Evaluation of Intravenous Dornase Alfa for Functional Independence Post-Subarachnoid Hemorrhage: A Multicenter Randomized Controlled Trial

The primary objective of this study is to evaluate the efficacy of a daily intravenous infusion of **dornase alfa** (125 micrograms per kilogram) administered for up to 14 days following a subarachnoid hemorrhage (SAH) on achieving an excellent functional prognosis at 6 months. This is clinically relevant as it aims to improve long-term functional independence in patients who have experienced SAH, a condition associated with significant morbidity and mortality.

Secondary objectives include: - Evaluating the efficacy of the treatment on the incidence of clinical respiratory failure (CRF) up to 21 days post-SAH or until hospital discharge if earlier. - Assessing functional prognosis and cognitive abilities at 6 months. - Determining the incidence of ischemic lesions on magnetic resonance imaging (MRI) at 21 days post-SAH or the last imaging performed if discharged earlier. - Evaluating the need for and total number of days of vasospasm treatment within 21 days post-SAH or until discharge. - Monitoring mortality at 21 days post-SAH or at hospital discharge if earlier. - Investigating the incidence of serious adverse events requiring a change in treatment. - Analyzing the evolution of neutrophil extracellular traps (NETs) blood concentration from inclusion to 21 days post-SAH or until discharge.

The clinical trial focuses on evaluating the efficacy of a daily intravenous infusion of dornase alfa in patients with **subarachnoid hemorrhage**. The study population includes both male and female participants aged 18 years and older. Participants are required to have been admitted to the hospital for a subarachnoid hemorrhage due to a ruptured aneurysm, with the onset of symptoms occurring less than 48 hours prior to admission. Effective aneurysm exclusion must have been achieved within the last 24 hours, with no complications during the procedure as confirmed by a post-procedure CT scan. The initial brain CT scan should show a Fisher score greater than 1. Participants must be beneficiaries of a social protection scheme and provide informed consent, either personally or through a family member or trusted support person if their condition does not allow them to express consent in writing. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **dornase alfa** administered intravenously for up to 14 days following a **subarachnoid hemorrhage**. This is a multicenter, open-label, randomized controlled trial of the PROBE type, with a primary objective to assess the occurrence of an excellent functional prognosis at six months. The trial is structured as a Phase 4 study, with participants randomly assigned in a 1:1 ratio, and the primary endpoint assessment is blinded. The trial is expected to commence recruitment on June 2, 2025, and conclude by December 1, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, recent hospital admission for **subarachnoid hemorrhage** due to a ruptured aneurysm, and effective aneurysm exclusion. The inclusion visit will also involve obtaining informed consent. Follow-up visits will occur throughout the treatment period, with assessments including neurological evaluations and imaging studies. The end-of-study visit will take place at six months post-treatment to evaluate the primary endpoint, defined by a score of 0 or 1 on the modified Rankin Scale, assessed by a certified professional via telephone.

The expected duration of participant involvement is approximately six months, with the treatment phase lasting up to 14 days. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or withdrawal of consent. Secondary endpoints include assessments of neurological deficits, ischaemic lesions, and mortality, among others. The trial aims to provide comprehensive data on the safety and efficacy of **dornase alfa** in improving functional outcomes following **subarachnoid hemorrhage**.

The clinical trial involves the administration of **dornase alfa**, marketed under the name Pulmozyme 2500 U/2.5 ml, as a **nebuliser solution**. The experimental medication is formulated as a solution for inhalation via a nebulizer, but in this study, it is administered through **intravenous (IV) injection** or **IV infusion**. The dosage is set at 125 micrograms per kilogram of body weight, administered daily for a maximum treatment period of 14 days. The maximum daily dose is 12,500 micrograms, with a total maximum dose of 175,000 micrograms over the treatment period. The active substance, dornase alfa, is a protein of non-human origin, specifically classified under the ATC code R05CB13. The pharmaceutical product is manufactured by Roche and is not a pediatric formulation.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of the experimental medication, dornase alfa, in achieving an excellent functional prognosis at six months post-subarachnoid hemorrhage. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the achievement of an excellent functional prognosis, defined by a score of 0 or 1 on the **modified Rankin Scale (mRS)** at 6 months. This assessment will be centralized and conducted via telephone by a certified professional who is blinded to the randomization arm.

Secondary endpoints include the occurrence of focal neurological deficits or a decrease in the Glasgow score by at least 2 points for at least 1 hour, not immediately after aneurysmal occlusion and not entirely related to another cause, as per the SAHIT definition. Additional secondary endpoints are the mRS score at 6 months, the presence of ischaemic lesions on MRI at day 21 post-subarachnoid haemorrhage (SAH) or at discharge if before day 21, and the treatment of vasospasm through specific interventions. The number of days with prescribed treatments for vasospasm within 21 days post-SAH, the MoCA-5min score at 6 months, all-cause mortality at day 21 or at hospital discharge if before day 21, serious adverse events, and changes in NETs blood concentration between inclusion and day 21 or discharge if before day 21, will also be evaluated.

These efficacy parameters will be measured and collected at specified timepoints, with MRI scans analyzed centrally by a radiologist blinded to the randomization arm. The trial is designed as a multicenter, open-label, randomized controlled trial of the PROBE type, with a planned duration of up to 14 days of treatment and follow-up assessments at 6 months.