Failures and findings from randomized clinical trials in COVID-19 convalescent plasma

Six major epidemics have occurred in the 21st century, for which the causative agents were the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome (MERS), influenza A(H1N1), Ebola, Zika, and SARS-CoV-2. Convalescent plasma (CP) was used in five of these outbreaks and was also considered for the Zika virus.

The availability of CP and the requirement of minimal resources for its extraction or deployment, unlike with drugs and monoclonal antibodies, coupled with its low costs makes it an attractive modality of treatment in low-resource settings.

Study: COVID-19 convalescent plasma and randomized clinical trials: rebuilding confidence by explaining failures and finding signals of efficacy. Image Credit: Elkhophoto / Shutterstock.com

CP use for treating COVID-19

Countries like Italy and China that experienced early waves of the coronavirus disease 2019 (COVID-19) disease employed COVID-19 CP (CCP) in March 2020. Initially, the only data available was from case series or small phase II clinical trials.

By late March 2020, the United States expanded access program (EAP) generated a large and robust treatment dataset that provided the first clear evidence regarding the safety of CP. This was essential in the early phases of the pandemic, as antibody-dependent enhancement was a compelling concern. An analysis of the first 3,082 patients from the EAP provided evidence that early administration of high-titer CCP to non-ventilated hospitalized patients was associated with reduced mortality.

There have been several published reviews employing either randomized controlled trials (RCTs) or propensity-matched (PSM) controls. However, data from these studies are extremely conflicting, with most RCTs finding a little overall effect on mortality, whereas the PSM studies and smaller trials report mortality benefits. Such inconclusive results have reduced the enthusiasm of using CCP, as RCT data bear a greater impact on physicians’ opinions, specialty societies, and government regulators.

A new study

In a new study published on the preprint server medRxiv*, researchers completed a PubMed search for clinical trials on CCP in COVID-19, which identified 23 RCTs and 12 PSMs. The variables analyzed in each study included NCT identifier, recruitment, randomization strategy, type of control arm, baseline patient status, median neutralizing antibody (NAb) titer in both recipients (before CCP transfusion) and CCP units, type of viral neutralization test (VNT), the primary endpoint, signals of efficacy, and reasons for failure.

Another source of information was the ClinicalTrials.gov database with CCP RCTs worldwide. On this platform, eight completed RCTs with no pre-published/published findings were found. Notably, seven active studies were listed that were not yet recruiting patients, along with 10 studies that were still recruiting.

With conflicting data variables associated with the efficacy, the variables analyzed in the current study included clinical settings, disease severity, CCP antibody levels and function, dosage, the timing of administration (time from onset of symptoms/molecular diagnosis/diagnosis of pneumonia/hospitalization/serostatus), outcomes (hospitalization, requirement for ventilation, clinical improvement or mortality), CCP provenance, and time for collection, and criteria for efficacy. The objective was to ensure a scientific basis to the conclusions.

In clinical trials, indications of CCP have been defined by the patient’s status, disease severity, the time elapsed before recruitment, or by serological status. This variability has resulted in marked heterogeneity in the recruited patients.

Although CCP should ideally be administered early on in the course of the disease, it may be provided later than originally proposed, owing to issues like ABO incompatibility and related waiting time. Such delays are magnified during the pandemic situation due to inadequacies of the healthcare facilities to tackle the patient overflow to the emergency department and delays in diagnosis and laboratory confirmation. Time management strategies can involve the administration of fully screened CCP collected from eligible donors immediately after diagnosis with PCR.

In August 2020, the United States Food and Drug Administration (FDA) provided Emergency Use Authorization (EUA) for high-titer CCP on the basis of correlation with a reference standard, the Broad Institute the live-virus, 5-dilution VNT as a 50% inhibitory dilution (ID50) of 1:250 or more. The exclusive use of high-titer CCP was formally recommended by the FDA in March 2021.

Study findings

CCP exhibits a dose-response relationship, which is also evident in high-throughput assays. Both geography and time of collection of CCP are important variables in treatment efficacy.

SARS-CoV-2 viruses vary enough in their antigenic composition to create dissimilar antibody responses at different geographical locations. Additionally, CCP collected during early pandemic phases could be less effective against currently circulating variants of concern (VOC).

Initially, robust evidence of successful treatments by CCP was documented. However, later evidence failed to detect evidence of efficacy due to late collection of nasopharyngeal swabs, following the spike in the endogenous immune response.

CCP contains a spectrum of biologically active molecules, and the safety of its use has been established. In fact, polyclonal antibodies like CCP or CCP-derived hyperimmune globulins may offer better protection against variants than monoclonal antibodies. In addition, there is minimal evidence of immune escape in immunocompromised patients with this therapy.

However, CCP is less likely to benefit patients requiring oxygen support. Thus, early administration is the key to successful treatment with CCP.

Recent evidence supports the initiation of CCP treatment within 44-72 hours of the onset of symptoms and using CCP with a nAb titer >1:160. Clinical benefits are not apparent when administered in low NAb titers or when given to patients with severe disease, especially when administered after one week of symptom onset. Meanwhile, immunosuppressed patients benefit from CCP even at later stages.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Nidhi Saha

Written by

Nidhi Saha

I am a medical content writer and editor. My interests lie in public health awareness and medical communication. I have worked as a clinical dentist and as a consultant research writer in an Indian medical publishing house. It is my constant endeavor is to update knowledge on newer treatment modalities relating to various medical fields. I have also aided in proofreading and publication of manuscripts in accredited medical journals. I like to sketch, read and listen to music in my leisure time.

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