Subarachnoid HemorrhagePhase 3FIVHeMANCT03187405
Intraventricular Fibrinolysis for Aneurysmal Subarachnoid Hemorrhage.
A Phase 3 study testing EVD + IVF with Alteplase in people with Subarachnoid Hemorrhage, run by University Hospital, Caen at 1 site in France.
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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Subarachnoid Hemorrhage
- What is being tested?
- EVD + IVF with Alteplase
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 81 participants
- Where
- 1 siteFrance
- Study dates
- 21 Feb 2018to 5 Feb 2025
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- Subarachnoid Hemorrhage
- Being tested
- EVD + IVF with Alteplase
- Keywords
- Subarachnoid Hemorrhage, Intracranial Aneurysm, Cerebral Ischemia, Ventriculostomy, Tissue Plasminogen Activator
- Medical subject headings
- Subarachnoid Hemorrhage, Intracranial Aneurysm, Brain Ischemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EVD + IVF with AlteplaseDrug
Also called Intraventricular fibrinolysis with Alteplase
Intraventricular fibrinolysis: Injection through the EVD of 1mg in 1 mL of Alteplase every eight hours during 3 days (9 doses).
| Study group | Role | What they receive |
|---|---|---|
| EVD alone | No intervention | In the EVD alone group group, the EVD will be managed as usual - i.e. will only be used to drain CSF. |
| EVD + IVF with Alteplase | Experimental | Intraventricular fibrinolysis: Injection through the EVD of 1mg in 1 mL of Alteplase every eight hours during 3 days (9 doses). Receives: Drug: EVD + IVF with Alteplase |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 6 months.
Secondary outcomes (10)
Death
Risk of death
Measured: 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.
Measured: 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
Measured: 1 month
EVD obstruction.
Numbers of permanent catheter obstruction requiring the insertion of a new catheter.
Measured: 1 month
Internal CSF shunt surgery.
Rate of internal CSF shunt surgery.
Measured: 3 months
Rebleeding.
A new ICH identified on a CT-scan performed after IVF that was not present before IVF.
Measured: 4 days
Catheter related infection.
Clinical picture of infection associated with a positive CSF culture.
Measured: 3 month
Rate of patients who returned to work.
Proportion of patient who returned to their previous professional activity.
Measured: 6 months
Quality of life evaluated by the MOS SF-36 scale
MOS SF-36 scale
Measured: 6 months
Asthenia.
Asthenia scale of Pichot
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jun 2017
- Study start21 Feb 2018
- Primary completion5 Feb 2024
- Study completion5 Feb 2025
Why it stopped: lack of patient
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Subarachnoid HemorrhageStudies of the same condition, open and under way.
- More trials run by University Hospital, CaenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 81 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Caen
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Thomas Gaberel, MD, PhD, Study chair, University Hospital, Caen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03187405
- Sponsor's protocol ID
- FIVHeMA
- Acronym
- FIVHeMA
- Status last verified
- Jul 2025
- First submitted
- 6 Jun 2017
- Last updated
- 25 Jul 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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.
PubMed 23735957Goulay 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.
PubMed 28526764Hanley 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.
PubMed 28081952
Study at a glance
From the registry record, last updated by the sponsor on 25 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intraventricular Fibrinolysis Versus External Ventricular Drainage Alone in Aneurysmal Subarachnoid Hemorrhage: a Randomized Controlled Trial.
- ClinicalTrials.gov ID
- NCT03187405
- Acronym / sponsor ID
- FIVHeMA / FIVHeMA
- Conditions
- Subarachnoid Hemorrhage
- Keywords
- Subarachnoid Hemorrhage, Intracranial Aneurysm, Cerebral Ischemia, Ventriculostomy, Tissue Plasminogen Activator
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: lack of patient
- Enrolment
- 81 participants (actual)
- Lead sponsor
- University Hospital, CaenUniversity, hospital or other
- Study start
- 21 Feb 2018 (actual)
- Primary completion
- 5 Feb 2024 (actual)
- Study completion
- 5 Feb 2025 (actual)
- First posted
- 15 Jun 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| EVD alone | No intervention | –In the EVD alone group group, the EVD will be managed as usual - i.e. will only be used to drain CSF. |
| EVD + IVF with Alteplase | Experimental | Drug: EVD + IVF with AlteplaseIntraventricular fibrinolysis: Injection through the EVD of 1mg in 1 mL of Alteplase every eight hours during 3 days (9 doses). |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EVD + IVF with AlteplaseAlso: Intraventricular fibrinolysis with AlteplaseIntraventricular 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 |
Primary outcome
Participants With Modified Rankin Scale (mRS) <=3 - Dichotomized Analysis.
Time frame: 6 months.
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).
10 secondary outcomes
Death
Time frame: 6 months
DCI.
Time frame: 6 weeks
Clinical deterioration caused by DCI.
Time frame: 1 month
EVD obstruction.
Time frame: 1 month
Internal CSF shunt surgery.
Time frame: 3 months
Rebleeding.
Time frame: 4 days
Catheter related infection.
Time frame: 3 month
Rate of patients who returned to work.
Time frame: 6 months
Quality of life evaluated by the MOS SF-36 scale
Time frame: 6 months
Asthenia.
Time frame: 6 months
Results and safety
The study was stopped early (reason given: lack of patient). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jul 2025.
- Background: PubMed 23735957Etminan 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.
- Background: PubMed 28526764Goulay 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.
- Background: PubMed 28081952Hanley 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Gaberel, MD, PhD study chair
University Hospital, Caen
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing EVD + IVF with Alteplase in people with Subarachnoid Hemorrhage, run by University Hospital, Caen at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: lack of patient). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Participants With Modified Rankin Scale (mRS) <=3 - Dichotomized Analysis. (time frame: 6 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03187405, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jul 2025.