Developing a Randomised Efficacy PREcision medicine Platform trial design for Cavernomas: the CARE PREP study

• Published in: Efficacy and Mechanism Evaluation
• Main Authors: Rustam Al-Shahi Salman, Kasia Adamczuk, Richard A Parker, Christopher J Weir, Roberto Latini, Helen Kim, David White, Helen Evans, Jana Bergholtz, Cornelia Lee, Carlos Casaus
• Format: Article
• Language: English
• Published: NIHR Journals Library 2025-03-01
• Subjects: haemangioma; cavernous; central nervous system; humans; animals; sample size; propranolol; consensus; leadership; aspirin; feasibility studies; seizures; phenotype; biomarkers; randomised controlled trials as topic
• Online Access: https://doi.org/10.3310/TYUP6982

Background Symptomatic cerebral cavernous malformations are a rare sporadic or familial disease, which may cause haemorrhagic strokes or epileptic seizures. In 2015, a James Lind Alliance Priority Setting Partnership ranked targeted drug therapies as fourth of the top 10 research priorities for cerebral cavernous malformations. There are no disease-modifying drugs for cerebral cavernous malformations, but there are several promising candidates with proof of concept in human and animal studies. There are no platform trials for cerebral cavernous malformations. Objectives (1) Consolidate and initiate international collaborations between cerebral cavernous malformations researchers, cerebral cavernous malformations patient and public involvement groups, cerebral cavernous malformations research networks, and commercial partners; (2) Finalise a protocol for an efficient, international platform trial of multiple drugs using precision medicine (sporadic vs. familial cerebral cavernous malformations) that is both feasible and acceptable to patients and regulators; (3) Estimate the research, support and treatment costs of the platform trial and apply to the National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme. Methods A National Institute for Health and Care Research Efficacy and Mechanism Evaluation Application Acceleration Award funded this project from September 2022 to August 2023. A trial manager supported the Chief Investigator in growing and leading a multidisciplinary international collaboration, including a patient and public involvement advisory group, in a series of meetings to optimise study design, equality, diversity and inclusion. Edinburgh Innovations established connections with commercial partners with candidate drugs. We assessed feasibility by scoping potential funding agencies, and clinical networks that might support recruitment internationally. We agreed upon a final design and sample size through a process of consensus, enlightened by scenarios simulated by statisticians varying key parameters, which informed a comprehensive estimate of the budget for a stage 1 submission to the National Institute for Health and Care Research Efficacy and Mechanism Evaluation programme. Setting International collaboration. Participants Clinicians, researchers, patient and public involvement groups, cerebral cavernous malformations research networks, and commercial partners. Results There was one face-to-face meeting, nine virtual meetings of the co-applicants, and five meetings of the patient and public involvement advisory group. We identified 14 countries with clinical leadership, a cerebral cavernous malformation research network, and a funding agency that could support an international trial. We contacted three potential commercial partners and obtained one letter of collaboration. We sent monthly newsletters to collaborators. Our meetings and simulations concluded that a three-arm, two-stage multiarm multistage adaptive treatment selection randomised trial design was suitable for evaluating aspirin and propranolol as the first two interventions compared with standard care in a platform trial. We submitted a stage 1 proposal for this Cavernous malformations A Randomised Efficacy MAster Protocol study to the National Institute for Health and Care Research Efficacy and Mechanism Evaluation call 23/15 in May 2023, and a resubmission was encouraged. Limitations The National Institute for Health and Care Research Efficacy and Mechanism Evaluation funding committee would have required further justification for the choice of the intermediate phenotype used for treatment selection, biomarker validation work, and details about the pipeline of interventions. Future work We have addressed these limitations and re-applied to the National Institute for Health and Care Research Efficacy and Mechanism Evaluation programme. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number NIHR153811. Plain language summary What was the aim? A cerebral cavernous malformation, also known as ‘cavernoma’, is a cluster of blood vessels that form blood-filled caverns in the brain. Cerebral cavernous malformations can bleed to cause a stroke or cause epileptic seizures. In 2015, a partnership between patients and doctors ranked finding drugs to treat cerebral cavernous malformations as the fourth research priority for cerebral cavernous malformations. There are no specific drugs for cerebral cavernous malformations, but human and animal studies have identified several promising drugs. We obtained funding from the National Institute for Health and Care Research to plan for a future study that would test promising drugs. What did we do? Between September 2022 and August 2023, we set up a large international collaboration of doctors, researchers, and patients. An international patient and public involvement advisory group advised the collaboration. We identified promising drugs that are already available. We also approached companies that were developing new drugs for cerebral cavernous malformations. We grew our international collaboration. We agreed on the details and design of an innovative study, called a ‘platform trial’, that could compare several promising drugs with standard care to treat cerebral cavernous malformations. We met face-to-face once and online nine times. The patient and public involvement advisory group met five times. Fourteen countries seemed suitable for an international study. One pharmaceutical company was willing to collaborate. With the patient and public involvement advisory group, we agreed on a design for a platform trial to compare aspirin and propranolol with standard care. We submitted a funding proposal to the National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme in May 2023. The National Institute for Health and Care Research Efficacy and Mechanism Evaluation Funding Committee encouraged us to resubmit the application and provided suggestions to improve the design. We addressed the feedback and re-applied. We sent monthly newsletters to collaborators. We presented our work at the 2022 Alliance to Cure Cavernous Malformation International Scientific Meeting. We worked with the patient and public involvement advisory group to produce plain English newsletters, social media posts and a project summary.