Milrinone Infusion for VAsospam Treatment in Subarachnoid hemoRrhage

Phase 3

Recruiting

• Conditions: Vasospasm
• Interventions: Drug: Saline solution for injection; Drug: Milrinone 1 Mg/mL Solution for Injection

• Registration Number: NCT04362527
• Lead Sponsor: University Hospital, Angers

Brief Summary

Subarachnoid hemorrhage (SAH) is a frequent and severe disease. Mortality can reach 40%. The most frequent complication of SAH is arterial vasospasm, with estimated incidence as high as 70%. Vasospasm is responsible for cerebral ischemia leading to severe morbidity, poorer quality of life and increased mortality.

Intravenous Milrinone, because of vasodilatory properties could be a therapeutic option. We hypothesize that intravenous infusion of Milrinone will improve the neurological recovery of patients with vasospasm following aneurysmal SAH at 3 months.

This is a Phase III, multi-center, randomized, double-blinded, placebo-controlled study. The primary outcome will be the proportion of patients with a good outcome 3 months (defined as a modified rankin score ≤2).

Detailed Description

Subarachnoid hemorrhage (SAH) is relatively frequent, accounting for 5% of strokes, and affects a relatively young population. It is essentially caused by cerebral aneurysm rupture. Mortality can reach 40%. The most frequent complication of SAH is arterial vasospasm, with estimated incidence as high as 70%. Vasospasm is responsible for cerebral ischemia, delayed or not, which in turn is responsible for severe morbidity (neurological deficit, neuro psychiatric disorders...), poorer quality of life (institutionalization, inability to return to work ...) and increased mortality.

The pathophysiology of vasospasm is complex, multifactorial and far from being fully understood. Many drugs have been studied in the treatment of symptomatic vasospasm but none has really proven its efficacy. Milrinone is proposed for the treatment of cerebral vasospasm, either as intra-arterial injection (during angiography) or intravenously using continuous infusion. Indeed, among new vasospasm's treatments, Milrinone seems to have good angiographic and clinical results. There is no randomized controlled trials evaluating Milrinone for preventive and/or curative treatment of cerebral vasospasm following aneurysmal SAH. The literature is made only of clinical cases, cases series with angiographic studies or interventional studies not controlled and with no more than 10 patients.

Thus we hypothesize that the intravenous infusion of Milrinone will improve the neurological recovery of patients with vasospasm following aneurysmal SAH at 3 months.

Adult patients, hospitalized for a vasospasm complicating subarachnoid hemorrhage secondary to intracranial aneurysm rupture will be included and randomized within 6 hours of the CT-scanner confirming the vasospasm diagnosis to receive either the study drug (milrinione, a 0,1 mg/kg bolus followed by a 1 μg/kg/min perfusion) or placebo (saline, with a bolus and a continuous infusion). Study drug administration will be formalized (minimum duration 48 hours, maximum duration 14 days).The primary endpoint will be the proportion of patients with a good outcome 3 months (defined as a modified rankin score ≤2).

Study Timeline

• Study First Submitted: 2020-04-09
• Study First Submitted QC: 2020-04-22
• Study First Posted: 2020-04-27
• Study Start: 2020-08-10
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-28
• Last Update Posted: 2025-04-02
• Primary Completion: 2026-05-10
• Study Completion: 2026-05-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 370

Inclusion Criteria

• Adult patients hospitalized for aneurysmal SAH
• First episode of vasospasm, with a diagnosis confirmed on cerebral arterial CT-scanner
• Delay between diagnosis of vasospasm (i.e. CT-scanner) and inclusion ≤6 hours

Exclusion Criteria

• Initial Glasgow score at 3 with a bilateral mydriasis
• Moribund patient
• Pregnant woman
• Contraindication to Milrinone (obstructive cardiomyopathy...)
• Cerebral infarction in the vasospasm area already present on the CT-scanner at the time of diagnosis (lack of expected benefit of treatment in this case- according to medical judgement)
• Non-affiliation to French health care coverage,
• Adult patient protected under the law (guardianship)
• Cardiac failure necessitating inotropic agents
• Uncontrolled Intracranial hypertension (ICP>25 mmHg for more than 20 min)
• Inclusion in an interventional study using Milrinone, or evaluating a treatment of cerebral vasospasm or with the same primary endpoint (mRS at 3 months).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Placebo	Saline solution for injection	The patients randomized to this arm will have Saline solution
Milrinone	Milrinone 1 Mg/mL Solution for Injection	The patients randomized to this arm will have Milrinone (Laboratoires STRAGEN, France)

Primary Outcome Measures

Name	Time	Method
Proportion of patients with a good outcome at 3 months	3 months	modified Rankin score ≤2 (0 = No symptoms, 1 = No significant disability. Able to carry out all usual activities, despite some symptoms, 2 = Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities, 3 = Moderate disability. Requires some help, but able to walk unassisted, 4 = Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted, 5 = Severe disability. Requires constant nursing care and attention, bedridden, incontinent, 6 = Death)

Secondary Outcome Measures

Name	Time	Method
Evaluation of the radiologic effectiveness of the treatment	3 months	Volume of infarcted areas at MRI control if available
Evaluation of the hemodynamic tolerance of the treatment	24 hours	need to introduce and/or increase doses of catecholamines by + 50% during the first 24 hours
Evaluation of the metabolic tolerance of the treatment	up to 14 days	The occurrence of dysnatremia (\<135 mmol / L or\> 155 mmol / L), Daily diuresis.
cerebral artery flow velocities	H0, H+2, H24+/-12h, H48+/-12h	Describe treatment-related variations in middle cerebral artery flow velocities.
EQ-5D	up to 6 months	Obtained by centralized telephone interview
Mortality rates in intensive care and in hospital	up to 6 months	To assess mortality rates in intensive care and in hospital at 3 and 6 months after aneurysm rupture.
Modified Rankin Score at 6 months	6 months	0 = No symptoms, 1 = No significant disability. Able to carry out all usual activities, despite some symptoms, 2 = Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities, 3 = Moderate disability. Requires some help, but able to walk unassisted, 4 = Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted, 5 = Severe disability. Requires constant nursing care and attention, bedridden, incontinent, 6 = Death
Glasgow outcome scale Extended at 3 and 6 months	up to 6 months	1= Death, 2=Persistent vegetative state, 3=Sever disability, 4=Moderate disability, 5=Good recovery 2. Persistent vegetative state; 3. Severe disability 4. Moderate disability 5. Low disability

Trial Locations

Locations (16)

CHU Besançon; 🇫🇷 Besançon, France

CHU Bordeaux; 🇫🇷 Bordeaux, France

CHU Brest; 🇫🇷 Brest, France

CHU Caen; 🇫🇷 Caen, France

CHU Dijon; 🇫🇷 Dijon, France

CHU Lille; 🇫🇷 Lille, France

Hôpital Civils de Lyon; 🇫🇷 Lyon, France

APHP Lariboisière; 🇫🇷 Paris, France

Hôpital Fondation ROTHSCHILD; 🇫🇷 Paris, France

CHU Tours; 🇫🇷 Tours, France

CHU Angers; 🇫🇷 Angers, France

Hôpital Gabriel Montpied; 🇫🇷 Clermont-Ferrand, France

Hôpital Gui de Chauliac; 🇫🇷 Montpellier, France

CHU Nantes; 🇫🇷 Nantes, France

CHU Rennes; 🇫🇷 Rennes, France

Hôpital de Hautepierre; 🇫🇷 Strasbourg, France