Is Adding Cilostazol to Nimodipine Improving Neurological Outcome of Patients With Aneurysmal Subarachnoid Hemorrhage? A Randomized, Double Blind, Placebo-controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 630
- 主要终点
- Modified Rankin Scale (mRS) Score at 6 Months After Aneurysmal Subarachnoid Hemorrhage
研究概览
简要总结
The CASH study is a randomized, double-blind, placebo-controlled trial evaluating whether adding cilostazol to standard nimodipine therapy improves neurological outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). The primary objective is to assess functional outcome at 6 months using the modified Rankin Scale. A total of 630 patients will be enrolled within 96 hours of aSAH onset and treated for 14 days. The study is conducted across 9 centers in France, funded by a PHRC, and overseen by an independent monitoring board.
详细描述
The CASH trial (Cilostazol in Aneurysmal Subarachnoid Hemorrhage) is a multicenter, randomized, double-blind, placebo-controlled Phase III clinical trial investigating whether the addition of cilostazol to standard nimodipine therapy improves long-term neurological outcomes in patients suffering from aneurysmal subarachnoid hemorrhage (aSAH).
Secondary brain injury following aSAH, particularly delayed cerebral ischemia (DCI) and vasospasm, remains a major cause of mortality and long-term disability. Currently, nimodipine is the only drug with proven efficacy in improving neurological outcomes after aSAH. However, emerging data-mostly from studies conducted in Japan-suggest that cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor with antiplatelet and vasodilatory effects, may further reduce the risk of ischemic complications and disability when added to standard care.
The cilostazol mechanism includes inhibition of platelet aggregation via cAMP enhancement, vasodilation via nitric oxide release, and endothelial protection. Experimental studies also suggest neuroprotective effects such as attenuation of cortical spreading depolarizations and inhibition of vascular smooth muscle cell proliferation.
The trial will enroll 630 adult patients admitted to intensive care units within 96 hours of a confirmed aSAH due to a ruptured aneurysm that has been secured by either surgical clipping or endovascular coiling. Patients will be randomly assigned to receive either cilostazol 100 mg twice daily for 14 days (administered orally or via gastric tube) or placebo, alongside the standard 21-day nimodipine regimen.
The primary endpoint is the neurological outcome at 6 months, assessed by the modified Rankin Scale (mRS). Secondary outcomes include cognitive performance (MoCA score), return to work, independence in daily activities, hospital and ICU stay durations, 28-day mortality, and incidence of DCI, vasospasm, and cerebral infarctions as defined by imaging or clinical criteria.
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
- Triple (Participant, Care Provider, Investigator)
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
- •Adult patients admitted to an ICU with SAH related to a ruptured cerebral aneurysm occurring within the last 96 hours.
- •Aneurysm successfully secured by surgical clipping or endovascular coiling
- •Consent of the patient or, if not possible, from a proxy (emergency clause).
- •Registration in a national health care system
排除标准
- •- Precritical modified Rankin Scale (mRS) > 2
- •Nonaneurysmal SAH
- •Delayed >96h admission after first symptoms of SAH
- •Coma defined by GCS of 3-5 with untreatable aneurysm will be excluded"
- •Known allergy to cilostazol
- •Pregnancy
- •Pre-existing major hepatic, renal, pulmonary or cardiac disease
- •Concomitant use of one other anti-platelet and/or anticoagulant agent
- •SAH diagnosed on Lumbar puncture with no evidence of blood on CT.
- •Tutelage or guardianship
研究组 & 干预措施
Cilostazol + Nimodipine
In the cilostazol arm, patients will receive standard care for aneurysmal subarachnoid hemorrhage, including nimodipine administration as recommended by French and European guidelines for delayed cerebral ischemia (DCI) prevention. In addition, participants will receive cilostazol 100 mg twice daily, administered orally or via gastric tube if swallowing is not possible, for 14 consecutive days, starting within 96 hours of hemorrhage onset. Cilostazol tablets may be crushed for enteral administration. All other preventive and curative treatments for vasospasm or DCI-such as hypertensive therapy, milrinone, or endovascular interventions-are permitted at the discretion of the treating physician. Monitoring will include clinical status, occurrence of vasospasm, DCI, cerebral infarction, and cilostazol-related adverse events. Follow-up visits and safety assessments will be identical to the placebo arm.
干预措施: Cilostazol (Pletal®) 100 mg Tablets (Biological)
Cilostazol + Nimodipine
In the cilostazol arm, patients will receive standard care for aneurysmal subarachnoid hemorrhage, including nimodipine administration as recommended by French and European guidelines for delayed cerebral ischemia (DCI) prevention. In addition, participants will receive cilostazol 100 mg twice daily, administered orally or via gastric tube if swallowing is not possible, for 14 consecutive days, starting within 96 hours of hemorrhage onset. Cilostazol tablets may be crushed for enteral administration. All other preventive and curative treatments for vasospasm or DCI-such as hypertensive therapy, milrinone, or endovascular interventions-are permitted at the discretion of the treating physician. Monitoring will include clinical status, occurrence of vasospasm, DCI, cerebral infarction, and cilostazol-related adverse events. Follow-up visits and safety assessments will be identical to the placebo arm.
干预措施: Nimodipine group (Drug)
Nimodipine + Placebo
In the placebo arm, patients will receive standard care for aneurysmal subarachnoid hemorrhage, which must include nimodipine for the prevention of delayed cerebral ischemia (DCI) as per French and European guidelines. Nimodipine will be administered orally/enterally or intravenously, with dose, route, and duration decided by the treating physician according to patient status and local practice. Participants will receive a placebo, visually identical to cilostazol tablets, given orally or via gastric tube twice daily for 14 days, starting within 96 hours of hemorrhage onset. All other preventive or curative treatments for vasospasm or DCI-such as hypertensive therapy, milrinone, or endovascular procedures-are allowed at the physician's discretion. Monitoring, follow-up, and safety assessments will be performed in the same manner as in the experimental arm.
干预措施: Placebo (Drug)
Nimodipine + Placebo
In the placebo arm, patients will receive standard care for aneurysmal subarachnoid hemorrhage, which must include nimodipine for the prevention of delayed cerebral ischemia (DCI) as per French and European guidelines. Nimodipine will be administered orally/enterally or intravenously, with dose, route, and duration decided by the treating physician according to patient status and local practice. Participants will receive a placebo, visually identical to cilostazol tablets, given orally or via gastric tube twice daily for 14 days, starting within 96 hours of hemorrhage onset. All other preventive or curative treatments for vasospasm or DCI-such as hypertensive therapy, milrinone, or endovascular procedures-are allowed at the physician's discretion. Monitoring, follow-up, and safety assessments will be performed in the same manner as in the experimental arm.
干预措施: Nimodipine group (Drug)
结局指标
主要结局
Modified Rankin Scale (mRS) Score at 6 Months After Aneurysmal Subarachnoid Hemorrhage
时间窗: At 6 months after aneurysmal subarachnoid hemorrhage
Neurological functional outcome will be measured using the modified Rankin Scale (mRS) at 6 months post-aneurysmal subarachnoid hemorrhage. The mRS is a 7-point ordinal scale ranging from 0 (no symptoms) to 6 (death), assessing the degree of disability or dependence in daily activities.
次要结局
- Functional Outcome at 6 Months Measured by the Subarachnoid Hemorrhage Outcome Tool (SAHOT)(6 months)
- In-hospital morbidity and mortality(28 days)
- Clinical and radiological events predictive of functional status(6 months)
- Incidence of Cilostazol-Related Major and Minor Adverse Events(6 months.)
- Cognitive Function at 6 Months Measured by the Montreal Cognitive Assessment (MoCA)(6 months)
- Return to Work at 6 Months(6 months)
- Activities of Daily Living (ADL) at 6 Months(6 months)
- Instrumental Activities of Daily Living (IADL) at 6 Months(6 months)