E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Aneurysmal Subarachnoid Hemorrhage |
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E.1.1.1 | Medical condition in easily understood language |
When a brain aneurysm (bulge) ruptures, it causes bleeding into the compartment surrounding the brain, the subarachnoid space and is therefore also known as aneurysmal subarachnoid hemorrhage (aSAH) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039330 |
E.1.2 | Term | Ruptured cerebral aneurysm |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042316 |
E.1.2 | Term | Subarachnoid haemorrhage |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To determine the efficacy of clazosentan in preventing clinical deterioration due to DCI, in subjects with aSAH. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of clazosentan on the incidence of all-cause new or worsened cerebral infarction ≥ 5 cm3 in total volume at Day 16 post-study drug initiation - To evaluate the effect of clazosentan on long-term clinical outcome, cognition, and health-related quality of life at Week 12 post-aSAH. - To evaluate the safety and tolerability of clazosentan in the selected population up to 24 hours post-study drug discontinuation.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent to participate in the study must be obtained from the subject or proxy/legal representative at any time from hospital admission to prior to initiation of any study-mandated procedure 2. Males and females aged 18 to 70 years (inclusive, at hospital admission). 3. Subjects with a ruptured saccular aneurysm, angiographically confirmed by DSA or CTA, which has been successfully secured within 72 hours of rupture, by surgical clipping or endovascular coiling 4. WFNS (World Federation of Neurosurgical Societies) grades 1–4 (based on Glasgow Coma Scale [GCS]) assessed after recovery from the aneurysm-securing procedure and after external ventricular drainage for hydrocephalus, if required 5. Subjects must meet one of the two following inclusion criteria:
A) High-risk prevention: Subjects with a "thick and diffuse clot" (thick and diffuse is defined as a thick confluent clot, more than 4 mm in thickness, involving 3 or more basal cisterns) on the hospital admission CT scan, absence of cerebral vasospasm at the time of randomization, and possibility to start study drug in the ICU (or equivalent environment where all protocol assessments can be performed and the Patient Management Guidelines followed), within 96 hours after the time of the aneurysm rupture. OR B) Early treatment: Subjects without a thick and diffuse clot on the hospital admission CT scan who develop asymptomatic or minimally symptomatic moderate to severe angiographic vasospasm, within the 14-day period post-aneurysm rupture, and for whom it is possible to start study drug in the ICU (or equivalent environment where all protocol assessments can be performed and the Patient Management Guidelines followed), within 24 hours of this angiographic diagnosis.
6. Presence of a cerebral CT scan, performed at least 8 hours post-aneurysm-securing procedure and within 24 hours prior to randomization, which rules out a significant (e.g., symptomatic) new or worsened cerebral infarct or re-bleeding of the repaired aneurysm.
7. A woman of childbearing potential is eligible only if the pregnancy test performed during the screening period is negative.
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E.4 | Principal exclusion criteria |
aSAH, aneurysm-securing procedure, vasospasm:
1. Subjects with SAH due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms, SAH associated with arterio-venous malformation, vertebral dissections). 2. Significant bleeding post aneurysm-securing procedure (e.g., due to intra-ventricular drain, intra-cerebral hemorrhage, epidural hematoma, vessel dissection or rupture, re-bleeding of the repaired aneurysm), based on investigator judgment. 3. Intra-or peri-aneurysm securing procedure complication requiring non-routine medical or interventional treatment such as administration of an antithrombotic or anti-platelet agent (e.g., abciximab), which is not completely resolved prior to randomization. 4. Intraventricular hemorrhage on the hospital admission CT scan, filling more than 50% of both lateral ventricles and with involvement of the 3rd and 4th ventricles. 5. Intracerebral hemorrhage on the hospital admission CT scan, with an approximate volume of > 50 mL. 6. Presence of cerebral vasospasm at hospital admission (initial admission or transfer from another hospital) believed to be associated with a prior bleed (i.e., occurring before the bleed for which the subject is currently hospitalized). Vasospasm occurring during the aneurysm-securing procedure is not an exclusion criterion.
Neurological and functional status:
7. Subjects with a new major neurological deficit occurring post aneurysm-securing procedure which is attributable to the procedure and does not improve to pre-procedure status before randomization. 8. Subjects with a GCS score of ≤ 9 at the time of randomization and without intracranial pressure (ICP) monitoring. 9. modified Rankin Score of 3 or higher, prior to the aSAH (i.e., due to a chronic condition).
Other clinical considerations:
10. Subjects with total bilirubin > 2 times the upper limit of normal, and/or a known diagnosis or clinical suspicion of liver cirrhosis or moderate to severe hepatic impairment 11. Hypotension (systolic blood pressure [SBP] ≤ 90 mmHg) at time of randomization that is refractory to treatment. 12. Unresolved pulmonary edema or significant pneumonia still present at the time of randomization, or severe hypoxia at the time of randomization in intubated subjects, defined as PaO2/FiO2 ≤ 200. 13. High sustained ICP (> 25 mmHg lasting > 20 minutes) at time of randomization, despite optimal treatment, in subjects with ICP monitoring. 14. Severe cardiac failure requiring inotropic support at the time of randomization.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Occurrence of clinical deterioration due to DCI from study drug initiation up to 14 days post-study drug initiation |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From study drug initiation up to 14 days post-study drug initiation |
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E.5.2 | Secondary end point(s) |
1- Main secondary endpoint: Occurrence of all-cause new or worsened cerebral infarction ≥ 5 cm3 (total volume) at Day 16 post study drug initiation
2- Other secondary endpoint: Long-term clinical outcome assessed by the Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized as follows: poor outcome (score ≤ 4) and good outcome (score > 4) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- At Day 16 post study drug initiation 2- At Week 12 post-aSAH |
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of life Biomarkers |
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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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
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 | No |
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 |
Canada |
Israel |
Korea, Republic of |
United States |
Austria |
Finland |
France |
Poland |
Sweden |
Spain |
Czechia |
Germany |
Italy |
Belgium |
Denmark |
Hungary |
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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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End of the trial is defined as last subject last visit (LSLV) |
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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 | |
E.8.9.1 | In the Member State concerned months | 27 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 27 |