| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Indication: Aneurysmal subarachnoid hemorrhage
Hemorragia Subaracnoidea aneurismática. |
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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 | LLT |
| E.1.2 | Classification code | 10042318 |
| E.1.2 | Term | Subarachnoid haemorrhage NOS |
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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 clazosentan reduces the incidence of cerebral vasospasm-related morbidity and all-cause mortality within 6 weeks post aneurysmal subarachnoid hemorrhage (aSAH) treated by surgical clipping. |
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| E.2.2 | Secondary objectives of the trial |
·To demonstrate that clazosentan improves clinical outcome at Week 12 post-aSAH treated by surgical clipping, 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 treated by surgical clipping, 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 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 >= 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. |
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| E.4 | Principal 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 >= 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) <= 90 mmHg) that is refractory to treatment.
9. Patients with aspiration pneumonia or pulmonary edema.
10. Patients with 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 >= 2.5 mg/dL (221 µmol/l) and/or total bilirubin > 3 mg/dL (51.3 µmol/l) measured at the local site laboratory.
13. 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.
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
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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 clipping, 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 (see detailed description of what constitutes a valid rescue therapy and a justifiable reason in the study protocol, Section 3.8.1.1). A CT scan and a cerebral angiography must be performed whenever DIND is suspected. In addition, clinical signs suggestive of vasospasm (e.g., unexplained fever, unexplained high white blood cell count, confusion, drowsiness), or suspicion of cerebral infarct, must lead to a cerebral angiography (DSA [preferred] or CTA). If a CTA was performed and is inconclusive or of poor quality, a DSA must be performed.
4.Neurological signs or symptoms (depending on state of consciousness), in the presence of confirmed cerebral vasospasm on angiography (DSA or CTA), leading to the administration of a valid rescue therapy* (see detailed definition of this endpoint component and the list of qualifying rescue therapies in the study protocol, Section 3.8.1.1).
*An independent Critical Events Committee (CEC) will adjudicate whether or not patients meet the primary endpoint and its individual morbidity components.It is expected that the incidence of vasospasm-related morbidity, and mortality of all causes, within 6 weeks post-aSAH is 40% in the placebo group. The treatment effect to be detected is a relative risk reduction of 30% (i.e., from 40% to 28%).As the baseline WFNS grade has a predictive value for the occurrence of the morbidity/mortality endpoint, an adjustment for this variable is made in the primary analysis. |
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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 | Information not present in EudraCT |
| 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 | No |
| 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.8.3 |
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 | 65 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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