Milrinone Infusion for VAsospam Treatment in Subarachnoid hemoRrhage

NCT ID: NCT04362527

Last Updated: 2026-01-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 370 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-10
• Study Completion Date: 2026-01-12

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).

Conditions

Vasospasm

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Milrinone

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

Group Type: EXPERIMENTAL

Milrinone 1 Mg/mL Solution for Injection

Intervention Type: DRUG

Blinding procedure will be set up for the administration of the treatment

Placebo

The patients randomized to this arm will have Saline solution

Group Type: PLACEBO_COMPARATOR

Saline solution for injection

Intervention Type: DRUG

Blinding procedure will be set up for the administration of the treatment

Interventions

Milrinone 1 Mg/mL Solution for Injection

Blinding procedure will be set up for the administration of the treatment

Intervention Type: DRUG

Saline solution for injection

Blinding procedure will be set up for the administration of the treatment

Intervention Type: DRUG

Other Intervention Names

Corotrope; Sodium Chloride 0.9%

Eligibility Criteria

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 (done by CT-scanner) and inclusion ≤6 hours
• Informed consent from a legal representative, or emergency procedure

Exclusion Criteria

• Initial Glasgow score at 3 with a bilateral mydriasis
• Moribund patient
• Contraindication to Milrinone (notably 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)
• Cardiac failure requiring inotrope administration at the time of randomisation
• Uncontrolled elevated intra-cranial pressure (i.e. ICP>25 mmHg for more than 20 minutes)
• Patient with flutter or cardiac arrhythmia (atrial fibrillation) poorly tolerated
• Major metabolic disturbance (uncorrected hypokalaemia <3 mmol/L)
• Non-affiliation to French health care coverage,
• Pregnant, breastfeeding or parturient woman
• Adult deprived of their liberty by judicial or administrative decision
• Adult under compulsory psychiatric care
• Adult patient protected under the law (guardianship or trusteeship)
• Inclusion in an interventional study using Milrinone, or evaluating a treatment of cerebral vasospasm or with the same primary endpoint (mRS at 3 months).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Angers

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Karim KL LAKHAL, PH

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Nantes

Olivier OH HUET, PU-PH

Role: PRINCIPAL_INVESTIGATOR

Cavale Blanche - University Hospital of Brest

Pierre-François PP PERRIGAULT, PU-PH

Role: PRINCIPAL_INVESTIGATOR

Hôpital Gui de Chauliac - University Hospital of Montpellier

Julien JP POTTECHER, PU-PH

Role: PRINCIPAL_INVESTIGATOR

Hôpital de Hautepierre, University Hospital of Strasbourg

Russel RC CHABANNE, PH

Role: PRINCIPAL_INVESTIGATOR

Hôpital Gabriel Montpied, University Hospital of Clermont-Ferrand

Benjamin BC Chousterman, PH

Role: PRINCIPAL_INVESTIGATOR

Hôpital Lariboisière, Paris (AP-HP)

Marc ML Laffon, PU-PH

Role: PRINCIPAL_INVESTIGATOR

Hôpital Bretonneau - University Hospital of Tours

Yoann YL Launey, PH

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Rennes

Claire CD Dahyot Fizelier, PU-PH

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Poitiers

Belaid BB Bouhemad, PU-PH

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Dijon

Locations

CHU Angers

Angers, , France

CHU Besançon

Besançon, , France

CHU Bordeaux

Bordeaux, , France

CHU Brest

Brest, , France

CHU Caen

Caen, , France

Hôpital Gabriel Montpied

Clermont-Ferrand, , France

CHU Dijon

Dijon, , France

CHU Lille

Lille, , France

Hôpital Civils de Lyon

Lyon, , France

Hôpital Gui de Chauliac

Montpellier, , France

CHU Nantes

Nantes, , France

APHP Lariboisière

Paris, , France

Hôpital Fondation ROTHSCHILD

Paris, , France

CHU Rennes

Rennes, , France

Hôpital de Hautepierre

Strasbourg, , France

CHU Tours

Tours, , France

Countries

France

References

Lasocki S, Lakhal K, de Courson H, Geslain M, Launey Y, Pottecher J, Trouiller P, Laffon M, Gakuba C, Parot-Schinkel E, Hamel JF, Campfort M, Gaillard T; MiVAR study group; ATLANREA group; SFAR research network. Milrinone infusion for vasospasm treatment in subarachnoid haemorrhage: protocol for a double-blind randomised clinical trial - the MiVAR study. BMJ Open. 2025 Oct 28;15(10):e101483. doi: 10.1136/bmjopen-2025-101483.

Reference Type: DERIVED

PMID: 41151960 (View on PubMed)

Lasocki S, Bruckert V, Campfort M, Leger M, Rineau E. Restrictive transfusion targets the heart now! Insight from the REALITY study. Anaesth Crit Care Pain Med. 2021 Apr;40(2):100854. doi: 10.1016/j.accpm.2021.100854. Epub 2021 Mar 27. No abstract available.

Reference Type: DERIVED

PMID: 33781988 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan: Statistical Analysis Plan

View Document

Related Links

https://doi.org/10.1136/bmjopen-2025-101483

Related Info

Other Identifiers

2019-002145-37

Identifier Type: -

Identifier Source: org_study_id