Cilostazol With Nimodipine to Improve Outcome After Aneurysmal Subarachnoid Hemorrhage

NCT ID: NCT07144956

Last Updated: 2025-09-10

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 630 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-15
• Study Completion Date: 2029-12-14

Brief Summary

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.

Detailed Description

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.

The study will be conducted over 49 months (42 months of enrollment + 6 months of follow-up), across 9 French centers, with an expected inclusion rate of 1.9 patients per center per month. Two interim analyses are planned. The study is funded by a Programme Hospitalier de Recherche Clinique (PHRC) and monitored by an independent data safety monitoring board (DSMB).

While cilostazol is generally well tolerated, especially in short-term use, potential side effects include headache, palpitations, diarrhea, arrhythmias, bleeding, and allergic reactions. Previous short-term studies suggest an acceptable safety profile in aSAH patients.

If positive, the CASH study may significantly impact clinical guidelines by supporting the inclusion of cilostazol as an adjunct therapy in the management of aneurysmal subarachnoid hemorrhage.

Conditions

Aneurysmal Subarachnoid Hemorrhage

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Cilostazol (Pletal®) 100 mg Tablets

Intervention Type: BIOLOGICAL

100 mg orally or via feeding tube twice daily for 14 days, starting within 96 hours after aneurysmal subarachnoid hemorrhage onset. Tablets may be crushed for enteral administration.

Nimodipine group

Intervention Type: DRUG

Administered orally, enterally, or intravenously for 21 days as part of standard of care. Dose, route, and duration determined by treating physician according to clinical condition and guidelines.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral or enteral placebo, visually identical to cilostazol, twice daily for 14 days, starting within 96 hours after hemorrhage onset.

Nimodipine group

Intervention Type: DRUG

Administered orally, enterally, or intravenously for 21 days as part of standard of care. Dose, route, and duration determined by treating physician according to clinical condition and guidelines.

Interventions

Cilostazol (Pletal®) 100 mg Tablets

100 mg orally or via feeding tube twice daily for 14 days, starting within 96 hours after aneurysmal subarachnoid hemorrhage onset. Tablets may be crushed for enteral administration.

Intervention Type: BIOLOGICAL

Placebo

Oral or enteral placebo, visually identical to cilostazol, twice daily for 14 days, starting within 96 hours after hemorrhage onset.

Intervention Type: DRUG

Nimodipine group

Administered orally, enterally, or intravenously for 21 days as part of standard of care. Dose, route, and duration determined by treating physician according to clinical condition and guidelines.

Intervention Type: DRUG

Other Intervention Names

Placebo (matching Cilostazol)

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• - 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre Hospitalier St Anne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Caroline SCHIMPF, Doctor

Role: STUDY_CHAIR

Chef de service Anesthésie - Réanimation GHU Paris - Neuro Sainte-Anne

Aurélien MAZERAUD, DOCTOR

Role: PRINCIPAL_INVESTIGATOR

Anesthésie - Réanimation GHU Paris - Neuro Sainte-Anne

Central Contacts

Khaoussou SYLLA, DR

Role: CONTACT

K.SYLLA@ghu-paris.fr

01.45.65.76.78 ext. +33

OUIZA MANSEUR, Project manager

Role: CONTACT

ouiza.manseur@ghu-paris.fr

01 45 65 84 86 ext. +33

Provided Documents

Document Type: Study Protocol

View Document

Other Identifiers

2024-516468-27-00

Identifier Type: CTIS

Identifier Source: secondary_id

D24-009

Identifier Type: -

Identifier Source: org_study_id