Title: Cavernomas A Randomised Effectiveness (CARE) pilot trial, to address the effectiveness of active treatment (with neurosurgery or stereotactic radiosurgery) versus conservative management in people with symptomatic brain cavernoma
Funder: Chief Scientist Office, Scotland

Abstract: Background_x000D_ _x000D_ A cavernoma is a cluster of blood vessels that form blood-filled ‘caverns’ in the brain that look like a raspberry. Cavernomas can bleed into the brain and cause a stroke. Cavernomas can also cause a seizure or epilepsy. These symptoms may lead to disability, handicap and occasionally death. About 160 people in the UK each year are diagnosed with a cavernoma that has caused symptoms. In standard practice in the UK, about one fifth of people with cavernomas have ‘active treatment’ with either brain surgery to remove a cavernoma or stereotactic radiosurgery to treat it with radiation. These treatments themselves can cause death, disability, and handicap._x000D_ _x000D_ The pros and cons of active treatment or avoiding it by just treating the symptoms (also known as 'conservative management') are finely balanced. The most reliable way of finding out which management is best is to do a randomised trial, in which suitable patients are allocated to active treatment or conservative management at random. This has never been done with cavernomas, and this was the top priority identified by a Priority Setting Partnership for cavernoma._x000D_ _x000D_ Aim_x000D_ _x000D_ The NIHR wants research to be done to find out whether enough patients can be found for a randomised trial comparing ‘active treatment’ with ‘conservative management’ of symptomatic cavernomas. We need to know this because cavernomas are rare and we do not know whether patients and doctors will take part._x000D_ _x000D_ Design and methods used_x000D_ _x000D_ In three years we will:_x000D_ (1) Create a network of specialists to do this study. We will include the UK and Ireland patient support organisations for people with cavernoma (Cavernoma Alliance UK) and doctors representing the relevant specialties at all the major hospitals specialising in decisions about cavernoma treatment in the UK and Ireland._x000D_ (2) Invite newly diagnosed patients to join a pilot phase of a randomised controlled trial. Of 190 people diagnosed with brain cavernoma in 18 months, we estimate that 60 of them will enrol in the randomised trial. We will study why some patients take part in the randomised trials and others don't. We will use this information to change the methods of the trial if recruitment to the randomised trial goes slowly._x000D_ (3) Estimate whether enough patients can be found for a full-scale randomised trial to be done to find out whether active treatment or conservative management of symptomatic brain cavernomas is best._x000D_ _x000D_ Patient and public involvement_x000D_ _x000D_ We involved people with cavernoma, carers, and representatives of Cavernoma Alliance UK in the design of this application. We held a focus group meeting with patients and carers on 6 July 2019: all approved the design of the project and the extent of patient and public involvement. The focus group wanted the trials to be as inclusive of patients as possible. The focus group recognised how the project would benefit from them contributing their 'lived experience' of brain cavernoma._x000D_ _x000D_ People with cavernoma, carers, and representatives of Cavernoma Alliance UK will also keep an eye on the research by forming an advisory group and meeting regularly to discuss the research. Two representatives of this group will join and advise the steering committee._x000D_ _x000D_ Dissemination_x000D_ _x000D_ We will publish our findings in medical journals. We will work with Cavernoma Alliance UK to produce a plain English summary and circulate it to patients via newsletters, email, the web, and social media.

Lay abstract: Research question_x000D_ _x000D_ We will conduct a pilot randomised controlled trial (RCT) to assess the feasibility of conducting a definitive main phase RCT to address the commissioned research question, "How effective is treatment (with neurosurgery or stereotactic radiosurgery) versus conservative management in people with symptomatic brain cavernoma?" We will assess collaborator engagement; proportions of screened patients that are eligible, approached, consented, or randomised; barriers to recruitment; RCT procedure implementation; adherence; data completeness; outcome event rates; and generalisability._x000D_ _x000D_ Background_x000D_ _x000D_ At least 160 people with brain cavernomas are newly diagnosed after symptoms due to stroke or epilepsy in the UK each year. A James Lind Alliance Priority Setting Partnership found that the top research priority for cavernoma was, “Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?” A RCT is required to answer this question, but our systematic reviews and trial register searches have not revealed any such randomised trials. _x000D_ _x000D_ Aims and objectives_x000D_ _x000D_ 1. Engage a collaboration of specialists and patient advocacy groups in the UK & Ireland._x000D_ 2. Establish a pilot RCT, with an embedded qualitative study to understand the anticipated recruitment processes and address any barriers._x000D_ 3. Estimate the feasibility of performing a definitive main phase of the RCT._x000D_ _x000D_ Methods_x000D_ _x000D_ (1) We will engage collaborating representatives of all relevant specialties at all neuroscience centres in the UK & Ireland, prepare study documents, create software applications, and obtain regulatory approvals._x000D_ _x000D_ (2) We will establish a pilot RCT including:_x000D_ _x000D_ i. A pilot phase of the Cavernomas A Randomised Effectiveness (CARE) parallel group RCT for patients with symptomatic brain cavernoma, comparing conservative management versus active treatment (neurosurgery or stereotactic radiosurgery), with randomisation stratified by preferred type of active treatment. Collaborators will keep screening logs to capture characteristics of patients screened, eligible, approached, consented and randomised. We estimate that this prospective randomised open blinded end-point RCT will recruit ~60 participants._x000D_ _x000D_ ii. An integrated Qualitative Research Integrated within Trials (QuinteT) recruitment intervention will evaluate screening logs and incorporate qualitative research to understand recruitment processes and barriers as well as actions to address barriers._x000D_ _x000D_ (3) We will use (1) and (2) to estimate the feasibility and generalisability of a definitive main phase of the CARE RCT by extending the UK collaboration to other patient support organisations and clinical communities elsewhere in the world (including, but not limited to, ten professional organisations, nine cavernoma clinical academics, and eight patient advocacy organisations from across the world who have provided letters of support, appended to this application)._x000D_ _x000D_ Timelines for delivery_x000D_ _x000D_ 0-9 months: set-up. 10-27 months: recruitment. 28-33 months: follow-up. 34-36 months: analysis._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ _x000D_ We will determine the feasibility of a main phase RCT with international collaborators and funders to address the commissioned research question, and publish these findings with a plain English summary. We will inform patients and carers via Cavernoma Alliance UK and social media.

Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CARDIOVASCULAR;NEUROLOGICAL