Clinical trial NCT03187405: Intraventricular Fibrinolysis for Aneurysmal Subarachnoid Hemorrhage.
Official title: Intraventricular Fibrinolysis Versus External Ventricular Drainage Alone in Aneurysmal Subarachnoid Hemorrhage: a Randomized Controlled Trial.
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE3
Conditions: Subarachnoid Hemorrhage
Keywords: Subarachnoid Hemorrhage
Intracranial Aneurysm
Cerebral Ischemia
Ventriculostomy
Tissue Plasminogen Activator
Lead sponsor: University Hospital, Caen
Sponsor class: OTHER
First posted: 2017-06-15
Enrollment: 440
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: We plan to perform a pragmatic randomized controlled trial: compare the standard of care, i.e. the EVD alone, to the experimental treatment, i.e. IVF. As the standard treatment does not include injection within the EVD, the trial will not include injection through the EVD in the control group, so the trial will have an open design.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Participants With Modified Rankin Scale (mRS) <=3 - Dichotomized Analysis.
timeFrame: 6 months.
Secondary outcomes:
measure: Death
timeFrame: 6 months
measure: DCI.
timeFrame: 6 weeks
measure: Clinical deterioration caused by DCI.
timeFrame: 1 month
measure: EVD obstruction.
timeFrame: 1 month
measure: Internal CSF shunt surgery.
timeFrame: 3 months
measure: Rebleeding.
timeFrame: 4 days
measure: Catheter related infection.
timeFrame: 3 month
measure: Rate of patients who returned to work.
timeFrame: 6 months
measure: Quality of life evaluated by the MOS SF-36 scale
timeFrame: 6 months
measure: Asthenia.
timeFrame: 6 months
Other outcomes:
Locations:
city: Caen
country: France
facility: University Hospital Of Caen
Study officials:
affiliation: University Hospital, Caen
name: Thomas Gaberel, MD, PhD
role: STUDY_CHAIR
References:
citation: Etminan N, Beseoglu K, Eicker SO, Turowski B, Steiger HJ, Hanggi D. Prospective, randomized, open-label phase II trial on concomitant intraventricular fibrinolysis and low-frequency rotation after severe subarachnoid hemorrhage. Stroke. 2013 Aug;44(8):2162-8. doi: 10.1161/STROKEAHA.113.001790. Epub 2013 Jun 4.
citation: Goulay R, Flament J, Gauberti M, Naveau M, Pasquet N, Gakuba C, Emery E, Hantraye P, Vivien D, Aron-Badin R, Gaberel T. Subarachnoid Hemorrhage Severely Impairs Brain Parenchymal Cerebrospinal Fluid Circulation in Nonhuman Primate. Stroke. 2017 Aug;48(8):2301-2305. doi: 10.1161/STROKEAHA.117.017014. Epub 2017 May 19.
citation: Hanley DF, Lane K, McBee N, Ziai W, Tuhrim S, Lees KR, Dawson J, Gandhi D, Ullman N, Mould WA, Mayo SW, Mendelow AD, Gregson B, Butcher K, Vespa P, Wright DW, Kase CS, Carhuapoma JR, Keyl PM, Diener-West M, Muschelli J, Betz JF, Thompson CB, Sugar EA, Yenokyan G, Janis S, John S, Harnof S, Lopez GA, Aldrich EF, Harrigan MR, Ansari S, Jallo J, Caron JL, LeDoux D, Adeoye O, Zuccarello M, Adams HP Jr, Rosenblum M, Thompson RE, Awad IA; CLEAR III Investigators. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017 Feb 11;389(10069):603-611. doi: 10.1016/S0140-6736(16)32410-2. Epub 2017 Jan 10.