Title: Accelerated development of Cavernomas: A Randomised Efficacy PREcision medicine Platform trial (CARE PREP)
Funder: Medical Research Council

Abstract: BACKGROUND A cerebral cavernous malformation, also known as 'CCM' or 'cavernoma' for short, is a cluster of blood vessels that form blood-filled caverns in the brain that look like a raspberry. CCM can bleed and cause a stroke. CCM can cause epileptic seizures. These symptoms may happen repeatedly, and lead to disability and occasionally death. About 160 people in the UK each year are first diagnosed with a CCM that has caused symptoms. People with CCM can be treated with either brain surgery to remove CCM or focussed radiation treatment to try to stabilise CCM. Our CARE pilot phase randomised controlled trial, funded by NIHR HTA, is the most reliable test of whether using these treatments is better than avoiding them. Many patients invited to take part in this trial decline because they would rather avoid these treatments, and would prefer a drug. In 2015, a partnership between patients and doctors ranked targeted drug therapies as the fourth of the top 10 research priorities for CCM. There are no specific drugs for CCM, but human and animal studies have identified several promising drugs. AIMS, DESIGN AND METHODS Extensive PPI involvement has co-designed this acceleration award with researchers from the start. 1. A trial manager will support the Lead Applicant to coordinate, grow and strengthen collaborations to design the first international platform trial of targeted treatment for CCM with drugs. A platform trial is an efficient way to compare several drugs to placebo at once. Platform trials identified many of the treatments for COVID-19 quickly. We plan to start with 3 drugs that are used for other conditions: a beta-blocker, a statin, and aspirin. We will design the trial to study drug effects on patients grouped according to gene changes or CCM location (known as ‘stratification’), which will tell us whether these drugs can be targeted at patients (known as ‘precision medicine’). We will identify additional drugs and seek collaboration from commercial partners with drugs that might benefit CCM; one commercial partner is collaborating already. 2. Platform trials are complex. Regulations for clinical trials vary around the world. So we will seek information about these regulations to find a design that could work internationally. A senior statistician will use simulation techniques to find the most efficient design for the platform trial. 3. PPI co-applicants will help design the platform trial to be acceptable to patients and carers and maximise their diversity, by seeking feedback from PPI networks. We will assess the feasibility of recruiting enough patients via CCM clinical research networks. 4. We will use all of this information and conversations with international funding agencies to work out the cost of the platform trial, and which funders would consider contributing. We will apply for funding to NIHR EME in May 2023. PPI INVOLVEMENT The three PPI co-applicants will form a Patient and Pubic Advisory Group (PAG). Lee and White are both carers, and Bergholtz is a CCM patient/service user. They lead non-profit CCM organisations which offer support, information and events for patients, carers and the public. IMPACT AND DISSEMINATION We will design the first international platform trial of targeted drug treatment for CCM and apply for funding. We will present at the 2022 CCM International Scientific Meeting. With PAG, we will produce plain English newsletters, social media posts, and a summary about the project.

Lay abstract: RESEARCH QUESTIONS • What is the optimal design of an international platform trial of precision medicine with drugs for cerebral cavernous malformations (CCM, also known as brain cavernomas)? • Is delivery of the optimal platform trial design feasible? BACKGROUND Symptomatic CCM are a rare sporadic or familial disease. Approximately 160 people are first diagnosed with symptomatic CCM in the UK annually, but the impact of CCM is disproportionately high because they are usually diagnosed in young adults who are at risk of stroke due to intracranial haemorrhage (rate 0.8% to 6.2% per year) and epileptic seizures. In 2015, a James Lind Alliance Priority Setting Partnership ranked targeted drug therapies as the fourth of the top 10 research priorities for CCM. There are no disease-modifying drugs for CCM, but there are several promising candidates for sporadic or familial CCM with proof of concept in human and animal studies. There are no platform trials for CCM. AIMS AND OBJECTIVES 1. Consolidate and initiate international collaborations between CCM researchers, CCM patient and public involvement (PPI) groups, CCM research networks, and commercial partners. 2. Understand regulatory and governance requirements in collaborating countries. 3. Finalise a protocol for an efficient, international platform trial of multiple drugs using precision medicine (sporadic vs. familial CCM) that is feasible and acceptable to patients and regulators. 4. Estimate the research, support and treatment costs of the platform trial. METHODS A trial manager will support the chief investigator to lead our multidisciplinary international collaboration in a series of virtual meetings, and one face-to-face meeting. A PPI Advisory Group will inform the co-applicants about patients’ preferences for study design, and recommend how to maximise equality, diversity, and inclusion. Edinburgh Innovations will establish collaborations with pharmaceutical companies that manufacture candidate drugs. The trial manager will assess feasibility by scoping regulatory requirements for platform trials in co-applicants’ countries, potential funding agencies, and clinical networks that might support recruitment. Co-applicants will refine hypotheses, eligibility and precision/stratification criteria, interventions, comparator(s), adaptive trial design, allocation ratio, clinical/intermediate outcomes (prioritised with PPI input), and anticipated treatment effects, informed by scenarios simulated by the statistician using variations in these parameters. The final protocol for the platform trial will inform a comprehensive estimate of the budget, for a stage 1 submission to NIHR EME. TIMELINES FOR DELIVERY Months 1-12: Co-applicants meet monthly and consolidate collaborations. Two-monthly PPI Advisory Group meetings. Months 1-6: Identify regulatory requirements, funding opportunities, and CCM clinical networks; protocol design and development. Months 1-8: Develop commercial partnerships. Months 7-8: Protocol completion with a feasibility assessment and budget. Month 9: NIHR EME stage 1 submission. Months 10-12: NIHR EME stage 2 preparation. ANTICIPATED IMPACT AND DISSEMINATION This award will catalyse the design, delivery, and assessment of the feasibility of a protocol and funding application for the first CCM platform trial of drugs. We will present at the 2022 CCM International Scientific Meeting, produce newsletters for collaborators and PPI groups, and release a final report.

Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CARDIOVASCULAR;NEUROLOGICAL