Intraventricular Fibrinolysis for Aneurysmal Subarachnoid Hemorrhage. (FIVHeMA)

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

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.

Study Overview

• Status: Suspended
• Conditions: Subarachnoid Hemorrhage
• Intervention / Treatment: Drug: EVD + IVF with Alteplase

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.

• Study Type: Interventional
• Enrollment (Estimated): 440
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Caen, France, F-14000
    • University Hospital of Caen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: EVD alone; In the EVD alone group group, the EVD will be managed as usual - i.e. will only be used to drain CSF.
Experimental: 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).	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).; Other Names: Intraventricular fibrinolysis with Alteplase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Risk of death	6 months
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
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
EVD obstruction.	Numbers of permanent catheter obstruction requiring the insertion of a new catheter.	1 month
Internal CSF shunt surgery.	Rate of internal CSF shunt surgery.	3 months
Rebleeding.	A new ICH identified on a CT-scan performed after IVF that was not present before IVF.	4 days
Catheter related infection.	Clinical picture of infection associated with a positive CSF culture.	3 month
Rate of patients who returned to work.	Proportion of patient who returned to their previous professional activity.	6 months
Quality of life evaluated by the MOS SF-36 scale	MOS SF-36 scale	6 months
Asthenia.	Asthenia scale of Pichot	6 months

Collaborators and Investigators

• Sponsor: University Hospital, Caen
• Investigators: Study Chair: Thomas Gaberel, MD, PhD, University Hospital, Caen

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2018
• Primary Completion (Estimated): March 15, 2024
• Study Completion (Estimated): March 15, 2024

Study Registration Dates

• First Submitted: June 6, 2017
• First Submitted That Met QC Criteria: June 12, 2017
• First Posted (Actual): June 15, 2017

Study Record Updates

• Last Update Posted (Actual): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Subarachnoid Hemorrhage; Ventriculostomy; Intracranial Aneurysm; Cerebral Ischemia; Tissue Plasminogen Activator
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator
• Other Study ID Numbers: FIVHeMA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No