Intraventricular Fibrinolysis for Aneurysmal Subarachnoid Hemorrhage. (FIVHeMA)

Caen University Hospital

Status and phase

Suspended

Phase 3

Conditions

Subarachnoid Hemorrhage

Treatments

Drug: EVD + IVF with Alteplase

Study type

Interventional

Funder types

Other

Identifiers

NCT03187405

FIVHeMA

Details and patient eligibility

About

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating form of stroke, with delayed cerebral ischemia (DCI) as a major complication. There are several evidences, both in preclinical and in clinical studies that intraventricular fibrinolysis (IVF) controls the phenomenon that are leading to DCI. Here, the investigators propose to conduct a phase III trial to provide a clear evaluation of the impact of IVF after aneurysmal SAH.

Full description

Introduction: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating form of stroke, which often causes acute hydrocephalus requiring the insertion of an external ventricular drain (EVD). A major complication of aneurysmal SAH is delayed cerebral ischemia (DCI), which corresponds to the occurrence of an ischemic stroke up to 21 days after the aneurysm rupture. There are currently only few ways to prevent it. As DCI is linked to the presence of blood within the subarachnoid space, it has been hypothesized that removing this blood may decrease the risk of DCI. It could be obtained by injecting a fibrinolytic agent through the EVD, a therapeutic strategy named intraventricular fibrinolysis (IVF). There are several evidences, both in preclinical and in clinical studies that IVF controls the phenomenon that are leading to DCI. It has notably been shown in Phase I and Phase II trial that IVF in aneurysmal SAH is safe and may decrease the risk of DCI, with a trend to improve the rate of good functional outcome by about 10%. Here, the investigators propose to conduct a phase III trial to provide a clear evaluation of the impact of IVF after aneurysmal SAH.

Materials and methods: this study will include patients with aneurysmal SAH requiring external ventricular drainage. The investigators will perform a pragmatic randomized controlled trial: compare the standard of care, i.e. the EVD alone, to the experimental treatment, i.e. IVF, with an open design. After exclusion of the aneurysm, patients will be randomly allocated to receive either EVD alone or EVD+IVF (72 hours, 9 doses). The primary outcome will be the proportion of patients without severe disability 6 months after the aneurysm rupture, as evaluated by the modified Rankin Scale (mRS). The investigators plan to include 440 patients, to show an increase of the rate of good functional outcome of 10% in the EVD+IVF group compared to the EVD alone group (α=0.05 and β=0.8). To obtain such sample, a multicenter trial is mandatory, and to date 16 centers accepted to participate. Each center will include one patient per month, and the inclusion period is to last 48 months.

Enrollment

440 estimated patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Patients (age 18-75) with SAH on initial CT-Scan examination.
SAH associated with hydrocephalus requiring external ventricular drainage.
Confirmation of an associated intracranial aneurysm by vascular imaging.
Time from onset to admission under 24 hours.
Exclusion of the aneurysm by surgical clipping or endovascular coiling before IVF.
Oral information on research and informed consent of the patient and/or his relatives.

Exclusion criteria

Patient with severe clinical presentation on admission: WFNS score = 5.
Associated intracerebral hematoma of more than 2 cm in its larger width.
SAH diagnosed on lumbar puncture: original Fisher grade = 1.
Impossibility to exclude the aneurysm within 72 hours following its rupture.
Patient previously treated with antiplatelet therapy or treated with antiplatelet therapy after the aneurysm exclusion.
Severe coagulopathy, including oral vitamin K antagonist.
Pregnant or lactating woman.