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: Recruiting
• 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 (Anticipated): 360
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sigismond SL LASOCKI, PU-PH; Phone Number: 02 41 35 36 35; Email: silasocki@chu-angers.fr

Study Locations

• France
  • Angers, France
    • Recruiting
    • CHU Angers
    • Contact: Sigismond Lasocki, MD, PhD
  • Clermont-Ferrand, France
    • Active, not recruiting
    • Hopital Gabriel Montpied
  • Montpellier, France
    • Active, not recruiting
    • Hopital Gui de Chauliac
  • Nantes, France
    • Active, not recruiting
    • CHU Nantes
  • Rennes, France
    • Recruiting
    • CHU Rennes
    • Contact: Yoann Launey, MD, PhD; Email: Yoann.LAUNEY@chu-rennes.fr
  • Strasbourg, France, 67098
    • Recruiting
    • Hopital de Hautepierre
    • Contact: Julien Pottecher, MD, PhD
    • Contact: Email: julien.pottecher@chru-strasbourg.fr

Participation Criteria

Eligibility Criteria

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

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 (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 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
Mortality rates in intensive care and in hospital	To assess mortality rates in intensive care and in hospital at 3 and 6 months after aneurysm rupture.	up to 6 months
Modified Rankin Score at 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	6 months
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

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.

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2020
• Primary Completion (Anticipated): August 10, 2023
• Study Completion (Anticipated): February 10, 2024

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): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Milrinone
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Pharmaceutical Solutions; Milrinone
• Other Study ID Numbers: 2019-002145-37

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No