Indication: Aneurysmal subarachnoid hemorrhage MedDRA version: 9.1 Level: LLT Classification code 10042318 Term: Subarachnoid haemorrhage NOS
Conditions
Sponsors
Actelion Pharmaceuticals Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Males and females aged 18 to 75 years (inclusive). 2.Patients with a ruptured saccular aneurysm, confirmed by angiography (digital subtraction angiography [DSA] or computed tomography angiography [CTA]), and which has been successfully secured by surgical clipping. The time of aneurysm rupture must be known or possible to estimate with a reasonable degree of certainty. 3.World Federation of Neurological Surgeons (WFNS) grade I–IV measured prior to the clipping procedure, and which does not worsen to grade V post-procedure (based on regular Glasgow Coma Scale [GCS])* 4.Patients with any diffuse clot (long axis >= 20 mm, or any clot present across both hemispheres) on baseline CT scan. 5.Women of childbearing potential must have a negative serum pregnancy test and must use a reliable method of contraception during the 12 weeks following study drug discontinuation. 6.Written informed consent to participate in the study must be obtained from the patient or a legal representative prior to initiation of any study-mandated procedure and randomization. *Patients must be evaluable for WFNS grade prior to the clipping procedure. Patients who cannot be assessed for WFNS post-procedure due to a requirement for uninterrupted sedation (e.g., for high or unstable intracranial pressure [ICP]) may be included in the study provided that a CT scan is performed at least 12 hours post-procedure, but prior to randomization, ruling out any large procedure-related infarct. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Patients with subarachnoid hemorrhage (SAH) due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms). 2. Patients with intraventricular or intracerebral blood, in the absence of subarachnoid blood, or with only a local clot. 3. Presence of cerebral vasospasm seen on angiography prior to the clipping procedure. 4. Patients who experienced a major complication during the clipping procedure, such as massive bleeding, major arterial occlusion, a large territorial cerebral infarct defined as involving > 1/3 of a vascular territory, or a new major neurological deficit post-procedure (e.g., hemiplegia or aphasia lasting >= 12 hours post-aneurysm clipping).* 5. Patients for whom study drug cannot be started within 56 hours after the aneurysm rupture. 6. Patients who have had their aneurysm secured by coiling only. 7. Patients for whom it is known, at the time of screening, that certain follow-up, protocol-mandated imaging assessments will not be feasible. 8. Patients with hypotension (systolic blood pressure (SBP) = 2.5 mg/dL (221 µmol/l), and/or liver disease, as defined by total bilirubin > 2 fold the Upper Limit of Normal (ULN) as measured at the local laboratory, and/or known diagnosis or clinical suspicion of liver cirrhosis. 13. Patients receiving i.v. nimodipine or i.v. nicardipine must have these drugs discontinued at least 4 hours prior to initiation of the study treatment. 14. Patients receiving statins for less than 2 weeks prior to admission must have them discontinued prior to study drug initiation. 15. Patients receiving cyclosporin A or other calcineurin inhibitors (e.g., tacrolimus), or patients for whom it is known at the time of randomization that these medications will be started during the study drug infusion period. 16. Patients who have received an investigational product within 28 days prior to randomization or those who have already participated in the current study. 17. Patients unlikely to comply with the protocol (e.g., unable to return for follow-up visits). 18. Known hypersensitivity to other endothelin receptor antagonists. 19. Patients with current alcohol or drug abuse or dependence. *Further detail on exclusion criterion number 4: •‘Large territorial infarct’ refers to those infarcts detected during the clipping procedure or immediately post-procedure (i.e., CT performed for suspicion of cerebral infarct or other complication). This does not imply having to wait 24–48 hours post-procedure to perform the protocol-mandated CT scan in order to randomize a patient. • Evaluation for a new major neurological deficit post-procedure implies the reversal of sedation (or waiting for the patient to recover from sedation) and the performance of a GCS examination (verbal scores in intubated patients may be extrapolated from the eye-opening and motor scores using the values provided in the table included in Section 3.9.1.2.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate that clazosentan reduces the incidence of cerebral vasospasm-related morbidity and all-cause mortality within 6 weeks post aneurysmal subarachnoid hemorrhage (aSAH) treated by surgical clipping.;Secondary Objective: ·To demonstrate that clazosentan improves clinical outcome at Week 12 post-aSAH treated by surgical clipping, as measured by the dichotomized Glasgow Outcome Scale (extended version [GOSE]). ·To evaluate the impact of clazosentan on total infarct volume at Week 6 post-aSAH treated by surgical clipping, and on each individual component of the primary endpoint. ·To evaluate the safety and tolerability of clazosentan.;Primary end point(s): The primary efficacy endpoint of the study is the occurrence of cerebral vasospasm-related morbidity, and mortality of all causes, within 6 weeks post-aSAH, defined by at least one of the following: 1.Death (all causes) 2.New cerebral infarct(s) due to cerebral vasospasm as either the primary or relevant contributing cause, or not adjudicated to be entirely due to causes other than vasospasm (e.g., lesions arising from intra-cerebral hemorrhage, the aneurysm clipping, the primary injury, or ventricular drain encephalomalacia).* In this context, new cerebral infarct(s) are those that were not present at baseline and cerebral infarcts that were present at baseline but substantially worsened within 6 weeks post-aSAH, as confirmed by the CEC clinicians. 3.Delayed ischemic neurological deficit (DIND) due to cerebral vasospasm as either the primary or relevant contributing cause, or not adjudicated to be entirely due to causes other than vasospasm (e.g., hydrocephalus, seizure, etc.) . a) DIND is defined in patients in whom the neurological scales are assessable as: •A decrease of at least two points on the modified Glasgow Coma Scale (mGCS), or an increase of at least two points on the abbreviated National Institutes of Health Stroke Scale (abbrev. NIHSS), lasting for at least 2 hours. b) DI | — |
Countries
Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Italy, Latvia, Slovenia, Spain, Sweden
Outcome results
None listed