Evaluation of Milrinone Infusion Versus Placebo for Neurological Outcomes in Aneurysmal Subarachnoid Hemorrhage-Induced Vasospasm

The primary objective of this study is to evaluate the **efficacy** of Milrinone intravenous infusion compared to placebo in improving the neurological outcome at 3 months in patients experiencing vasospasm following an aneurysmal subarachnoid hemorrhage. This is clinically relevant as vasospasm is a significant complication of subarachnoid hemorrhage, potentially leading to poor neurological outcomes. The study aims to determine if Milrinone can effectively mitigate these effects, thereby improving patient prognosis.

Secondary objectives include:

• Assessing the effect of the treatment compared to placebo.
• Evaluating the tolerance of the treatment.

The clinical trial involves participants diagnosed with **aneurysmal subarachnoid hemorrhage** accompanied by vasospasm. The study population includes both male and female adults, as indicated by the age range category code "3," which typically corresponds to adults aged 18 years and older. Participants are required to have a confirmed diagnosis of vasospasm via cerebral angiographic CT-scanner, with a maximum delay of 6 hours between diagnosis and inclusion in the study. The trial does not focus on a vulnerable population, and participants are expected to be in a general health status that allows for hospitalization due to the condition. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria emphasize the necessity for either patient consent or consent from a relative, or an emergency procedure, to ensure ethical participation in the study.

The clinical trial is designed to evaluate the efficacy of **milrinone** intravenous infusion compared to placebo in improving neurological outcomes at three months in patients with vasospasm following an aneurysmal subarachnoid hemorrhage. This is a randomized, double-blind, controlled trial with an estimated duration from August 2020 to August 2025. The trial involves adult patients who have been hospitalized for aneurysmal subarachnoid hemorrhage, with a confirmed diagnosis of vasospasm via cerebral angiographic CT-scanner, and who can be included within six hours of diagnosis. The primary endpoint is the proportion of patients achieving a good outcome at three months, defined as a modified Rankin Scale score of 2 or less.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria. Follow-up visits will be scheduled to monitor the treatment's effectiveness and safety, with assessments including mortality rates, long-term clinical outcomes, quality of life, and radiologic success. The end-of-study visit will occur at the conclusion of the treatment period, which is a maximum of 14 days, to evaluate the final outcomes and any adverse events. The expected length of participant involvement is up to six months, with conditions for early termination including withdrawal of consent, significant adverse events, or protocol non-compliance.

The clinical trial involves the administration of **Milrinone**, marketed as **MILRINONE STRAGEN 1mg/ml, solution injectable**. This experimental medication is provided in the form of a **solution for injection**. The active substance, **milrinone**, is of chemical origin and is classified under the ATC code **C01CE02**. The medication is administered via **intravenous infusion**. The dosing regimen allows for a maximum daily dose of **21.6 mg/kg** and a maximum total dose of **302.4 mg/kg** over a treatment period not exceeding **14 days**. The pharmaceutical form is specifically designed for adult use, as it is not a pediatric formulation.

In this study, the experimental treatment with **Milrinone** is compared to a **placebo** to assess its efficacy in improving neurological outcomes in patients experiencing vasospasm following an aneurysmal subarachnoid hemorrhage. The placebo serves as the non-experimental treatment, providing a baseline for evaluating the therapeutic effects of the active medication. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen.

Efficacy in the clinical trial titled "MIVAR - Milrinone Infusion for VAsospam treatment in subarachnoid hemorrhage" will be assessed by comparing the neurological outcomes of patients receiving **Milrinone** intravenous infusion to those receiving a placebo. The primary endpoint for evaluating efficacy is the proportion of patients achieving a good outcome at 3 months, defined by a modified Rankin Scale (mRS) score of 2 or less. Secondary endpoints include mortality rates in the intensive care unit, in the hospital, and at 3 and 6 months post-aneurysm rupture, as well as long-term clinical outcomes measured by the modified Rankin score at 6 months and the Glasgow Outcome Scale Extended (GOS-E) score at 3 and 6 months.

Additional secondary endpoints involve assessing the long-term quality of life using the EQ-5D at baseline, 3, and 6 months, and evaluating the treatment's effectiveness on radiologic terms, such as angiographic success at days 7 and 14, and the volume of infarcted areas measured by MRI between 1 and 3 months after aneurysm rupture. The trial will also describe flow velocity variations in the middle cerebral artery due to treatment, the length of hospitalization in intensive care and hospital settings, and hemodynamic and metabolic tolerance, including the need for increased catecholamine doses and the occurrence of dysnatremia. These efficacy parameters will be collected and analyzed at specified time points to determine the treatment's impact on patients with vasospasm following an aneurysmal subarachnoid hemorrhage.