Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping

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 \> or = 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)\< or = 90 mmHg) that is refractory to treatment.
• •9. Patients with aspiration pneumonia.
• •10. Patients with pulmonary edema or severe cardiac failure requiring inotropic support.
• •11. Any severe or unstable concomitant condition or disease (e.g., known significant neurological deficit, cancer, hematological, or coronary disease), or chronic condition (e.g., psychiatric disorder), which, in the opinion of the investigator, would affect the assessment of the safety or efficacy of the study drug.
• •12. Significant kidney and/or liver disease, as defined by plasma creatinine \> or = 2.5 mg/dL (221 micromol/l) and/or total bilirubin \> 3 mg/dL (51.3 micromol/l) measured at the local site laboratory.
• •13. Patients receiving i.v. nimodipine, i.v. nicardipine, or fasudil hydrochloride, 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 3.9.1.2.1 of the protocol). In the event of a new major neurological deficit that does not improve within 12 hours after the clipping procedure, the patient cannot be included in the study.