Evaluation of Cilostazol Addition to Nimodipine on Neurological Outcomes in Aneurysmal Subarachnoid Hemorrhage: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate whether the addition of **Cilostazol** at a dosage of 100 mg twice daily for 14 days improves the modified Rankin scale at 6 months in patients with **Aneurysmal Subarachnoid Hemorrhage** (SAH) who are being treated with nimodipine, compared to a placebo. This is clinically relevant as it aims to enhance neurological outcomes in a condition associated with significant morbidity and mortality.

Secondary objectives include assessing the functional status at 6 months using various tools such as the SubArachnoid Hemorrhage Outcome Tool (SAHOT) Score, MOCA score, return to work, and activities of daily living. Additionally, the study will evaluate in-hospital morbi-mortality, including the length of ICU and hospital stay, and 28-day mortality. Other secondary objectives are the occurrence of delayed cerebral ischemia, defined by focal neurological impairment or a decrease of at least 2 points on the Glasgow Coma Scale, cerebral artery vasospasm identified through angiography, and cerebral infarcts detected on CT or MRI within 6 weeks, not present on earlier scans and not attributable to other causes.

The clinical trial involves participants diagnosed with **aneurysmal subarachnoid hemorrhage**. The study population includes both male and female adults, with an age range corresponding to categories 3 and 4, which typically represent individuals aged 18 to 64 years. Participants are required to have been admitted to an intensive care unit with a subarachnoid hemorrhage related to a ruptured cerebral aneurysm within the last 96 hours, and the aneurysm must have been successfully secured by surgical clipping or endovascular coiling. The trial population is selected based on the consent of the patient or, if not possible, from a proxy under an emergency clause, and all participants must be registered in a national health care system. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, indicating that special considerations are in place to protect the rights and welfare of the participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **cilostazol** in improving neurological outcomes in patients with **Aneurysmal Subarachnoid Hemorrhage** (SAH) when added to standard treatment with nimodipine. This study is a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, thus minimizing bias. The trial is set to commence recruitment on April 1, 2025, and is expected to conclude by April 30, 2029. Participants will be involved in the study for a maximum of 14 days, during which they will receive 100 mg of cilostazol or a placebo twice daily.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as recent admission to an ICU with SAH due to a ruptured cerebral aneurysm, successful aneurysm securing, and consent obtained from the patient or a proxy. Follow-up visits will occur throughout the treatment period to monitor the participants' health and adherence to the study protocol. The primary endpoint is the assessment of the modified Rankin Scale (mRS) at six months post-treatment, with a favorable outcome defined as an mRS score of 0 to 2. Secondary endpoints include cognitive assessments, ICU and hospital stay durations, and the occurrence of delayed cerebral ischemia and cerebral infarctions.

The end-of-study visit will involve a comprehensive evaluation of the participants' health status and the collection of final data for analysis. Participants may be withdrawn from the study early if they experience major adverse events related to cilostazol, such as arrhythmia or abnormal bleeding, or if they withdraw consent. The trial's rigorous design and structured visits aim to provide robust data on the potential benefits of cilostazol in this patient population.

The clinical trial involves the administration of **Cilostazol-Elpen 100 mg Tabletten**, which is an experimental medication used to assess its efficacy in improving neurological outcomes in patients with Aneurysmal Subarachnoid Hemorrhage (SAH). The active substance in this medication is **cilostazol**, a chemical compound. The pharmaceutical form of the medication is a tablet, and it is administered orally. The dosage regimen involves administering 100 mg of cilostazol twice daily, resulting in a maximum daily dose of 200 mg. The treatment period is set for 14 days. The medication is manufactured by ELPEN PHARMACEUTICAL CO. INC. and is identified by the marketing authorization number 90515.00.00 in Germany. The trial aims to evaluate the improvement in the modified Rankin scale at 6 months when cilostazol is added to the standard treatment with nimodipine.

In addition to the experimental medication, a **placebo** is used as a comparator in this double-blind, placebo-controlled trial. The placebo is designed to mimic the appearance of the Cilostazol-Elpen 100 mg Tabletten but does not contain any active substance. The placebo is administered in the same manner as the experimental medication, ensuring that the study remains blinded. The use of a placebo allows for the assessment of the true efficacy of cilostazol by comparing outcomes between the treatment and placebo groups. The placebo is identified as "Placebo de Cilostazol-Elpen 100mg, comprimé" and does not have a specific pharmaceutical form or active substance listed.

Efficacy in this clinical trial will be assessed primarily through the **Modified Rankin Scale (mRS)**, which will be evaluated at 6 months post-treatment. The mRS is a widely used scale for measuring the degree of disability or dependence in daily activities of people who have suffered a stroke or other causes of neurological disability. A favorable outcome is defined by an mRS score of 0 to 2, while an unfavorable outcome is indicated by a score of 3 to 6. This assessment will be conducted through a structured face-to-face interview.

Secondary endpoints include a range of additional measures to provide a comprehensive evaluation of the treatment's efficacy. These include cognitive impairment assessments using specific scales such as the MOCA, ADL, and IADL, as well as the SAHOT (SAH-outcome tool). Other criteria include the length of Intensive Care Unit (ICU) stay, length of hospital stay, and 28-day mortality. Delayed cerebral ischemia will be monitored, defined by the appearance of a focal neurological deficit or a decrease of at least 2 points on the Glasgow Coma Scale. The short-term course of angiographically defined vasospasm and cerebral infarctions will also be evaluated using CT, MRI, or catheter angiography. Additionally, the occurrence of cilostazol-related major and minor adverse events will be recorded.