Milrinone Infusion for VAsospam Treatment in Subarachnoid hemoRrhage (MIVAR)

University Hospital, Angers

Status and phase: Enrolling; Phase 3

Conditions: Vasospasm

Treatments: Drug: Saline solution for injection; Drug: Milrinone 1 Mg/mL Solution for Injection

Study type: Interventional

Funder types: Other

Identifiers

NCT04362527

2019-002145-37

Details and patient eligibility

About

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).

Full 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).

Enrollment: 370 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Triple Blind

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370 participants in 2 patient groups, including a placebo group

Milrinone

Experimental group

Description:

The patients randomized to this arm will have Milrinone (Laboratoires STRAGEN, France)

Treatment:

Drug: Milrinone 1 Mg/mL Solution for Injection

Placebo

Placebo Comparator group

Description:

The patients randomized to this arm will have Saline solution

Treatment:

Drug: Saline solution for injection