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Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia (OPTIMIL)

Primary Purpose

Aneurysmal Subarachnoid Hemorrhage

Status
Recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Milrinone Injection
Placebo
Sponsored by
University Hospital, Toulouse
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aneurysmal Subarachnoid Hemorrhage focused on measuring Milrinone, Vasospasm, Delayed Cerebral Ischemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • patients with severe SAHa (WFNS IV and V,) whose neurological examination is impossible because of coma or need for sedation at D3
  • absence of pre-existing neurological handicap (mRS 0-2)
  • major patient (≥ 18 years)
  • affiliation to social security or benefiting through a third person
  • free patient, without tutorship or curatorship or under judicial protection
  • obtaining a signed informed consent by a relative (or the person of trust) after clear and fair information about the study.

Exclusion Criteria:

  • patients with non-severe SAHa (WFNS I, II and III)
  • Occurrence of a documented ischemic complication during the procedure of aneurysm treatment: transient or permanent arterial occlusion, visualization of a thrombus, and dissection of an axis requiring stenting.
  • heart failure requiring inotropic administration at the time of randomization
  • ICHT at the time of randomisation (ICP> 25 mmHg for at least 20 min)
  • known severe obstructive heart diseases
  • flutter patient or atrial fibrillation
  • hypotension and / or severe hypovolemia with hemodynamic instability
  • septic shock
  • acute / chronic renal insufficiency (Cl <50ml / min)
  • major hydroelectrolytic disorders (hypokalemia <3 mmol / L)
  • known hypersensitivity to milrinone or any of the excipients
  • pregnancy, breastfeeding
  • permanent contraindications to MRI
  • participation in another clinical study

Sites / Locations

  • University Hospital Bordeaux
  • CHUGA
  • University Hospital of La RéunionRecruiting
  • HCLRecruiting
  • University Hospital of ToulouseRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Milrinone

Standard Care

Arm Description

"milrinone" group benefiting from an identical treatment to the standard care group and in addition, administration of milrinone (0.75 μg / kg / min, intravenous) from Day 4 to Day 14. In case of suspicion of vasospasm and after ineffective effect of medical measures (euvolemia and increase in mean arterial pressure), an endovascular treatment will be possible. The occurrence of vasospasm will be monitored closely with clinical examination and cerebral tissue oxygen pressure (PtiO2). From D4 to D14, general and biological data, clinical examination will be collected daily. Intensive care unit complications (neurologic, pulmonary, cardiac and septic complications) will be collected. At 1 month, the volume of DCI lesions will be measured on CT scan. Neurologic prognosis, quality of life and mortality will be studied at 1 month, 3 month, 6 month and 1 year. Adverse events will be monitored closely.

The standard care group will follow the recommended management of SAHa and will receive a placebo (intravenous glucose 5%) from Day 4 to Day 14. In case of suspicion of vasospasm and after ineffective effect of medical measures (euvolemia and increase in mean arterial pressure), an endovascular treatment will be possible. The occurrence of vasospasm will be monitored closely with clinical examination and cerebral tissue oxygen pressure (PtiO2). From D4 to D14, general and biological data, clinical examination will be collected daily. Intensive care unit complications (neurologic, pulmonary, cardiac and septic complications) will be collected. At 1 month, the volume of DCI lesions will be measured on CT scan. Neurologic prognosis, quality of life and mortality will be studied at 1 month, 3 month, 6 month and 1 year. Adverse events will be monitored closely.

Outcomes

Primary Outcome Measures

volume of delayed cerebral ischemia lesions
volume of DCI lesions measured on CT scan and validated by Magnetic Resonance Imaging (MRI) imaging at 1 month

Secondary Outcome Measures

Radiological parameters on CT at 1 month
percentage of patients with DCI lesions
Evolution in intensive care: Neurological complications 1
number of episodes of PtiO2 below the ischemic threshold in intensive care: PtiO2 <20 mmHg (moderate hypoxia) and <15 mm Hg (severe hypoxia) for at least 15 minutes
Evolution in intensive care: Neurological complications 2
total duration of episodes of PtiO2 <20 mm Hg (moderate hypoxia) and <15 mm Hg (severe hypoxia)
Evolution in intensive care: Neurological complications 3
number of recourse to an endovascular treatment
Evolution in intensive care: Neurological complications 4
intracranial hypertension in intensive care: ICP> 20 mmHg for at least 15 minutes.
Number and type of non-neurological complications
non-neurological complications
Number of days in intensive care
Number of days in intensive care
Number of days with mechanical ventilation
Number of days with mechanical ventilation
neurological prognosis at 1 month: Rankin score
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
neurological prognosis at 1 month: Glasgow Outcome scale
evaluated by the Glasgow Outcome Scale (GOS) (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3).
neurological prognosis at 3 month: Rankin score
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
neurological prognosis at 3 month: Glasgow Outcome scale
evaluated by the the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
neurological prognosis at 6 month: Rankin score
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
neurological prognosis at 6 month: Glasgow Outcome scale
evaluated by the the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
neurological prognosis at 1 year: Rankin score
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
neurological prognosis at 1 year: Glasgow Outcome scale
evaluated by the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Mortality at 1 month
Mortality at 1 month
Mortality at 3 month
Mortality at 3 month
Mortality at 6 month
Mortality at 6 month
Mortality at 1 year
Mortality at 1 year
number of days of hospitalization
number of days of hospitalization

Full Information

First Posted
February 17, 2020
Last Updated
March 29, 2023
Sponsor
University Hospital, Toulouse
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1. Study Identification

Unique Protocol Identification Number
NCT04282629
Brief Title
Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia
Acronym
OPTIMIL
Official Title
Efficacy of 10 Days Intravenous Milrinone Treatment to Optimize Cerebral Hemodynamic and Prevent Delayed Cerebral Ischemia (DCI) in Patients With Severe Subarachnoid Hemorrhage Due to Intracranial Aneurysm Rupture
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 25, 2021 (Actual)
Primary Completion Date
July 2025 (Anticipated)
Study Completion Date
July 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Toulouse

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The present study is a randomized, multi-center, double-blind, prospective study that tests the efficacy of intravenous milrinone to optimize cerebral hemodynamic and prevent delayed cerebral ischemia (DCI) during the high-risk period (day 4- day 14) in patients with severe subarachnoid hemorrhage due to intracranial aneurysm rupture (SAHa) (WFNS IV-V). The main objective is to evaluate, in comatose patients and / or sedated on D3 following a severe SAHa (WFNS IV -V), the effect of 10 days of milrinone versus placebo, in addition to the usual management, on the volume of DCI lesions measured on CT scan at 1 month.
Detailed Description
After SAHa, approximately 28% of patients will present DCI. DCI is a major cause of death and disability and will condition the neurological prognosis. Its treatment is not really codified, because of the absence of scientific proof of good level. Milrinone, an inhibitor of type III phosphodiesterase, seems particularly interesting in the management of DCI. This molecule has indeed a powerful vasodilator action. In addition, its anti-inflammatory effects could inhibit the abnormal proliferation of vascular smooth muscle cells and the remodelling observed in patients with DCI via an action on interleukin-6. Finally, because of its positive inotropic effect, it is an interesting choice in these patients with neurogenic cardiomyopathy where the administration of catecholamines is to be avoided. Strong evidence for efficacy of milrinone in the treatment and / or prevention of DCI is still lacking. All patients will benefit from a computed tomography (CT) brain imaging at 48 hrs following aneurysm treatment to define baseline imaging. The standard care (SC) group will follow the recommended management of SAHa and will receive a placebo (intravenous glucose 5%) from day 4 to day 14. The milrinone (M) group will receive, in addition to standard care, administration of milrinone (0.75 μg / kg / min, intravenous) from day 4 to day 14. In case of suspicion of vasospasm and after ineffective effect of medical measures (euvolemia and increase in mean arterial pressure), an endovascular treatment will be possible. The occurrence of vasospasm will be monitored closely with clinical examination and cerebral tissue oxygen pressure (PtiO2). From day 4 to day 14, general and biological data, clinical examination will be collected daily. Intensive care unit complications (neurologic, pulmonary, cardiac and septic complications) will be collected. At 1 month, the volume of DCI lesions will be measured on CT scan. Neurologic prognosis, quality of life and mortality will be studied at 1 month, 3 month, 6 month and 1 year. Adverse events will be monitored closely.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aneurysmal Subarachnoid Hemorrhage
Keywords
Milrinone, Vasospasm, Delayed Cerebral Ischemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Group milrinone versus group placebo
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
234 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Milrinone
Arm Type
Experimental
Arm Description
"milrinone" group benefiting from an identical treatment to the standard care group and in addition, administration of milrinone (0.75 μg / kg / min, intravenous) from Day 4 to Day 14. In case of suspicion of vasospasm and after ineffective effect of medical measures (euvolemia and increase in mean arterial pressure), an endovascular treatment will be possible. The occurrence of vasospasm will be monitored closely with clinical examination and cerebral tissue oxygen pressure (PtiO2). From D4 to D14, general and biological data, clinical examination will be collected daily. Intensive care unit complications (neurologic, pulmonary, cardiac and septic complications) will be collected. At 1 month, the volume of DCI lesions will be measured on CT scan. Neurologic prognosis, quality of life and mortality will be studied at 1 month, 3 month, 6 month and 1 year. Adverse events will be monitored closely.
Arm Title
Standard Care
Arm Type
Placebo Comparator
Arm Description
The standard care group will follow the recommended management of SAHa and will receive a placebo (intravenous glucose 5%) from Day 4 to Day 14. In case of suspicion of vasospasm and after ineffective effect of medical measures (euvolemia and increase in mean arterial pressure), an endovascular treatment will be possible. The occurrence of vasospasm will be monitored closely with clinical examination and cerebral tissue oxygen pressure (PtiO2). From D4 to D14, general and biological data, clinical examination will be collected daily. Intensive care unit complications (neurologic, pulmonary, cardiac and septic complications) will be collected. At 1 month, the volume of DCI lesions will be measured on CT scan. Neurologic prognosis, quality of life and mortality will be studied at 1 month, 3 month, 6 month and 1 year. Adverse events will be monitored closely.
Intervention Type
Drug
Intervention Name(s)
Milrinone Injection
Intervention Description
administration of milrinone (0.75 μg / kg / min, intravenous) from Day 4 to Day 14
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
administration of placebo (intravenous glucose 5%) from Day 4 to Day 14
Primary Outcome Measure Information:
Title
volume of delayed cerebral ischemia lesions
Description
volume of DCI lesions measured on CT scan and validated by Magnetic Resonance Imaging (MRI) imaging at 1 month
Time Frame
1 month
Secondary Outcome Measure Information:
Title
Radiological parameters on CT at 1 month
Description
percentage of patients with DCI lesions
Time Frame
1 month
Title
Evolution in intensive care: Neurological complications 1
Description
number of episodes of PtiO2 below the ischemic threshold in intensive care: PtiO2 <20 mmHg (moderate hypoxia) and <15 mm Hg (severe hypoxia) for at least 15 minutes
Time Frame
1 month
Title
Evolution in intensive care: Neurological complications 2
Description
total duration of episodes of PtiO2 <20 mm Hg (moderate hypoxia) and <15 mm Hg (severe hypoxia)
Time Frame
1 month
Title
Evolution in intensive care: Neurological complications 3
Description
number of recourse to an endovascular treatment
Time Frame
1 month
Title
Evolution in intensive care: Neurological complications 4
Description
intracranial hypertension in intensive care: ICP> 20 mmHg for at least 15 minutes.
Time Frame
1 month
Title
Number and type of non-neurological complications
Description
non-neurological complications
Time Frame
1 month
Title
Number of days in intensive care
Description
Number of days in intensive care
Time Frame
1 month
Title
Number of days with mechanical ventilation
Description
Number of days with mechanical ventilation
Time Frame
1 month
Title
neurological prognosis at 1 month: Rankin score
Description
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Time Frame
1 month
Title
neurological prognosis at 1 month: Glasgow Outcome scale
Description
evaluated by the Glasgow Outcome Scale (GOS) (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3).
Time Frame
1 month
Title
neurological prognosis at 3 month: Rankin score
Description
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Time Frame
3 month
Title
neurological prognosis at 3 month: Glasgow Outcome scale
Description
evaluated by the the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Time Frame
3 month
Title
neurological prognosis at 6 month: Rankin score
Description
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Time Frame
6 month
Title
neurological prognosis at 6 month: Glasgow Outcome scale
Description
evaluated by the the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Time Frame
6 month
Title
neurological prognosis at 1 year: Rankin score
Description
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Time Frame
1 year
Title
neurological prognosis at 1 year: Glasgow Outcome scale
Description
evaluated by the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Time Frame
1 year
Title
Mortality at 1 month
Description
Mortality at 1 month
Time Frame
1 month
Title
Mortality at 3 month
Description
Mortality at 3 month
Time Frame
3 month
Title
Mortality at 6 month
Description
Mortality at 6 month
Time Frame
6 month
Title
Mortality at 1 year
Description
Mortality at 1 year
Time Frame
1 year
Title
number of days of hospitalization
Description
number of days of hospitalization
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: patients with severe SAHa (WFNS IV and V,) whose neurological examination is impossible because of coma (Glasgow coma score of 8 or less) or need for sedation at D3 absence of pre-existing neurological handicap (mRS 0-2) major patient (≥ 18 years) affiliation to social security or benefiting through a third person free patient, without tutorship or curatorship or under judicial protection obtaining a signed informed consent by a relative (or the person of trust) after clear and fair information about the study. Exclusion Criteria: patients with non-severe SAHa (WFNS I, II and III) Occurrence of a major complication (haemorrhagic or ischaemic) documented during the procedure of securing the aneurysm and endangering the short-term vital prognosis heart failure requiring inotropic administration at the time of randomization ICHT at the time of randomisation (ICP> 25 mmHg for at least 20 min) known severe obstructive heart diseases flutter patient or atrial fibrillation hypotension and / or severe hypovolemia with hemodynamic instability septic shock acute / chronic renal insufficiency (Cl <50ml / min) major hydroelectrolytic disorders (hypokalemia <3 mmol / L) known hypersensitivity to milrinone or any of the excipients early limitation of life-sustaining care pregnancy, breastfeeding permanent contraindications to MRI participation in another clinical interventional study
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Thomas Geeraerts, MD PhD
Phone
05 61 77 21 00
Ext
33
Email
geeraerts.t@chu-toulouse.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Nadera AINAOUI, PhD
Phone
05 61 77 24 98
Ext
33
Email
nadera.ainaoui@inserm.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Geeraerts, MD PhD
Organizational Affiliation
University Hospital, Toulouse
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Bordeaux
City
Bordeaux
Country
France
Individual Site Status
Active, not recruiting
Facility Name
CHUGA
City
Grenoble
Country
France
Individual Site Status
Active, not recruiting
Facility Name
University Hospital of La Réunion
City
La Réunion
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Romain ASMOLOV, MD
First Name & Middle Initial & Last Name & Degree
Romain ASMOLOV, MD
Facility Name
HCL
City
Lyon
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Baptiste BALANCA, MD
First Name & Middle Initial & Last Name & Degree
Baptiste BALANCA
Facility Name
University Hospital of Toulouse
City
Toulouse
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
GEERAERTS Thomas, MD
First Name & Middle Initial & Last Name & Degree
Thomas GEERAERTS, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia

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