Since the beginning of the PROACT EU-Response project, the protocol writing committee, composed of representatives of 26 project partners, including the European Patients’ Forum, has been working on the development of the protocol for the European Syndromic Adaptive Clinical Trial (EU-SyndAct). This article introduces EU-SyndAct and explores how it fosters patient-centric research through innovative trial design, patient involvement and a focus on patient-important outcomes.
An innovative approach to clinical trials through the use of platform trials
EU-SyndAct is an adaptive clinical trial platform for patients hospitalised with a severe acute respiratory tract infection, based on an innovative methodological approach, for which regulatory and operational frameworks are still evolving. Platform trials enable the testing of multiple therapies within a disease area, both new and repurposed, alone or in combination, in a continuous manner. Therapies are allowed to enter or leave the platform based on a decision algorithm while the trial continues to run. This helps make the trial more efficient because the trial infrastructure remains consistently up and running, participating teams gain expertise as the trial progresses, and the platform is ready to operate in the event of a public health emergency. In EU-SyndAct, different levels of site commitment, from minimum data capture to advanced contributions and addressing further research questions, also ensure the inclusion of more trial sites. A process evaluation examining how the trial is being implemented, including feedback from participating patients, will help us learn and improve future trials, both within the PROACT EU-Response project and outside the project.
Platform trials can also allow more patients to have access to promising treatments, as a shared control group – receiving the current standard of care – can be used across several treatment arms. This is particularly relevant in the field of antivirals for respiratory diseases, on which EU-SyndAct focuses, where few treatments exist, and the standard of care often consists mainly of supportive care. EU-Syndact builds on some of the outputs and templates developed through the EU-PEARL project (EU-Patient Centric Clinical Trial Platforms), an important reference project for the design, set-up and implementation of patient-centric collaborative platform trials in Europe, funded by the Innovative Medicines Initiative (IMI) 2 and active between November 2019 and April 2023.
Protocol development and trial set up
Since the beginning of the project, the protocol writing committee has been working on an umbrella protocol that describes the overall principles of EU-SyndAct, as well as pathogen-specific master protocols for treatments of SARS-CoV-2 (COVID-19), influenza virus A/B (FLU), and Respiratory Syncytial Virus (RSV). Importantly, a readiness master protocol is also being developed for pathogen X, a potential future new and emerging pathogen, to strengthen preparedness and ensure that trial sites are ready to initiate clinical trials of potential therapies in the event of a new health threat. The eligible patient population includes adults hospitalised with a confirmed viral respiratory infection and symptoms of acute respiratory illness who are not receiving invasive mechanical ventilation at the start of the trial. Considerations around inclusiveness and representativeness have also been taken into account in the trial design, recognising the importance of recruiting a patient population that reflects the diversity of people affected.
As the objectives and outcomes to be collected in the trial were being discussed, significant attention was paid to collecting patient experience data, particularly patient-reported outcomes (PROs). While the primary objective of the trial is to evaluate the efficacy of treatments on recovery in adults hospitalised with a viral respiratory infection, other objectives include evaluating the efficacy of treatments on short-term symptom severity and longer-term health-related quality of life (HRQoL). Beyond traditional outcomes such as the need for organ support, viral load, or hospital discharge, understanding therapies’ impacts on symptoms and patients’ quality of life helps assess how they perform in real-world settings and better measure the value they provide to patients. Only patients can tell us what “recovery” means, based on how they feel and the symptoms they experience in the short, medium, and long term. This is why collection of patient-reported outcomes is critical.
Capturing what matters to patients through PROs
Patient-reported outcomes (PROs) bring significant value in assessing the potential benefits and disadvantages of a new treatment, but they also present specific challenges.
In particular, methodologists are concerned about the use of potentially non-validated instruments. Ensuring that patient-reported outcome measures (PROMs) are appropriately developed and validated, and that they capture patient experiences consistently and reliably is essential to maintaining the usability of the data and the credibility of the research. There are still relatively few validated instruments. In the field of respiratory diseases, commonly used tools include FLU-PRO/FLU-PRO Plus, which measure the presence and severity of symptoms associated with influenza and other acute respiratory infections. Access to some instruments comes at a high cost, which trial sponsors are not always able to afford. Recourse to academically developed, validated tools can provide an alternative. In the case of EU-SyndAct, a solution was found using a COVID-19-specific health-related quality-of-life questionnaire developed by the University of Oslo, validated through patient involvement, and available in 13 languages.
Another important challenge is finding the right balance in the volume and administration of PROM questions, so as not to overburden trial participants – enabling them to share how they feel and capturing everything that is relevant to them, without overwhelming them.
To ensure the approach was fit for purpose, at different stages of the protocol’s development, project partners consulted PROACT EU-Response’s Patient Advisory Group, currently composed of nine patient representatives across respiratory and non-respiratory diseases.
Looking ahead: from patient experience to evidence
Encouraging the development of validated questionnaires and increasing awareness of available tools are important steps towards better and more systematic collection of patient experience data. Involving patients in this process is also essential to ensure that questionnaires remain accessible and do not pose an unnecessary burden. As the European Medicines Agency advances its work on Patient Experience Data, and Health Technology Assessment (HTA) bodies increasingly integrate the patient perspective, ensuring that robust, meaningful and patient-relevant data, such as PROMs, are systematically collected in clinical trials will become ever more important to demonstrate and explain the value of new treatments to regulators, HTA bodies, healthcare professionals and, of course, patients. Through its approach to patient involvement and patient-reported outcomes, EU-SyndAct will provide an important opportunity to put these principles into practice.
