 ≤ 93% on room air).
 
The moderate COVID-19 patients were on various drugs, including antivirals, antibiotics, immunomodulators, and on oxygen by various routes, as well as mechanical ventilation, depending on the treatment center’s protocols.
 
Eventually 224 patients in the treatment arm received two doses of convalescent plasma at 200 mL each, 24 hours apart, preferably from different donors to increase the odds of receiving Nab-containing plasma, in addition to the participating center’s best standard of care (BSC). Patients were admitted to the ICU according to the protocols followed at each center.
 
The control arm had 225 patients who received only BSC (best standard of care).
 
In the study, all patients but two were followed up to 28 days. There were similar baseline characteristics across both arms of the trial. Most donors were male, most had recovered from mild COVID-19, and their mean age was 34 years. The Nab titer was over 1:20 for more than two-thirds of the donors, the median titer being 1:40. The plasma was collected at a median of 41 days from diagnosis.
 
The main composite outcome was the ability to prevent progression to severe disease or death from any cause during the 28 days of the study period.
 
The study team failed to find any difference in the intervention arm. The mortality was comparable across both groups, as well as the proportion of patients who progressed to severe disease. The composite outcome was achieved in about 18% of patients in either arm.
 
Participants in the intervention arm were more likely to report easier breathing and reduced fatigue, but not reduced fever or cough. There was a reduction in the median FiO2 on days 3 and 5 from the day of enrolment, by 5 vs. 3.7, and by 9 vs. 7, in the intervention and control arms. Thus, the oxygenation status improved after the intervention. Thereafter, the reduction in FiO2 remained similar across both arms.
 
However the rate at which PCR became negative by day 7 was slightly higher in the convalescent plasma arm compared to the control arm.
 
Significantly, there was no difference in the progression of the disease, or clinical severity by the WHO ordinal scale at any time point, or in the mean levels of inflammatory markers over the first 7 days. Of the 38 patients who were on mechanical ventilation, only 2 were alive at 28 days from the start of the trial.
 
Interestingly, the study analysis showed that at least one unit of convalescent plasma with detectable NAbs was given to 160 participants. Even with this subgroup, there was no difference in the composite outcome compared to those who received NAbs at a titer of 1:80, or with no detectable NAbs at all, or to the control arm.
 
It must be noted that the NAb titer of the participants was also measured, but there was no difference in either arm concerning the composite outcome, whether they had detectable NAbs or not.
 
This also remained true even when those who received convalescent plasma with detectable NAb were compared with those who received BSC alone, or when those who got CP with NAb titers at or above 1:80, or the controls.
 
However the use of convalescent plasma was linked to a lower need for FiO2 on day 3 and day 5, but not after that. More patients became PCR negative in the CP arm.
 
It should be noted that in the Chinese RCT, including 103 patients with severe or critical COVID-19, there was no clinical impact from the use of CP. However, when the subgroup of 45 patients with severity comparable to that of the patients in the current Indian trial, there was a clinical improvement in the convalescent plasma group.
 
The study team also compared their results to that of the ConCOVID trial, in which almost 80% had detectable antibodies at the start of the trial, and other studies showing that a third or so of patients showed very low or no detectable antibodies.
 
It was observed that NAb titers were higher with age and severe disease, and in fact, convalescent plasma had lower NAb titers than the CP donors because the latter were typically younger and had recovered from mild disease.
 
The study team commented, “There may not be any benefit of CP collected from young mild COVID -19 recovered donors compared to moderate to severely sick elderly patients who have a robust antibody response.”
 
Also an interesting sidelight on the feasibility of convalescent plasma therapy is seen in that convalescents who had had moderate to severe disease were not typically ready to donate plasma. This could seriously affect the availability of convalescent plasma as and when this therapy is scaled up.
 
The Indian PLACID trial, therefore, found no difference with respect to either mortality or prevention of progression of disease severity at 28 days following the administration of CP, when used in a group of moderately severe COVID-19 patients who also received BSC.
 
The trial findings echo that of a recent Cochrane review of 20 studies that concluded that “there is uncertainty regarding the effectiveness of CP in improving mortality or clinical improvement in COVID-19 patients.”
 
Some of the adverse effects that the patients in the trial experienced include pain at the infusion site or chills, dizziness, and bradycardia, in one patient each. Three patients in each arm had a fever and tachycardia. Two patients in each arm had difficulty with breathing and intravenous catheter blockage.

Importantly mortality in three patients was judged to be possibly related to the convalescent plasma infusion.
 
The trial findings thus showed evidence that CP could result in the reversion of a positive PCR to a negative one but failed to turn up proof of better clinical outcomes with this therapy. Convalescent plasma also failed to show any immunomodulatory effect, as shown by the absence of any difference in the inflammatory marker titers. This may explain the lack of difference in the primary outcome.
 
Significantly the safety profile of convalescent plasma was confirmed, with the three possibly related deaths being those which occurred within 6 hours of convalescent plasma but could also have been due to exacerbation of COVID-19.
 
It must be noted that the PLACID trial included both public and private hospitals, which allowed a wide range of healthcare facilities and socioeconomic and demographic factors to be covered, as well as coexisting diseases. This also allows a better feel of real-world conditions in which convalescent plasma is likely to be administered in such resource-stretched regions and the expected outcomes.
 
However this also limits the trial findings, since it was not blinded and thus subjective improvement may have been due to bias in ascertainment. Different test kits were used for the biomarkers of inflammation. The number of patients varied across centers since the pandemic was in different phases in different regions in India.
 
The trial findings clearly show that convalescent plasma does not improve the outcomes of moderate COVID-19 patients. Further research is warranted to validate its use in COVID-19, including its efficacy in patients who lack NAb and the usefulness of convalescent plasma with high NAb titers.
 
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