Evaluation of Levosimendan in the Management of Acute Aneurysmal Subarachnoid Hemorrhage in High-Risk Patients: A Pilot Study

The primary objective of this study is to assess the efficacy of **levosimendan** in patients admitted to intensive care for subarachnoid hemorrhages of aneurysmal origin (HSAa) at high risk of acute symptomatic vasospasm (ASV), specifically those with WFNS Grade I to IV and Fisher score 3 or 4, on the occurrence of ASV. This is clinically relevant as ASV is a significant complication following HSAa, potentially leading to increased morbidity and mortality.

Secondary objectives include evaluating the effects of treatment with levosimendan on:

• Mortality on days 14, 28, and 90, and the occurrence of intracranial complications within 14 days of the bleeding.
• The modified Rankin Scale (mRS) at 3 months.
• Cardiac dysfunction.
• Cerebral perfusion.
• The length of stay in intensive care.

The clinical trial focuses on patients with **subarachnoid hemorrhages of aneurysmal origin (HSAa)**, specifically those at high risk of acute symptomatic vasospasm (ASV). The study population includes both male and female adults aged 18 to 75 years, who are hospitalized in surgical intensive care with a clinical score of WFNS Grade I to IV and a Fisher score of 3 or 4. The trial involves a vulnerable population, as participants are admitted to intensive care. The sponsor has not provided information regarding the total number of participants. Participants' general health status is characterized by their admission to intensive care for HSAa, and no specific lifestyle considerations such as diet or physical activity are mentioned. The selection criteria include adult patients within the specified age range and clinical scores, ensuring a focused study on those at high risk of ASV.

The clinical trial is designed to evaluate the efficacy of **levosimendan** in patients with subarachnoid hemorrhages of aneurysmal origin (HSAa) who are at high risk of cerebral arterial vasospasm. This study is a randomized, double-blind, controlled trial, categorized as Phase 4, and is not considered low intervention. The trial will involve the administration of ZIMINO 2.5 mg/ml solution for infusion, with a maximum daily dose of 12.5 mg and a total dose not exceeding 25 mg over a treatment period of up to 2 days. The trial is expected to commence recruitment on October 14, 2023, and conclude by October 14, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 to 75 years) and clinical scores (WFNS Grade I to IV and Fisher score 3 or 4). Following the screening, participants will be randomized to receive either the active treatment or a placebo, which is a glucose 5% solution for infusion. The primary endpoint is the occurrence of cerebral arterial vasospasm within 14 days post-bleeding. Secondary endpoints include the cumulative incidence of death, incidence of vasospasms, the modified Rankin Scale (mRS) score at 6 months, and the impact of levosimendan on cardiac dysfunction.

Participants will be involved in the study for a duration that includes the initial treatment period and follow-up visits to assess outcomes. The end-of-study visit will mark the completion of the trial for each participant. Conditions that may lead to early termination from the study include adverse reactions to the treatment, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial aims to provide valuable insights into the management of HSAa and the potential benefits of levosimendan in reducing the risk of vasospasm and improving patient outcomes.

The clinical trial involves the administration of **ZIMINO 2.5 mg/ml**, a **solution for infusion** containing the active substance **levosimendan**. This experimental medication is provided in a pharmaceutical form suitable for infusion and is manufactured by Orion Corporation. The maximum daily dose of levosimendan is 12.5 mg, with a total maximum dose of 25 mg over a treatment period of up to 2 days. The administration route is intravenous infusion, and the dosing schedule is determined based on the patient's clinical condition and response to treatment. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the study utilizes **GLUCOSE 5% B.BRAUN**, a solution for infusion, as a non-experimental treatment. This solution serves as a placebo or comparator treatment within the trial. The glucose solution is administered intravenously, and its use is intended to provide a control for evaluating the efficacy of the experimental medication. The administration of the glucose solution follows a similar schedule to the experimental treatment, ensuring consistency in the study design. Compliance with the administration of the glucose solution is also monitored to maintain the integrity of the trial results.

The efficacy of **levosimendan** in the management of the acute phase of aneurysmal subarachnoid hemorrhages will be assessed in this clinical trial. The primary endpoint for evaluating efficacy is the occurrence of cerebral arterial vasospasm within 14 days of the bleeding event. Secondary endpoints include the cumulative incidence of death rate, incidence of ischemic cerebral damage (ICDs), and vasospasms, as well as the modified Rankin Scale (mRS) score at 6 months and the impact of levosimendan treatment on cardiac dysfunction.

Data collection will occur at specified timepoints, with the primary endpoint being measured within the first 14 days post-bleeding. Secondary endpoints will be evaluated over a longer duration, including a 6-month follow-up for the mRS score. The trial will utilize validated clinical scales and assessments to ensure accurate and reliable measurement of these endpoints. The trial is designed to provide comprehensive data on the efficacy of levosimendan in this patient population, contributing to the understanding of its potential benefits in reducing complications associated with aneurysmal subarachnoid hemorrhages.