| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Prevention of ischaemic complications related to vasospasm in patients with aneurysmal subarachnoid haemorrhage | |
| MedDRA Classification |
| 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 assess the efficacy of 3 dose levels (1 mg/h, 5 mg/h and 15 mg/h) of clazosentan in preventing the occurrence of cerebral vasospasm following aSAH | |
| E.2.2 | Secondary objectives of the trial | ·To assess the ability of clazosentan to reduce the occurrence of early morbidity/mortality.
·To assess the effect of clazosentan on clinical outcome.
·To assess the safety and tolerability of three dose levels of clazosentan. | |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria | 1.Male or female patients aged 18 to 70 years (inclusive).
2.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.
3.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
4.Onset of aSAH clinical symptoms within the 48 hours preceding screening.
5.World Federation of Neurological Surgeons (WFNS) Grades I–IV, and those Grade V patients who improve to Grade IV or less after ventriculostomy.
6.In the case of multiple aneurysms, the aneurysm that has ruptured is identified with a high likelihood during the screening period.
7.Women of childbearing potential with pre-treatment negative serum pregnancy test.
8.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.
9.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. | |
| E.4 | Principal exclusion criteria | 1.Patients with SAH due to other causes (e.g., trauma or rupture of fusiform or mycotic aneurysms).
2.Patients with intraventricular or intracerebral blood, in the absence of subarachnoid blood.
3.No visualized clot or presence of only localized thin clot on CT (< 20 mm x 4 mm)
4.Presence of moderate (>=34 %) or severe cerebral vasospasm on screening angiogram.
5.Patients with hypotension (systolic blood pressure (SBP) <=90 mmHg) refractory to fluid therapy.
6.Patients with neurogenic pulmonary edema or severe cardiac failure requiring inotropic support.
7.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.
8.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).
9.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.
10.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.
11.Patients who have received thrombolytics, including intracisternal administration, intrathecal treatments and therapeutic hypothermia for treatment of the SAH.
12.Patients who have received an investigational product within 28 days prior to randomization.
13.Patients with current alcohol or drug abuse or dependence. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Occurrence of moderate or severe cerebral vasospasm, as measured by cerebral angiography at Day 9 ± 2 post-aneurysm rupture. 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.
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | | Last visit of the last patient | |
| 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 | 6 |
| 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 | 6 |
