Lancet Neurol. 2024 Jun;23(6):565-576. doi: 10.1016/S1474-4422(24)00096-6. Epub 2024 Apr 18.
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.
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.
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.
This pilot phase trial exceeded its recruitment target, but a definitive trial will require extensive international engagement.
National Institute for Health and Care Research.
有症状的脑动静脉畸形患者面临的首要不确定性是选择接受医学治疗和手术还是仅接受医学治疗。我们开展了一项先导性随机对照试验，旨在评估在确定性试验中解决这一不确定性的可行性。
CARE 先导试验是一项在英国和爱尔兰的神经科学中心开展的前瞻性、随机、开放标签、评估者设盲、平行组试验。我们旨在招募 60 名任何年龄、性别和种族、有精神能力、居住在英国或爱尔兰、且患有症状性脑动静脉畸形的患者。采用计算机化、基于网络的随机化，将参与者（1:1）分为医学治疗和手术（神经外科切除术或立体定向放射外科手术）组或仅接受医学治疗组，根据神经外科医生和参与者在随机分组前对手术类型的共识进行分层。分配对研究者、参与者和照顾者开放，但不对临床结局事件裁决者开放。可行性结局包括参与度、招募、手术管理选择、保留率、依从性、数据质量、临床结局事件发生率和方案实施。主要临床结局是在至少 6 个月的随访期间，由于脑动静脉畸形或手术而出现症状性颅内出血或新的持续性或进行性非出血性局灶性神经功能缺损。我们根据分配的治疗方案对所有随机分配的参与者进行了数据分析。本试验在 ISRCTN（ISRCTN41647111）注册，现已完成。
在 2021 年 9 月 27 日至 2023 年 4 月 28 日期间，40 个（70%）参与中心中有 28 个参与，研究人员筛查了 511 名患者，其中 322 名（63%）符合纳入标准，202 名患者被邀请入组，96 名患者与神经外科医生对是否需要手术治疗症状性脑动静脉畸形存在共同的不确定性。在中位时间为 287（IQR 67-591）天的最近一次症状发作后，322 名符合条件的患者中有 72 名（22%）被随机分配（平均每月每个中心招募 0.2 [SD 0.25]名参与者）。参与者的中位年龄为 50.6（IQR 38.6-59.2）岁，72 名参与者中 68 名（94%）为成年人，41 名（57%）为女性，66 名（92%）为白人，56 名（78%）有过颅内出血史，28 名（39%）有过癫痫发作史。在随机分组前，计划手术类型为神经外科切除术的有 19 名（26%），立体定向放射外科手术的有 44 名（61%），还有 9 名（13%）无手术偏好。所有参与者的基线临床和影像学数据均完整。36 名参与者被随机分配到医学治疗和手术组（12 名接受神经外科切除术，24 名接受立体定向放射外科手术），36 名参与者被分配到单独的医学治疗组。72 名参与者中有 3 名（4%）退出，1 名失访，1 名拒绝面对面随访，67 名（93%）在 6 个月的临床随访时保留。67 名有随访数据的参与者中，61 名（91%）依从了分配的治疗策略。主要临床结局发生在随机分配到医学治疗和手术组的 33 名参与者中的 2 名（6.0%，每年 2.0-32.1/100 人）和随机分配到单独医学治疗组的 34 名参与者中的 2 名（6.0%，每年 1.9-30.1/100 人）。研究者报告没有死亡、严重不良事件、1 例方案违反和 61 例方案偏离。
这项先导性试验阶段的试验超过了其招募目标，但需要广泛的国际参与才能开展确定性试验。
英国国家卫生与保健研究院。
