Ensayos clínicos

Inclusion Criteria:

• Written informed consent to participate in the study must be obtained from the subject or proxy/legal representative at any time from hospital admission to prior to initiation of any study-mandated procedure.
• *Consent will be obtained by a procedure that is based on local regulations and acceptable to local authorities (including; e.g., deferral of consent). The consent form must also be signed by the investigator or delegate prior to any study-mandated procedure. Information that is available prior to the consent as part of local standard practice can be used to determine subject eligibility for the study, as applicable.
• Males and females aged 18 to 70 years (inclusive, at hospital admission).
• Subjects with a ruptured saccular aneurysm, angiographically confirmed by DSA or CTA, which has been successfully secured* within 72 hours of rupture, by surgical clipping or endovascular coiling.**
• *A successfully secured aneurysm (clipping or coiling) is defined as > 80% exclusion by volume with < 50% narrowing of parent vessel or adjacent branches (assessed locally). In addition, successful implies no additional intervention planned on the repaired aneurysm in the 3-month period following the initial procedure.
• **The aneurysm may have been secured by both clipping and coiling. Stent-assisted coiling and other endovascular devices (e.g., Web® device) are not allowed. The temporary use of approved devices during the coiling procedure is allowed, provided their use does not require anti-platelet or other agents affecting clotting mechanisms. 
• WFNS (World Federation of Neurosurgical Societies) grades 1-4 (based on Glasgow Coma Scale [GCS]) assessed after recovery from the aneurysm-securing procedure and after external ventricular drainage for hydrocephalus, if required.
• High-risk prevention: Subjects with a "thick and diffuse clot"* (thick and diffuse is defined as a thick confluent clot, more than 4 mm in thickness, involving 3 or more basal cisterns) on the hospital admission CT scan, absence of cerebral vasospasm at the time of randomization, and possibility to start study drug in the ICU (or equivalent environment where all protocol assessments can be performed and the Patient Management Guidelines followed), within 96 hours after the time of the aneurysm rupture.
• *Thick and diffuse is defined as a thick confluent clot, more than 4 mm in thickness, involving 3 or more basal cisterns.
• Presence of a cerebral CT scan performed at least 8 hours post aneurysm-securing procedure and within 24 hours prior to randomization.
• Absence of a significant (e.g., symptomatic or large) new or worsened* cerebral infarct or re-bleeding of the repaired aneurysm on the post-procedure CT scan.
• *This CT scan will be compared with the admission and any routinely performed post-procedure CT scan(s) to detect new or worsened infarcts and re-bleeding which appear after the aneurysm-securing procedure.
• A woman of childbearing potential is eligible only if the serum pregnancy test performed during the screening period is negative. Agreement must be obtained to take the necessary precautions to avoid pregnancy from hospital discharge until 30 days post-study drug discontinuation. If breastfeeding, agreement must be obtained to refrain for the duration of the treatment with study drug and until 30 days post-study drug discontinuation.
• Males are eligible for study participation only if they agree to take the necessary precautions to avoid pregnancy in a female partner from hospital discharge until 30 days post-study drug discontinuation.

Exclusion Criteria:

• Subjects with SAH due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms, SAH associated with arterio-venous malformation, vertebral dissections).
• Subjects with at least one unruptured aneurysm for whom a subsequent intervention is planned within 3 months of the aSAH.
• Significant bleeding post aneurysm-securing procedure (e.g., due to intra-ventricular drain, intra-cerebral hemorrhage, epidural hematoma, vessel dissection or rupture, re-bleeding of the repaired aneurysm*), based on investigator judgment. *Re-bleeding prior to the aneurysm-securing procedure is not an exclusion criterion.
• Intra- or peri-aneurysm securing procedure complication, requiring non-routine medical or interventional treatment such as administration of an antithrombotic or anti-platelet agent (e.g., abciximab), which is not completely resolved prior to randomization.
• IVH on the hospital admission CT scan, filling more than 50% of both lateral ventricles and with involvement of the 3rd and 4th ventricles.
• Intra-cerebral hemorrhage on the hospital admission CT scan, with an approximate volume of > 50 mL.
• Presence of cerebral vasospasm at hospital admission (initial admission or transfer from another hospital) believed to be associated with a prior bleed (i.e., occurring before the bleed for which the subject is currently hospitalized). Vasospasm occurring during the aneurysm-securing procedure is not an exclusion criterion. 
• Subjects with a new major neurological deficit occurring post aneurysm-securing procedure,* which is attributable to the procedure and does not improve to pre-procedure status before randomization.
• *Evaluation for a new major neurological deficit post procedure implies the reversal of sedation (or waiting for the subject to recover from sedation) and the performance of a neurological examination.
• Subjects who are still under the influence of pharmacological sedation at the time of randomization or who are, for whatever reason, not evaluable for baseline and regular daily neurological assessments.
• WFNS grade 5 (based on GCS) immediately prior to planned randomization, assessed after external ventricular drainage for hydrocephalus, if required.
• Subjects with a GCS score of ≤ 9 at the time of randomization and without intracranial pressure (ICP) monitoring.
• Modified Rankin Scale (mRS) score of 3 or higher, prior to the aSAH (i.e., due to a chronic condition). 
• Subjects with total bilirubin > 2 × the upper limit of normal, and/or a known diagnosis or clinical suspicion of liver cirrhosis or moderate to severe hepatic impairment.
• Any concomitant condition or disease (including psychiatric and neurological conditions, drug abuse, severe alcoholism) which, in the opinion of the investigator, would affect the assessment of the safety or efficacy of the study treatment.
• Hypotension (systolic blood pressure [SBP] ≤ 90 mmHg) at time of randomization that is refractory to treatment.
• Unresolved pulmonary edema or significant pneumonia still present at the time of randomization, or severe hypoxia at the time of randomization in intubated subjects, defined as PaO2/FiO2 ≤ 200.
• High sustained ICP (> 25 mmHg lasting > 20 minutes) at time of randomization, despite optimal treatment, in subjects with ICP monitoring.
• Severe cardiac failure requiring inotropic support at the time of randomization. 
• Lumbar and/or cisternal drainage performed specifically to prevent or treat cerebral vasospasm at any time from hospital admission to randomization.
• Prophylactic or therapeutic administration of intra-arterial vasodilators* or ozagrel, or performance of cerebral angioplasty** at any time from hospital admission to randomization. *Mechanically induced vasospasm occurring during the aneurysm-securing procedure may be treated with local administration of vasodilators (e.g., intra-arterial, topical). **Balloon assisted vascular remodeling during the aneurysm-coiling procedure is permitted.
• Subjects for whom at the time of randomization administration of urgent rescue therapy (i.e., cerebral angioplasty, intra-arterial/intrathecal/intra-cisternal/intra-ventricular administration of vasodilators or ozagrel) is anticipated.
• Use of intrathecal, intra-cisternal, or intra-ventricular* thrombolytics at any time from hospital admission to randomization. *Use of thrombolytics to open an occluded drain is permitted.
• Administration of intrathecal, intra-cisternal, and intra-ventricular vasodilators (e.g., nimodipine), i.v. nicardipine (except for blood pressure control), or i.v. milrinone*, within 4 hours prior to randomization.
• *Administration of i.v. milrinone at any time from hospital admission to randomization is exclusionary if used to prevent or treat cerebral vasospasm.
• Administration of i.v. fasudil or i.v. ozagrel within 24 hours prior to randomization.
• Use of intra-aortic balloon counter-pulsation devices at any time from hospital admission to randomization.
• Use at any time from hospital admission to randomization, of any investigational drugs, procedures or devices, including:
  • investigational clipping material and investigational coiling material such as liquid embolic material, stents or flow diverting devices; and
  • any other medication administered to prevent or treat vasospasm, reduce ischemic complications, or to improve clinical outcome post-aSAH, that has not been approved for these specific indications by local health authorities (e.g., new post-hospital admission prescription of “statins”, therapeutic hypothermia).
• Subjects receiving strong inhibitors of organic anion transporting polypeptide (OATP)1B1 and OATP1B3 transporter proteins (e.g., cyclosporin A, rifampicin, lopinavir/ritonavir), or subjects for whom it is likely at the time of randomization that these medications will be started during the study treatment infusion period.
• Known hypersensitivity to clazosentan or any excipient in the formulation.