Clazosentan in Preventing the Occurrence of Cerebral Vasospasm Following an Aneurysmal Subarachnoid Hemorrhage (aSAH)

Study Overview
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Brief Summary
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The purpose of the study is to measure how effective and safe three different doses of the drug clazosentan are in preventing vasospasm after subarachnoid hemorrhage.

Official Title
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A Phase IIb, Multi-center, International, Double-blind, Randomized, Placebo-controlled, Parallel-group, Dose-finding Study for the Prevention of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage (aSAH) by Intravenous Administration of Clazosentan, a Selective Endothelin A (ETA) Receptor Antagonist

Conditions
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Aneurysmal Subarachnoid Hemorrhage

Intervention / Treatment
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* Drug: Clazosentan 1 mg/h
* Drug: Clazosentan 5 mg/h
* Drug: Clazosentan 15 mg/h
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients aged 18 to 70 years (inclusive) or male patients aged 45 to 70 (inclusive) or males aged 18 to 44 (inclusive) who are surgically or naturally sterile or can personally sign the core Informed Consent Patients with a ruptured saccular aneurysm that has been confirmed by digital subtraction angiography (DSA) and for which clipping or coiling (endovascular obliteration) is possible. Patients with a diffuse or localized thick subarachnoid clot on baseline CT scan. Measurements defining clot thickness and extension are as follows: Diffuse: Clot with long axis >= 20 mm, or any clot if present in both hemispheres Localized: Clot with long axis < 20 mm Thick: Clot with short axis >= 4 mm Thin: Clot with short axis < 4 mm Start of screening within 48 hours post onset of aSAH clinical symptoms World Federation of Neurological Surgeons (WFNS) Grades I-IV, and those Grade V patients who improve to Grade IV or less after ventriculostomy In the case of multiple aneurysms, the aneurysm that has ruptured is identified with a high likelihood during the screening period Women of childbearing potential with pre-treatment negative serum pregnancy test Patient is able to start the study drug infusion within 56 hours after the rupture of the aneurysm, and the procedure option (clipping or coiling) must either be started within a maximum of 12 hours after the start of study drug infusion or should have been already performed Written informed consent to participate in the study must be obtained from the patient or a legal representative prior to initiation of any study-related procedure and enrollment Exclusion criteria: Patients with SAH due to other causes (e.g., trauma or rupture of fusiform or mycotic aneurysms) Patients with intraventricular or intracerebral blood, in the absence of subarachnoid blood No visualized clot or presence of only localized thin clot on CT (< 20 mm x 4 mm) Presence of any degree of cerebral vasospasm on screening angiogram Patients with hypotension (systolic blood pressure (SBP) <=90 mmHg) refractory to fluid therapy Patients with neurogenic pulmonary edema or severe cardiac failure requiring inotropic support 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 Advanced kidney and/or liver disease, as defined by plasma creatinine >=2 mg/dl (177 micromol/l) and/or total bilirubin > 3 mg/dl (51.3 micromol/l) Any known or CT evidence of previous major cerebral damage (e.g., stroke [> 2 cm], traumatic brain injury [> 2 cm], previously treated cerebral aneurysm, arterial venous malformation [AVM]), or other preexisting cerebrovascular disorders, which may affect accurate diagnosis and evaluation of SAH Patients receiving prophylactic i.v. nimodipine or i.v. nicardipine. If present, these must be stopped at least 4 hours prior to initiation of the study treatment Patients who have received thrombolytics, including intracisternal administration, intrathecal treatments and therapeutic hypothermia for treatment of the SAH Patients who have received an investigational product within 28 days prior to randomization Patients with current alcohol or drug abuse or dependence

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clazosentan 1 mg/h<br>intravenous clazosentan at 1 mg/h starting within 56 hours maximum after aneurysm rupture and continuing until Day 14 post-aneurysm rupture | Drug: Clazosentan 1 mg/h<br>* Subjects receive intravenous clazosentan at a rate of 1 mg/h starting within 56 hours maximum after aneurysm rupture and continuing until Day 14 post-aneurysm rupture<br>* Other names: ACT-108475;|
| Experimental: Clazosentan 5 mg/h<br>intravenous clazosentan at 5 mg/h starting within 56 hours maximum after aneurysm rupture and continuing until Day 14 post-aneurysm rupture | Drug: Clazosentan 5 mg/h<br>* Subjects receive intravenous clazosentan at a rate of 5 mg/h starting within 56 hours maximum after aneurysm rupture and continuing until Day 14 post-aneurysm rupture<br>* Other names: ACT-108475;|
| Experimental: Clazosentan 15 mg/h<br>intravenous clazosentan at of 15 mg/h starting within 56 hours maximum after aneurysm rupture and continuing until Day 14 post-aneurysm rupture | Drug: Clazosentan 15 mg/h<br>* Subjects receive intravenous clazosentan at a rate of 15 mg/h starting within 56 hours maximum after aneurysm rupture and continuing until Day 14 post-aneurysm rupture<br>* Other names: ACT-108475;|
| Placebo Comparator: Placebo<br>intravenous placebo starting within 56 hours maximum after aneurysm rupture and continuing until Day 14 post-aneurysm rupture | Drug: Placebo<br>* Subjects receive intravenous placebo starting within 56 hours maximum after aneurysm rupture and continuing until Day 14 post-aneurysm rupture<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of moderate or severe cerebral vasospasm, as measured by cerebral angiography | If the patient develops clinical or sonographic changes suggestive of vasospasm prior to or after Day 9 ± 2 and until Day 14 post-aneurysm rupture, an angiogram will be performed to confirm the vasospasm. If vasospasm is documented prior to Day 9 ± 2, the Day 9 ± 2 angiogram is no longer required. In the case that a patient only develops clinical symptoms suggestive of vasospasm later than Day 9 ± 2 and up to Day 14, an additional angiogram should be performed to confirm the diagnosis of vasospasm. If the latter shows a higher grade of vasospasm than the previous one, it will be used for comparison to the baseline angiogram for evaluation of the primary endpoint. | Up to day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of vasospasm-related morbidity, and mortality of all causes defined as the occurrence of death of any cause within the first 6 weeks post-aneurysm rupture OR |  | Within 6 weeks | 
| Occurrence of vasospasm-related morbidity, and mortality of all causes defined as the occurence of new cerebral infarct within first 6 weeks post-aneurysm rupture based on local investigator reading of post-baseline CT scans OR |  | Within 6 weeks | 
| Occurrence of vasospasm-related morbidity, and mortality of all causes defined as the occurence of delayed ischemic neurological deficits (DIND) due to vasospasm (based on investigator assessments) within 14 days post-aneurysm rupture OR |  | Within 14 days | 
| Occurrence of vasospasm-related morbidity, and mortality of all causes defined as occurrence of use of rescue medication due to vasospasm within 14 days post-aneurysm rupture |  | Within 14 days | 
| Clinical outcome at 12 weeks post-aneurysm rupture as measured by the Modified Rankin Scale (mRS) score |  | At 12 weeks | 
| Clinical outcome at 12 weeks post-aneurysm rupture as measured bythe Glasgow Outcome Scale - Extended Version (GOSE) score |  | At 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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delayed ischemic neurological deficits (DIND), vasospasm, clazosentan, cerebral vasospasm, computer tomography scan (CT scan), digital subtraction angiography (DSA), endothelin A receptor, aneurysmal subarachnoid hemorrhage (aSAH)