Treat_CCM Clinical Trial A Multicenter Randomized Clinical Trial on Propranolol in Familial Cerebral Cavernous Malformation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 71
- 试验地点
- 6
- 主要终点
- Adverse clinical events CCM-related.
研究概览
简要总结
Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease which can be either congenital in origin or sporadic and is characterized by the presence of isolated or multiple CCM lesions, causing recurrent headache, seizures, focal neurological deficits and hemorrhages. Inasmuch, to date, the only curative treatment available is limited to surgical lesion eradication or stereotactic radiosurgery. It is therefore necessary to find an effective medical treatment that may limit disease progression and decrease the burden of adverse clinical events. The non-selective betablocker propranolol has been found to be effective in the treatment of infantile cutaneous hemangioma, and anecdotal reports have been published on its efficacy in CCM. The safety profile of propranolol has been documented in millions of patients of all ages.
The primary objective of this exploratory trial is to test whether a chronic treatment with propranolol will reduce the burden of cerebrovascular lesions, of clinical events and symptoms in patients with familial CCM.
详细描述
The project will consist of a multicenter, open-label, randomized study (PROBE design) in patients with CCM to be randomized in a 2:1 ratio (propranolol:control) and will allow comparison of 2 groups: one receiving propranolol (recommended initial dose is 40 mg bid, to be uptitrated to 80 mg bid, however, doses as low as 10 mg bid and up to 160 mg bid are acceptable according to tolerability) on the top of recommended standard care, the other receiving recommended standard care. This investigator-driven study will be open-label with a PROBE design will be applied so that each MRI exam will be centrally read and all adverse clinical events will be centrally adjudicated. It should be pointed out that by no means surgery, whenever indicated, will be delayed and/or avoided because of study treatment allocation.
The purpose of this exploratory trial is to test whether a chronic treatment with propranolol will reduce the burden of cerebrovascular lesions, of clinical events and symptoms in patients with familial CCM. Inherited CCM is a rare disease with a prevalence of less than 5/10.000. Thus, since the number of patients to be included in this exploratory trial will be insufficient to prove or disprove a statistically significant beneficial effect of propranolol on clinical events, the extension to more centers and patients is formally included in the present protocol. Special care will be paid to the biologic consistency of the different endpoints, even if none of them will yield statistically significant differences. The assessment of the tolerability of propranolol in normotensive otherwise healthy patients is another clinically relevant endpoint.
If the overall evaluation of the safety (no difference in AEs and SAEs between propranolol and control arms), and of the efficacy profile (assessed as consistency between incidence of adverse clinical events and magnetic resonance brain imaging results between propranolol and control arms) at the conclusion of the present study, will be reassuring for propranolol, a protocol for a definitive Phase 2 trial will be submitted for approval to Regulatory Authorities. This second trial may be designed as single-arm as far as adequate data on incidence of endpoint events will be available from Treat_CCM.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Treat_CCM is a Prospective Randomized Open Trial with Blinded Evaluation of outcomes (PROBE).
Clinical events CCM-related (i.e. intra-cerebral hemorrhage and focal neurological deficits excluding seizures) will be blindly adjudicated by an independent Event Committee.All MRI exams will be read in a Central Laboratory by experienced neuroradiologists, unaware of patient identification and study treatment.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with Familial cerebral cavernous malformations (FCCM);
- •history of clinical symptoms or events: intracerebral hemorrhage, stroke, permanent or transient focal deficits, seizures, disability or any other neurological symptom supposedly related to CCM;
- •age of at least 18 years.
- •Written informed consent to participate in the study prior to any study procedures.
排除标准
- •Implanted pacemaker or any other condition preventing the magnetic resonance imaging (MRI);
- •bradycardia (<50 bpm) or 2nd or 3rd degree AV block, hypotension (symptomatic);
- •unstable diabetes;
- •severe asthma;
- •renal and/or liver failure;
- •current use of verapamil and diltiazem for risk of excessive bradycardia;
- •previous brain surgery (within 6 months);
- •known hypersensitivity to study drug (propranolol or any of the ingredients)
- •pregnant or lactating women or women of childbearing potential who are not protected from pregnancy by an accepted method of contraception
- •participation to another clinical trial;
- •inability to cooperate with the trial procedures.
研究组 & 干预措施
Propranolol
Initial oral dose 40 mg bid, uptitrated to 80mg bid doses as low as 10 mg bid and up to 160 mg bid, 20 to 320mg daily, are acceptable according to tolerability.
干预措施: Propranolol (Drug)
结局指标
主要结局
Adverse clinical events CCM-related.
时间窗: up to 24 months
New occurrence of clinical events CCM-related, that is intra-cerebral hemorrhage (ICH) and focal neurological deficits (FND) excluding seizures.
次要结局
- Diameter of CCM lesions at MRI.(up to 24 months)
- De novo CCM lesions depiction on MRI.(up to 24 months)
- Location and MRI signal characteristics of CCM lesions at MRI.(up to 24 months)
- Length of CCM lesions at MRI(up to 24 months)
- Dynamic contrast enhanced permeability (DCEP) at MRI.(up to 24 months)
- Adverse clinical outcomes, other than ICH and FND.(up to 24 months)
- Micro-hemorrhages at MRI.(up to 24 months)