Clinical trial NCT00558311 (phase 3, status: completed)
Conditions: aneurysmal subarachnoid hemorrhage
ICD codes: I60.8, I60.9, I69.020, I69.021, I69.022, I69.090, I69.091
Drugs: clazosentan, placebo
SMILES: COC1=CC=CC=C1OC1=C(NS(=O)(=O)C2=CC=C(C)C=N2)N=C(N=C1OCCO)C1=CC=NC(=C1)C1=NN=NN1, CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C=CC=C2)C#N)C1=O
Eligibility 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 > or = 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 12 hours
                  post-procedure, but prior to randomization, ruling out any large
                  procedure-related infarct.

        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.