Medical management and intervention (using neurosurgical resection or stereotactic radiosurgery) versus medical management alone for symptomatic brain cavernoma: the CARE pilot RCT.

Abstract

Background: The top priority for research into symptomatic cerebral cavernous malformation (also known as brain cavernoma) is whether to have medical management and intervention (using neurosurgical resection or stereotactic radiosurgery) or medical management alone.

Objectives: The primary objective was to assess the feasibility of performing a definitive randomised trial addressing this top priority. The secondary objectives were to set up a collaboration involving patient advocacy organisations and clinicians in the United Kingdom and Ireland; perform a QuinteT Recruitment Intervention to identify facilitators and address barriers to recruitment; and conduct a pilot randomised trial with ≈60 participants.

Design: Prospective, randomised, open-label, assessor-blinded, parallel-group trial. A mixed-methods QuinteT Recruitment Intervention analysed sites' screening logs and qualitative data from audio-recorded recruitment discussions, interviews with healthcare professionals and patients, investigator workshops and observation of meetings.

Setting: Neuroscience hospitals in the United Kingdom and Ireland.

Participants: We aimed to recruit ≈60 people of any age, gender and ethnicity who had mental capacity, resided in the United Kingdom/Ireland, and had a brain cavernoma that had caused symptoms due to intracranial haemorrhage, non-haemorrhagic progressive/persistent focal neurological deficit or epileptic seizure(s).

Interventions: We identified and addressed barriers and facilitators to optimise informed consent and recruitment. Computerised, web-based randomisation assigned participants (1 : 1) to treatment of their symptomatic brain cavernoma with medical management and intervention (using neurosurgical resection or stereotactic radiosurgery) or medical management alone. Assignment was open to investigators, participants and carers but not clinical outcome event adjudicators.

Main outcome measures: Feasibility outcomes included site engagement, recruitment, choice of surgical management, retention, adherence, data quality, clinical outcome event rate and protocol implementation. The primary clinical outcome was symptomatic intracranial haemorrhage or new persistent/progressive non-haemorrhagic focal neurological deficit due to brain cavernoma or intervention during ≥ 6 months of follow-up.

Results: Investigators screened 511 patients at 28/40 (70%) sites in the United Kingdom: 322 (63%) eligible, 202 (63%) approached, 96 (48%) uncertain about whether to have intervention and 72 participants [median age was 51 years (interquartile range 39-59), 41 (57%) female, 66 (92%) white, 56 (78%) with prior intracranial haemorrhage and 28 (39%) with prior epileptic seizure] were randomly assigned to medical management and intervention (n = 36; 12 to neurosurgical resection and 24 to stereotactic radiosurgery) or medical management alone (n = 36) after a recruitment extension. Sixty-seven participants completed follow-up (retention 93%), and adherence was 91%. Barriers to recruitment included usual-care practices and logistical issues with stereotactic radiosurgery, whereas facilitators were neurosurgeons' preparedness to offer intervention to more people than in usual care, multidisciplinary team equipoise and presenting the study as a solution to equipoise. The primary clinical outcome occurred in 2/33 assigned to medical management and intervention and 2/34 assigned to medical management alone. There were no deaths or serious adverse events.

Limitations: We could not activate sites in Ireland. The generalisability of our findings outside the United Kingdom is unknown.

Conclusions: This pilot randomised trial identified facilitators and barriers to recruitment, exceeded its recruitment target and met some feasibility metrics.

Future work: A definitive randomised trial will need extensive engagement from international funders and networks of clinicians, researchers and patient groups to recruit 590-1900 participants.

Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128694.