13 Dec COVID-19: Study Finds Changes in Convalescent Plasma Efficacy Over Time
MedicalResearch.com Interview with:
Liise-anne Pirofski, M.D.
Mitrani Professor of Biomedical Research
Chief, Division of Infectious Diseases
Albert Einstein College of Medicine and
Montefiore Medical Center
Liise-anne Pirofski, MD on behalf of lead authors Mila Ortigoza MD, PhD, Assistant professor at NYU Langone Health and Hyunah Yoon MD, Assistant Professor, Albert Einstein Medical Center
and the CONTAIN COVID-19 trial authors and team
MedicalResearch.com: What is the background for this study?
Response: The study was designed to determine the efficacy of COVID-19 convalescent plasma (CCP) in hospitalized patients with COVID-19. It was designed and launched in New York City in April 2020 during the height of the first COVID-19 pandemic wave and later extended to sites in Miami, Houston, and other regions affected by subsequent waves of the pandemic. At that time, there were no validated therapeutic options for COVID-19, and there was clinical equipoise for CCP use in hospitalized patients. COVID-19 convalescent plasma was considered worthy of investigation because of the historical success of convalescent plasma in prior pandemics and epidemics dating to the beginning of the 20th century, and importantly, biological plausibility because convalescent plasma contains antibodies to agents from which people have recovered, and case series and observational studies showing signals of CCP efficacy in patients with COVID-19. The trial was designed to focus on patients with moderate to severe COVID-19 who required supplemental oxygen, but not mechanical intubation. At the time the trial was designed, hospitals in New York City were overwhelmed with severely and critically ill patients with COVID-19, an entirely new disease about which more and more was learned over the 11 months the trial was conducted.
MedicalResearch.com: What are the main findings?
Response: Overall, over the 11 months of the trial, there was no difference in the primary outcome, clinical status at day 14 measured by World Health Organization Ordinal Scale for Clinical Improvement (WHO score), between COVID-19 convalescent plasma and placebo recipients. However, subgroup analyses were conducted because patient characteristics, treatment modalities, and the virus changed over time. The subgroup analysis by enrollment quarter showed a change in COVID-19 convalescent plasma efficacy over time. There was a likely benefit of CCP in the first quarter of the trial (Q2, April-June 2020) when remdesivir and corticosteroids were not standard of care. Additionally, in Q2, study participants were older, less severely ill by WHO score, and received CCP with high neutralizing titer (>1:160). These findings point to a heterogeneous treatment effect of CCP over time. Another factor that may have contributed to this effect was that viral variants emerged as the trial progressed. The results of our study have important explanatory power. They provide insight into how evolving knowledge about the virus and immune response to SARS-CoV-2, the introduction of therapies, and changes in the standard of care for COVID-19 help to explain the nuanced outcome of our trial. In this regard, our report provides a roadmap to dissect the results of other trials in which, like ours, the primary outcome was not met, by taking a deeper look at the effects of time, disease severity, CCP titer, and concurrent medications on clinical outcomes. As reported by others, CCP was safe and well tolerated.
MedicalResearch.com: What should readers take away from your report?
Response: Our report pertains to COVID-19 convalescent plasma use in hospitalized patients. It showed that high-titer CCP was effective early in the pandemic when other therapies were not in use. Thus, convalescent plasma should be considered a validated treatment option for emergent pandemic or epidemic diseases for which other treatments are not available, including for SARS-CoV-2 variants resistant to monoclonal antibodies and other therapies.
Clinicians should consider the use of high-titer CCP 2 for hospitalized patients with COVID-19 who:
1) are in the early, or viral phase of the disease,
2) have mild hypoxia and have not developed the inflammatory phase of the disease, and
3) do not meet criteria for corticosteroids, or remdesivir, or are in settings where remdesivir is not available or contraindicated.
Therefore, as shown in many other trials, case series, and observational studies, COVID-19 convalescent plasma should be administered as early as possible when a patient is admitted to the hospital, preferably when the decision to admit the patient is made.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Future research should focus on the identification of the characteristics of optimally effective COVID-19 convalescent plasma and the patients who will benefit from CCP the most. When the trial began, standardized assays to characterize CCP were not available. Many platforms to characterize CCP are available now. The full range of COVID-19 convalescent plasma activity should be studied. Its efficacy is a function of the amount and functional activity the antibodies it contains. Some antibodies neutralize the virus, some exert anti-viral activity by collaborating with cells of the immune system, and some have the capacity to control inflammation. ‘Next-generation’ CCP, from patients who recovered from COVID-19 and were subsequently vaccinated has very high levels of a diverse array of broadly reactive antibodies. The characteristics and efficacy of CCP from such individuals should be studied.
A lesson learned from our trial, which is highlighted by the results of other trials, is that high-titer COVID-19 convalescent plasma must be given early in the course of COVID-19. The clinical course and stages of COVID-19 were not understood at the onset of the pandemic when the trial began. Future studies should leverage the knowledge gained about COVID-19 to identify the correct time to give CCP and the patients who would benefit the most. There is already ample data that CCP is effective in immunocompromised COVID-19 patients, particularly those with antibody and B cell deficiency.
The trial was conducted over almost a year amid a rapidly evolving pandemic that was not predictable at the time of the study was designed. Future studies must consider how changes in the standard of care and characteristics of the affected patient population and virus over time can affect the study outcome independent of the treatment arm. Given that evidence from the onset of a pandemic may not be applicable as it progresses, tools and study instruments are needed to incorporate the effect of change, patient heterogeneity, and the pathogenesis and outcomes of a complex disease. 40% of the study population was Hispanic, and 14% was non-Hispanic Black.
Future studies must include diverse patient populations, especially those who are disproportionately affected by COVID-19. Strategies are needed to gain the trust of those who confront barriers to care and access to research opportunities due to social determinants of health. This will enhance the generalizability of evidence from clinical studies and promote health equity. The challenges posed by recruitment in the setting of shifting pandemic waves point to the critical need to invest in a nimble clinical trial infrastructures that can launch rapidly, shift to new areas as needed, and prioritize diversification of participant recruitment and retention.
MedicalResearch.com: Is there anything else you would like to add?
Response: The trial adds to evidence from observational, matched case-control studies, and small randomized clinical trials that COVID-19 convalescent plasma is most likely to be effective when high-titer COVID-19 convalescent plasma is given early in the course of COVID-19. The consistency of this observation, which underscores historical and biological data showing that convalescent plasma is most effective early in the course of an infectious disease, is remarkable given that understanding of the course of COVID19 and patient outcomes unfolded while research was being conducted amid a rapidly spreading pandemic.
Therefore, consideration of CCP use in hospitalized patients should be driven by the overall weight of evidence, including the robust evidence that it is safe and well tolerated. Consideration should also be given to CCP use in lower/middle income countries where remdesivir may not be available and corticosteroids (which can lead to the emergence of fungal infections) may be overused. Its safety and availability (from survivors) make it a feasible option deserving of resource allocation. Finally, and importantly in the current state of the pandemic, strong consideration should be given to the use of COVID-19 convalescent plasma in settings where circulating viral variants are resistant to monoclonal antibodies.
We do not have any disclosures.
Ortigoza MB, Yoon H, Goldfeld KS, et al. Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial. JAMA Intern Med. Published online December 13, 2021. doi:10.1001/jamainternmed.2021.6850
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