Clinical trial NCT05664191: Levosimendan as Treatment of Aneurysmal SubArachnoid Haemorrhage
Official title: Use of Levosimendan as Treatment of Aneurysmal SubArachnoid Hemorrhage
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Sub-arachnoid Haemorrhage
Keywords: Sub-arachnoid haemorrhage
vasospasm
delayed cerebral ischemia
stroke
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Orion Corporation, Orion Pharma
First posted: 2022-12-23
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Sub-arachnoid haemorrhage (SAH) are often due to ruptured intracerebral aneurysms and are associated with an importante morbi-mortality. SAH are often complicated by delayed cerebral ischemia (DCI) potentially due to cerebral vasospasm (CVS). A recent study showed that levosimendan, an inotropic and vasodilatory drug, could reduce the incidence of CVS and potentially improve patient outcome.

In this pilot randomized controlled trial, we will evaluate the impact Levosimendan vs Placebo in SAH patient on the occurrence of CVS and DCI.

Study population: adult patient admitted to ICU for aneurysmal SAH WFNS grade I-IV and mFisher 3-4.

Intervention: Levosimendan (0.1 µg/kg/min) or placebo infusion at Day 1 and 8.

Primary outcome: incidence of DCI or CVS at day 14

Duration of the study: 24 months

Number of patients: 30 (15 patients per group) Number of center: 1

Detailed description: Background

Aneurysmal subarachnoid hemorrhage (aSAH) is a frequent type of stroke. It is associated with a significant morbidity and mortality and particularly affects young subjects. Complications that can occur after an aSAH include acute cardiac dysfunction and cerebral arterial vasospasm (CVS), which produces delayed cerebral ischemia (DCI). These complications are associated with a worsened outcome for aSAH patients. There is no proven preventive treatment for these complications.

Clinical and experimental data show that Levosimendan could be ideal to prevent these complications. In a recent study (Trinh-Duc et al, Crit Care 2021), treatment with Levosimendan was associated with a reduced incidence of CVS in a SAH patients.

The use of levosimendan, a non-catecholaminergic vasodilator inotrope in a context of already maximal endogenous adrenergic stimulation, thus seems to be suitable and able to improve the prognosis of aSAH patients.

Experimental design

Single-center, phase II, comparative, randomized, superiority, placebo-controlled, double-blind, pilot drug trial using Bayesian inference.

Study drug

Patient treated with levosimendan infusion at 0.1 microgram/kg/min for 24 hours at D1 and D8.

Number of patients

30 patients, i.e. 15 patients per group

Number of centre : 1

Duration of inclusion: 24 months

Total duration of the trial: 27 months

Statistical analysis

Primary endpoint:

The proportion of patients with at least one of the following: death, vasopasm, or DCI within 14 days of inclusion will be compared using Bayesian analysis.

Secondary endpoints:

* Qualitative secondary endpoints will be analyzed by Chi-2 test. An exact probability test will be used if the Chi-2 validity criteria are not met.
* Quantitative secondary endpoints will be compared by Student's t test. Qualitative secondary endpoints will be compared by Wilcoxon test
* The evolution of mortality will be compared using a log-rank test
* The tests will be two-sided at the 5% significance level.

Support

This study is supported by Assistance Publique - Hôpitaux de Paris (AP-HP) and Orion Pharma.

Eligibility criteria: Inclusion Criteria:

* All adult patients (18 to 75 years old),
* hospitalized in surgical intensive care at Lariboisière Hospital for subarachnoid haemorrhage of aneurysmal origin
* WFNS clinical score of I to IV and a mFisher score of 3 or 4.

Exclusion Criteria:

* pregnant women
* contraindications to levosimendan (including hypersensitivity to levosimendan, severe hypotension (mean arterial pressure less than 65 mmHg), tachycardia (heart rate greater than 120 bpm), cardiac mechanical obstructions)
* severe renal failure (creatinine clearance \< 30 ml/min)
* severe hepatic failure (signs of hepatic encephalopathy) or chronic liver disease
* history of torsades de pointes
* pre-existing severe neurovascular pathologies.
* Moribund patients.
* Patient not affiliated to social security
* Patient participating in another interventional research
* Patients under legal guardianship or curatorship

Primary outcomes:
measure: SAFETY / TOLERABILITY / EFFICACY
timeFrame: within 14 days of inclusion
measure: SAFETY / TOLERABILITY / EFFICACY
timeFrame: day 14, day 28, day 90
Secondary outcomes:
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Lariboisière, Service d'anesthésie Réanimation
Study officials:
affiliation: Hôpital Lariboisière
name: Benjamin Glen Chousterman
role: STUDY_DIRECTOR
References:
citation: Trinh-Duc A, Labeyrie MA, Caillard A, Ben Hassen W, Mebazaa A, Chousterman BG. Effects of levosimendan on occurrence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a case-control study. Crit Care. 2021 Nov 16;25(1):396. doi: 10.1186/s13054-021-03824-x. No abstract available.