Clinical trial NCT04362527: Milrinone Infusion for VAsospam Treatment in Subarachnoid hemoRrhage
Official title: Milrinone Infusion for VAsospam Treatment in Subarachnoid hemoRrhage
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Vasospasm
Keywords: Milrinone
Lead sponsor: University Hospital, Angers
Sponsor class: OTHER_GOV
First posted: 2020-04-27
Enrollment: 370
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Phase 3, multicenter, international (France, Switzerland), randomized, double blinded, placebo-controlled study
Primary purpose: TREATMENT

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).

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 (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).

Primary outcomes:
measure: Proportion of patients with a good outcome at 3 months
timeFrame: 3 months
Secondary outcomes:
measure: Mortality rates in intensive care and in hospital
timeFrame: up to 6 months
measure: Modified Rankin Score at 6 months
timeFrame: 6 months
measure: Glasgow outcome scale Extended at 3 and 6 months
timeFrame: up to 6 months
measure: EQ-5D
timeFrame: up to 6 months
measure: Evaluation of the radiologic effectiveness of the treatment
timeFrame: up to 14 days
measure: Evaluation of the radiologic effectiveness of the treatment
timeFrame: 3 months
measure: Evaluation of the hemodynamic tolerance of the treatment
timeFrame: 24 hours
measure: Evaluation of the metabolic tolerance of the treatment
timeFrame: up to 14 days
measure: cerebral artery flow velocities
timeFrame: H0, H+2, H24+/-12h, H48+/-12h
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU Angers
city: Besançon
country: France
facility: CHU Besançon
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Brest
country: France
facility: CHU Brest
city: Caen
country: France
facility: CHU Caen
city: Clermont-Ferrand
country: France
facility: Hôpital Gabriel Montpied
city: Dijon
country: France
facility: CHU Dijon
city: Lille
country: France
facility: CHU Lille
city: Lyon
country: France
facility: Hôpital Civils de Lyon
city: Montpellier
country: France
facility: Hôpital Gui de Chauliac
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: APHP Lariboisière
city: Paris
country: France
facility: Hôpital Fondation ROTHSCHILD
city: Rennes
country: France
facility: CHU Rennes
city: Strasbourg
country: France
facility: Hôpital de Hautepierre
city: Tours
country: France
facility: CHU Tours
Study officials:
affiliation: University Hospital of Nantes
name: Karim KL LAKHAL, PH
role: PRINCIPAL_INVESTIGATOR
affiliation: Cavale Blanche - University Hospital of Brest
name: Olivier OH HUET, PU-PH
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Gui de Chauliac - University Hospital of Montpellier
name: Pierre-François PP PERRIGAULT, PU-PH
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital de Hautepierre, University Hospital of Strasbourg
name: Julien JP POTTECHER, PU-PH
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Gabriel Montpied, University Hospital of Clermont-Ferrand
name: Russel RC CHABANNE, PH
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Lariboisière, Paris (AP-HP)
name: Benjamin BC Chousterman, PH
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Bretonneau - University Hospital of Tours
name: Marc ML Laffon, PU-PH
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Rennes
name: Yoann YL Launey, PH
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Poitiers
name: Claire CD Dahyot Fizelier, PU-PH
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Dijon
name: Belaid BB Bouhemad, PU-PH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.