E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Aneurysmal Subarachnoid Hemorrhage |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042316 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that at least one dose (5 or 15 mg/h) of clazosentan reduces the incidence of cerebral vasospasm-related morbidity and all-cause mortality within 6 weeks post aneurysmal subarachnoid hemorrhage (aSAH) in patients treated by endovascular coiling. |
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E.2.2 | Secondary objectives of the trial |
To demonstrate that at least one dose (5 or 15 mg/h) of clazosentan improves clinical outcome at Week 12 post-aSAH in patients treated by endovascular coiling, as measured by the dichotomized Glasgow Outcome Scale (extended version [GOSE]). To evaluate the impact of clazosentan on total infarct volume at Week 6 post-aSAH in patients treated by endovascular coiling, and on each individual component of the primary endpoint. To evaluate the safety and tolerability of clazosentan. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 endovascular coiling. The time of aneurysm rupture must be known or possible to estimate with a reasonable degree of certainty. 3) Patients with World Federation of Neurological Surgeons (WFNS) grade IIV measured prior to the endovascular coiling procedure, and which does not worsen to grade V post-procedure 4) Patients with any thick clot (short axis ≥ 4 mm) 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. |
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E.4 | Principal exclusion criteria |
1) Patients with subarachnoid hemorrhage (SAH) due to causes other than a saccular aneurysm 2) Patients with giant aneurysms(height or width &#8805; 25 mm). 3) Patients with intraventricular or intracerebral blood, in the absence of subarachnoid blood, or with only a thin clot(short axis < 4 mm). 4) Presence of cerebral vasospasm seen on angiography prior to the endovascular coiling procedure. 5)Patients who experienced 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 &#8805; 12 hours post-aneurysm coiling). 6) Patients who have had their current ruptured aneurysm previously secured (successfully or not) by clipping. 7) Patients coiled with coiling material, which has not been approved by local health authorities. 8) Use of liquid embolism aneurysmal treatment or flow diverting device. 9) Patients with several aneurysms among which the ruptured one cannot be identified with certainty and which are not all secured during the coiling procedure. 10) Patients planned to have another securing procedure for any aneurysm after randomization and prior Week 12 postaSAH. 11) Patients for whom study drug cannot be started within 56 hours after the aneurysm rupture. 12) Patients with hypotension (systolic blood pressure (SBP) &#8804; 90 mmHg) that is refractory to treatment. 13) Patients with aspiration pneumonia. 14) Patients with pulmonary edema or severe cardiac failure requiring inotropic support at the time of randomization. 15) 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. 16). Significant kidney and/or liver disease, as defined by plasma creatinine &#8805; 2.5 mg/dL (221 &#956;mol/l) and/or total bilirubin > 3 mg/dL (51.3 &#956;mol/l) measured at the local laboratory. 17). Patients receiving i.v. nimodipine or i.v. nicardipine must have these drugs discontinued at least 4 hours prior to initiation of the study treatment. 18) Known hypersensitivity to other endothelin receptor antagonists. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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: 1) Death (all causes) 2) 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 (e.g., lesions arising from intra-cerebral hemorrhage, the aneurysm endovascular coiling procedure,the primary injury, or ventricular drain encephalomalacia) 3)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 (e.g., hydrocephalus, seizure, etc.) a) DIND is defined in patients in whom the neurological scales are assessable as: a decrease of at least two points on the modified Glasgow Coma Scale (mGCS), or an increase of at least two points on the abbreviated National Institutes of Health Stroke Scale (abbrev. NIHSS), lasting for at least 2 hours b) DIND is defined in patients in whom the neurological scales are not assessable as:a valid rescue therapy started for a justifiable reason 4) Administration of a valid rescue therapy in the presence of confirmed cerebral vasospasm on angiography (DSA or CTA). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.3.1 | Comparator description |
- same IMP used at different dosage |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 67 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |