CARE pilot trial collaboration
2024년 4월 18일
The Lancet Neurology 2024; 23: 565-76
Published Online April 18, 2024
https://doi.org/10.1016/S1474-4422(24)00096-6
Abstract
Background
The highest priority uncertainty for people with symptomatic cerebral cavernous malformation is whether to have medical management and surgery or medical management alone. We conducted a pilot phase randomised controlled trial to assess the feasibility of addressing this uncertainty in a definitive trial.
Method
The CARE pilot trial was a prospective, randomised, open-label, assessor-blinded, parallel-group trial at neuroscience centres in the UK and Ireland. We aimed to recruit 60 people of any age, sex, and ethnicity who had mental capacity, were resident in the UK or Ireland, and had a symptomatic cerebral cavernous malformation. Computerised, web-based randomisation assigned participants (1:1) to medical management and surgery (neurosurgical resection or stereotactic radiosurgery) or medical management alone, stratified by the neurosurgeon’s and participant’s consensus about the intended type of surgery before randomisation. Assignment was open to investigators, participants, and carers, but not clinical outcome event adjudicators. 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 or progressive non-haemorrhagic focal neurological deficit due to cerebral cavernous malformation or surgery during at least 6 months of follow-up. We analysed data from all randomly assigned participants according to assigned management. This trial is registered with ISRCTN (ISRCTN41647111) and has been completed.
Findings
Between Sept 27, 2021, and April 28, 2023, 28 (70%) of 40 sites took part, at which investigators screened 511 patients, of whom 322 (63%) were eligible, 202 were approached for recruitment, and 96 had collective uncertainty with their neurosurgeon about whether to have surgery for a symptomatic cerebral cavernous malformation. 72 (22%) of 322 eligible patients were randomly assigned (mean recruitment rate 0·2 [SD 0·25] participants per site per month) at a median of 287 (IQR 67–591) days since the most recent symptomatic presentation. Participants’ median age was 50·6 (IQR 38·6–59·2) years, 68 (94%) of 72 participants were adults, 41 (57%) were female, 66 (92%) were White, 56 (78%) had a previous intracranial haemorrhage, and 28 (39%) had a previous epileptic seizure. The intended type of surgery before randomisation was neurosurgical resection for 19 (26%) of 72, stereotactic radiosurgery for 44 (61%), and no preference for nine (13%). Baseline clinical and imaging data were complete for all participants. 36 participants were randomly assigned to medical management and surgery (12 to neurosurgical resection and 24 to stereotactic radiosurgery) and 36 to medical management alone. Three (4%) of 72 participants withdrew, one was lost to follow-up, and one declined face-to-face follow-up, leaving 67 (93%) retained at 6-months’ clinical follow-up. 61 (91%) of 67 participants with follow-up adhered to the assigned management strategy. The primary clinical outcome occurred in two (6%) of 33 participants randomly assigned to medical management and surgery (8·0%, 95% CI 2·0–32·1 per year) and in two (6%) of 34 participants randomly assigned to medical management alone (7·5%, 1·9–30·1 per year). Investigators reported no deaths, no serious adverse events, one protocol violation, and 61 protocol deviations.

Interpretation
This pilot phase trial exceeded its recruitment target, but a definitive trial will require extensive international engagement.
요약
소개 : 증상이 있는 뇌혈관 기형(cavernous malformation) 환자들을 대상으로 한 파일럿 임상시험이다. 뇌혈관 기형 환자에서 내과적 치료는 간질, 통증 등을 조절하기 위해 사용되며, 수술적 치료는 뇌내 출혈이나 간질성 발작의 장기적인 예방을 위해 시행된다. 하지만 그동안 수술적 치료와 내과적 치료 단독을 비교하는 임상시험이 없었고 증상이 있는 뇌혈관 기형 환자에서 수술적 치료를 추천하기 위한 가이드라인이 마련되지 못했다. 증상이 있는 뇌혈관 기형에 대해 수술적 치료와 내과적 치료를 함께 받는 것과 내과적 치료 단독을 비교하기 위한 임상시험을 시행하였다.
방법 : 증상이 있는 뇌혈관 기형 환자들을 내과적 치료와 수술적 치료를 함께 받는 환자군과 내과적 치료 단독으로 받는 환자군으로 무작위 배정하여 임상시험을 진행하였다. 주요 임상결과(primary clinical outcome)는 증상이 있는 두개내 출혈이나, 뇌혈관 기형 또는 수술로 인한 새로운 비출혈성 국소 신경학적 결손이었으며, 이는 최소 6개월의 추적 관찰 기간 동안 평가되었다.
결과 : 위의 주요 임상결과는 내과적 치료만 받은 환자군에서 34명 중 2명에서 발생하였고(6%), 내과적 치료와 수술적 치료 모두 받은 환자군에서 33명 중 2명에서 발생하였다(6%).
결론 및 의의 : 본 연구의 결과 증상이 있는 뇌혈관 기형 환자에서 수술적 치료와 내과적 치료를 함께 시행하는 것과 내과적 치료를 단독으로 받는 환자군 간에 열등성을 보이지 않았고, 따라서 뇌혈관 기형 환자에서의 수술적 치료와 내과적 치료 단독을 비교하는 임상연구가 시행될 수 있음을 보여주었다.
#Cavernous malformation