Authors: José Javier García (Pivotal, Madrid, Spain)
In this interview we speak to José Javier García, Vice President of Data Management and Biostatistics at Pivotal (Madrid, Spain), about his company’s involvement in a large-scale clinical trial testing the safety and efficacy of hyperimmune convalescent plasma treatment in COVID-19 patients.
First, could you introduce yourself and tell us a bit about your background?
My name is José Javier García. I am medic by training and Vice President of Data Management and Biostatistics at Pivotal, an EU-wide Clinical Research Organization headquartered in Madrid (Spain) and with a broad presence across Europe. I am also Professor of Biostatistics and Epidemiology at the Autonomous University of Madrid School of Medicine (Spain) and have been involved in clinical research since 1987.
Could you tell us about the significance of this trial and the work that led up to it?
Previously published information  has shown that convalescent plasma (CP) can be used to safely treat patients infected by a coronavirus. Due to its scale and significant threat to life, the benefits of clinically trialling CP on patients in the early stages of COVID-19 infection outweigh the risks.
There is historical evidence to show that passive immunotherapy – where antibodies against a particular agent are administered to a susceptible individual – has helped prevent or treat certain diseases. For example, CP has been used effectively to treat infectious diseases such as poliomyelitis, measles, mumps, influenza (1918 H1N1 and 2009–2010 H1N1) and Ebola (2013). Indeed, some hyperimmune immunoglobulins – although more complex than CP – have been clinically used to aid treatment of certain diseases, including respiratory syncytial virus and hepatitis B.
There is a growing body of evidence to suggest that CP from previously infected patients is likely to be an effective and safe option for patients with a variety of severe acute respiratory infections (SARI) of viral aetiology. However, this evidence is currently based on predominantly low-quality uncontrolled studies.
As things stand, human CP is the sole source of antibodies available to be quickly used to combat SARS-CoV-2. There are many epidemic examples in recent history where SARI, caused by coronaviruses, have been treated with human CP, including SARS-1 in 2003 and MERS in 2012. These trials indicated CP was a safe treatment option and that it likely reduces mortality in SARI patients. One of the highlight studies was the testing of 80 SARS patients in Hong Kong in 2003. The trial and subsequent meta-analyses demonstrated that administering CP early after symptom onset – particularly within the first two weeks – is most impactful. However, CP therapy may be restricted because not all patients that recover from viral diseases continue to create antibodies – something that has been noted in 12% of SARS-1 patients. To mitigate this and select the most suitable antibody donors, antibody content must be measured in convalescent patients.
As early as February, China had already announced that it had trialled CP with 245 patients during the ongoing COVID-19 pandemic. Early reports including the signs from clinical indicators and symptoms were positive.
Initial indications from the current crop of uncontrolled studies show CP use has been safe and has led to improved patient outcomes. However, a comprehensive and controlled clinical trial must be undertaken to properly gauge the efficacy and safety of therapeutic CP being used to treat COVID-19 patients.
This is the therapeutic backdrop that has helped form the rationale of this study . It has been decided that it will be more impactful and effective to trial the use of human CP on COVID-19 patients still in the early stages of the disease, rather than critically ill patients further down the line who are currently undergoing mechanical ventilation.
Could you explain the advantages of using an adaptive study design?
Adaptive designs can make clinical trials more flexible by utilizing results accumulated in the proper trial to modify the trial’s course in accordance with pre-specified rules.
In this study, the data from the first 100 enrolled patients will be used to decide how to modify aspects of the study, without undermining the validity and integrity of the trial. As you know, COVID-19 is a recent illness and the medical community lacks proper information on patients’ evolution. The main endpoint is based on the ordinal scale proposed by the WHO R&D Blueprint and master protocol for COVID-19 therapeutic trials.
Once the first 100 patients are enrolled, the definition of the endpoint should be fine-tuned, through the correlation of outcomes of the clinical ordinal severity scale with the patient virologic state and seroconversion at the time of infusion, in order to ascertain that it is responsive to the eligible patient population and intervention. This is the reason why the Data Safety Management Board (DSMB), organized for this specific trial, will periodically evaluate study results, based on pre-planned cut-off points defined in the protocol, and determine the safety of the procedure on an ongoing basis and the suitability of the main endpoint as well as the sample size.
What are the challenges involved with the design and conduction of this trial and how can they be overcome?
Randomized and controlled clinical trials are the mainstay for the demonstration of efficacy and safety for the use of a novel therapy. The potential risks and challenges to be considered in this study are:
- Challenges regarding the coordination of any clinical trial involving the inclusion of patients who must comply with the inclusion criteria and who do not present any of the exclusion criteria.
- The set-up of an independent DSMB to perform supervision of the safety aspects of the trial. The DSMB has five members including at least one expert in clinical trial methodology and statistics, and one infectious diseases specialist independent from the study team. The DSMB has been established before the start of the trial and will follow the procedures established in the DSMB Charter.
- With modern blood banking techniques, any risks involving transfusion will be low.
- Another specific risk for patients with lung disease, such as those targeted in this trial, is the potential development of transfusion-related acute lung injury.
- For this trial, critically ill patients on mechanical ventilation with more advanced lung involvement have been excluded in order to avoid the small risk that virus-specific IgG may contribute to lung inflammatory damage.
How do you think future large-scale clinical trials for COVID-19 could be better streamlined?
We think that the master protocol of the WHO R&D Blueprint Clinical trials expert group [3,4], based on the deliberations of different experts including international clinical trialists, coronavirus experts, regulatory and ethics experts and clinicians, especially those who are treating COVID-19 patients, could facilitate the coordination of large-scale trials and streamline protocols in the design phase as well as the comparability among trials.
This trial’s protocol follows the master template, and since there are other ongoing clinical trials with different therapeutic alternatives, but with similar methodology based on the WHO initiative, this will allow more comprehensive evaluations to be made.
What impact do you think a convalescent plasma therapy could potentially have on patients’ health and the healthcare system?
There are only a few antiviral treatments available, which have limited efficacy in COVID-19 at present and, as mentioned above, human CP is currently the only source of antibodies available for immediate use against SARS-CoV-2. The robust design and methodology followed in this trial will hopefully provide strong evidence to inform decision making globally.
In our opinion, this alternative therapeutic tool could have a great impact due to donors’ availability in the general population and the relatively low cost of the treatment.
Finally, are there any other comments you would like to add?
As a medic and clinical trialist, I’m confident that this is a well-designed, appropriately planned and adequately powered trial that could shed light on the use of CP in COVID-19 patients, and hence inform decision makers and clinicians on the safety, efficacy and limitations of this therapeutic intervention.
I’m also confident that the enormous ongoing international effort in clinical trials for COVID-19 will eventually disentangle the best approach to reduce mortality rates as well as provide the most comprehensive approach in the prevention and treatment of this illness that has turned the world upside down.
- Rahimi-Levene N and Peer V. Vox Sanguinis International Forum on hospital transfusion services’ response to COVID-19. Vox. Sang. doi: 10.1111/vox.12944 (2020)
- ClinicalTrials.gov. Convalescent plasma therapy vs. SOC for the treatment of COVID-19 in hospitalized patients (ConPlas-19).
[Accessed 24 June 2020]
- World Health Organization R&D Blueprint. Novel coronavirus: COVID-19 therapeutic trial synopsis.
[Accessed 24 June 2020]
- World Health Organization R&D Blueprint. Novel coronavirus: outline of trial designs for experimental therapeutics.
[Accessed 24 June 2020]
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Infectious Diseases Hub or Future Science Group.
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