Intraventricular Fibrinolysis for Aneurysmal Subarachnoid Hemorrhage.

Subarachnoid Hemorrhage Clinical Trial

— FIVHeMA  

Official title:

Intraventricular Fibrinolysis Versus External Ventricular Drainage Alone in Aneurysmal Subarachnoid Hemorrhage: a Randomized Controlled Trial.

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT03187405
• Other study ID #: FIVHeMA
• Status: Suspended
• Phase: Phase 3
• Start date: February 21, 2018
• Est. completion date: March 15, 2024

Study information

• Verified date: February 2024
• Source: University Hospital, Caen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 440
• Est. completion date: March 15, 2024
• Est. primary completion date: March 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hemorrhage
• Subarachnoid Hemorrhage

Intervention

Drug:
• EVD + IVF with Alteplase
Intraventricular fibrinolysis: Injection through the EVD of 1mg in 1 mL of Alteplase every eight hours during 3 days (9 doses).

Locations

Country	Name	City	State
France	University Hospital Of Caen	Caen

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Caen

Country where clinical trial is conducted

France, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Participants With Modified Rankin Scale (mRS) <=3 - Dichotomized Analysis.	Proportion of patients without severe disability evaluated by the modified Rankin Scale (0-3). The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death).	6 months.
Secondary	Death	Risk of death	6 months
Secondary	DCI.	The presence of cerebral infarction on CT or MR scan on the latest CT or MR scan made before death within 6 weeks, not present on the CT or MR scan between 24 and 48 hours after early aneurysm occlusion, and not attributable to other causes such as surgical clipping or endovascular treatment.	6 weeks
Secondary	Clinical deterioration caused by DCI.	Occurrence of focal neurological impairment (such as hemiparesis, aphasia, apraxia, hemianopia, or neglect), or a decrease of at least 2 points on the Glasgow Coma Scale. This should last for at least 1 hour, is not apparent immediately after aneurysm occlusion, and cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies	1 month
Secondary	EVD obstruction.	Numbers of permanent catheter obstruction requiring the insertion of a new catheter.	1 month
Secondary	Internal CSF shunt surgery.	Rate of internal CSF shunt surgery.	3 months
Secondary	Rebleeding.	A new ICH identified on a CT-scan performed after IVF that was not present before IVF.	4 days
Secondary	Catheter related infection.	Clinical picture of infection associated with a positive CSF culture.	3 month
Secondary	Rate of patients who returned to work.	Proportion of patient who returned to their previous professional activity.	6 months
Secondary	Quality of life evaluated by the MOS SF-36 scale	MOS SF-36 scale	6 months
Secondary	Asthenia.	Asthenia scale of Pichot	6 months