Clazosentan in Aneurysmal Subarachnoid Hemorrhage

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to demonstrate that clazosentan, administered as a continuous intravenous infusion at either 5 mg/h or 15 mg/h until Day 14 post aneurysmal subarachnoid hemorrhage (aSAH), reduces the incidence of cerebral vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH treated by endovascular coiling. The primary 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: Death (all causes). 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. 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. Administration of a valid rescue therapy in the presence of confirmed cerebral vasospasm on angiography (DSA or CTA). An independent Critical Events Committee (CEC) will adjudicate whether or not patients meet the primary endpoint and its individual morbidity components.

Official Title
-----------------
A Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Efficacy and Safety of Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Endovascular Coiling.

Conditions
-----------------
Aneurysmal Subarachnoid Hemorrhage

Intervention / Treatment
-----------------
* Drug: Clazosentan 5 m/h
* Drug: Clazosentan 15 mg/h
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria : Males and females aged 18 to 75 years (inclusive). Patients with a ruptured saccular aneurysm, confirmed by angiography (digital subtraction angiography [DSA] or computed tomography angiography [CTA], investigator's assessment), and which has been successfully* secured by endovascular coiling. The time of aneurysm rupture must be known or possible to estimate with a reasonable degree of certainty. World Federation of Neurological Surgeons (WFNS) grade I-IV measured prior to the endovascular coiling procedure, and which does not worsen to grade V post-procedure (based on regular Glasgow Coma Scale [GCS]) Patients with any thick clot (short axis > or = 4 mm) on baseline CT scan (investigator's assessment). 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. 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. Exclusion Criteria : Subarachnoid hemorrhage (SAH) due to causes other than saccular aneurysm. Giant aneurysms (height or width > or = 25 mm). Intraventricular or intracerebral blood, in absence of subarachnoid blood, or or with only a thin clot (short axis < 4 mm) Cerebral vasospasm on angiography (investigator's assessment) prior to endovascular coiling (intraprocedural cerebral vasospasm is not an exclusion criterion). A major complication during the endovascular coiling procedure, such as massive intracranial bleeding, intracranial thromboembolism, coil migration, aneurysm perforation or rupture, arterial dissection, 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 coiling)*. Current ruptured aneurysm previously secured (successfully or not) by clipping. Coiling material used, which has not been approved by local health authorities. Use of liquid embolism aneurysmal treatment or flow diverting device. Several aneurysms among which the ruptured one cannot be identified with certainty and which are not all secured during the coiling procedure. No end-of-procedure DSA. Another securing procedure planned for any aneurysm between randomization and Week 12 post-aSAH. Study drug start >56 hours after the aneurysm rupture. Known, at time of screening, that certain follow-up, or protocol-mandated imaging assessments will not be feasible. Hypotension (systolic blood pressure < or = 90 mmHg) refractory to treatment. Aspiration pneumonia. Pulmonary edema or severe cardiac failure requiring inotropic support at time of randomization. Any severe or unstable concomitant condition or disease (e.g., known significant neurological deficit, cancer, hematological, coronary disease, psychiatric disorder), which would affect assessment of the safety or efficacy of the study drug (investigator's opinion). Significant kidney disease defined by plasma creatinine > or = 2.5 mg/dL (221 micromol/l) and/or liver disease defined by total bilirubin > 2-fold Upper Limit of Normal as measured at local laboratory, and/or known diagnosis or clinical suspicion of liver cirrhosis. Infusion of i.v. nimodipine or i.v. nicardipine must have these drugs discontinued at least 4 hours prior to initiation of study treatment. Infusion of i.v. fasudil within 24-hour period preceding planned start of study drug initiation. Start of statins less than 2 weeks prior to admission must have them discontinued prior to study drug initiation. Infusion of 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. Intake of an investigational product including investigational coil material within 28 days prior to randomization or those who have already participated in current study or CONSCIOUS-2 (AC-054-301). Unlikely event to comply with protocol (e.g., unable to return for follow-up visits). Known hypersensitivity to other endothelin receptor antagonists.26.current alcohol or drug abuse/dependence. Large territorial infarct refers to infarcts detected during the endovascular coiling 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 reversal of sedation and performance of a GCS examination (verbal scores in intubated patients may be extrapolated from the eye-opening and motor scores using predefined values). If a new major neurological deficit does not improve within 12 hours after the coiling procedure, the patient cannot be included.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clazosentan 5 mg/h<br>Continuous intravenous infusion of clazosentan (5 mg/h) started within 56 hours post-aSAH and scheduled to continue until Day 14 post-aSAH, or at least until Day 10 post-aSAH, for patients discharged before Day 14 | Drug: Clazosentan 5 m/h<br>* Continuous intravenous infusion of clazosentan (5 mg/h)<br>* Other names: ACT-108475 (AXV-034343);|
| Experimental: Clazosentan 15 mg/h<br>Continuous intravenous infusion of clazosentan (15 mg/h) started within 56 hours post-aSAH and scheduled to continue until Day 14 post-aSAH, or at least until Day 10 post-aSAH, for patients discharged before Day 14 | Drug: Clazosentan 15 mg/h<br>* Continuous intravenous infusion of clazosentan clazosentan (15 mg/h)<br>* Other names: ACT-108475 (AXV-034343);|
| Placebo Comparator: Placebo<br>Continuous intravenous infusion of placebo matching clazosentan started within 56 hours post-aSAH and scheduled to continue until Day 14 post-aSAH, or at least until Day 10 post-aSAH, for patients discharged before Day 14 | Drug: Placebo<br>* Continuous intravenous infusion of placebo-matching clazosentan<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol |  | Within 6 weeks post-aSAH | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized into good (score > 4) and poor (score ≤ 4) outcome. |  | Week 12 post-aSAH | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Subarachnoid, Aneurysmal, surgical clipping, PIVLAZ, vasospasm, cerebral vasospasm, clazosentan, Actelion, Hemorrhage