Milrinone Infusion for VAsospam Treatment in Subarachnoid hemoRrhage (MIVAR)

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).

Study Overview

• Status: Completed
• Conditions: Vasospasm
• Intervention / Treatment: Drug: Milrinone 1 Mg/mL Solution for Injection; Drug: Saline solution for injection

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 Type: Interventional
• Enrollment (Actual): 370
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France
    • CHU Angers
  • Besançon, France
    • CHU Besançon
  • Bordeaux, France
    • CHU Bordeaux
  • Brest, France
    • CHU Brest
  • Caen, France
    • CHU caen
  • Clermont-Ferrand, France
    • Hôpital Gabriel Montpied
  • Dijon, France
    • CHU Dijon
  • Lille, France
    • Chu Lille
  • Lyon, France
    • Hôpital Civils de Lyon
  • Montpellier, France
    • Hopital Gui de Chauliac
  • Nantes, France
    • CHU Nantes
  • Paris, France
    • APHP Lariboisière
  • Paris, France
    • Hôpital Fondation Rothschild
  • Rennes, France
    • Chu Rennes
  • Strasbourg, France, 67098
    • Hopital de Hautepierre
  • Tours, France
    • CHU Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Milrinone; The patients randomized to this arm will have Milrinone (Laboratoires STRAGEN, France)	Drug: Milrinone 1 Mg/mL Solution for Injection; Blinding procedure will be set up for the administration of the treatment; Other Names: Corotrope
Placebo Comparator: Placebo; The patients randomized to this arm will have Saline solution	Drug: Saline solution for injection; Blinding procedure will be set up for the administration of the treatment; Other Names: Sodium Chloride 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with a good outcome at 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)	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glasgow outcome scale Extended at 3 and 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	up to 6 months
EQ-5D	Obtained by centralized telephone interview	up to 6 months
Evaluation of the radiologic effectiveness of the treatment	Evaluation of the angiographic success according to angiographic CT-scannerwith blind analysis (coted as follows: light success, moderate success or important success)	up to 14 days
Evaluation of the radiologic effectiveness of the treatment	Volume of infarcted areas at MRI control if available	3 months
Evaluation of the hemodynamic tolerance of the treatment	need to introduce and/or increase doses of catecholamines by + 50% during the first 24 hours	24 hours
Evaluation of the metabolic tolerance of the treatment	The occurrence of dysnatremia (<135 mmol / L or> 155 mmol / L), Daily diuresis.	up to 14 days
cerebral artery flow velocities	Describe treatment-related variations in middle cerebral artery flow velocities.	H0, H+2, H24+/-12h, H48+/-12h
Length of stay in the intensive care unit and in the hospital	Number of days alive in the intensive care unit and in the hospital	3 months
live patient rate		3 months and 6 months
Mortality rates in intensive care and in hospital	To assess mortality rates in intensive care unit and in hospital and 6 months after aneurysm rupture.	up to 6 months
Modified Rankin Score at 3 and 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	3 and 6 months
Describe the number of therapeutic arteriographies	number of artheriographies	Day 14

Collaborators and Investigators

• Sponsor: University Hospital, Angers
• Investigators: Principal Investigator: Karim KL LAKHAL, PH, University Hospital of Nantes; Principal Investigator: Olivier OH HUET, PU-PH, Cavale Blanche - University Hospital of Brest; Principal Investigator: Pierre-François PP PERRIGAULT, PU-PH, Hôpital Gui de Chauliac - University Hospital of Montpellier; Principal Investigator: Julien JP POTTECHER, PU-PH, Hôpital de Hautepierre, University Hospital of Strasbourg; Principal Investigator: Russel RC CHABANNE, PH, Hôpital Gabriel Montpied, University Hospital of Clermont-Ferrand; Principal Investigator: Benjamin BC Chousterman, PH, Hôpital Lariboisière, Paris (AP-HP); Principal Investigator: Marc ML Laffon, PU-PH, Hôpital Bretonneau - University Hospital of Tours; Principal Investigator: Yoann YL Launey, PH, University Hospital of Rennes; Principal Investigator: Claire CD Dahyot Fizelier, PU-PH, University hospital of Poitiers; Principal Investigator: Belaid BB Bouhemad, PU-PH, University Hospital of Dijon

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2020
• Primary Completion (Actual): October 11, 2025
• Study Completion (Actual): January 12, 2026

Study Registration Dates

• First Submitted: April 9, 2020
• First Submitted That Met QC Criteria: April 22, 2020
• First Posted (Actual): April 27, 2020

Study Record Updates

• Last Update Posted (Actual): March 9, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Milrinone
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pharmaceutical Preparations; Therapeutics; Drug Administration Routes; Drug Therapy; Amines; Inorganic Chemicals; Chlorine Compounds; Crystalloid Solutions; Isotonic Solutions; Aminopyridines; Amrinone; Sodium Compounds; Chlorides; Hydrochloric Acid; Milrinone; Injections; Saline Solution; Solutions; Sodium Chloride
• Other Study ID Numbers: 2019-002145-37

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared upon reasonable request. Only de-identified data will be shared. Any data collected during the study may be shared. The protocol will be shared initially. Other documents may be shared later upon request (e.g., the CRF to allow a collaborator to select the data to which they wish to have access). The recipients of the data will be researchers. The data will be available for any purpose deemed relevant by the MIVAR investigator, based on a protocol provided by the applicant, after verification of obtaining regulatory authorizations, including the favorable opinion of an ethics committee.
• IPD Sharing Time Frame: The data will be shared after signing a negotiated data transfer contract (data access agreement), for the duration indicated in the contract.
• IPD Sharing Access Criteria: The data will be made available via secure transfer (sharing platform validated by Angers CHU: BlueFiles or Oodrive).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No