Clinical research study with clazosentan to evaluate its effects on preventing complications due to the narrowing of the blood vessels (vasospasm) in the brain, caused by bleeding onto the surface of the brai

Phase 1

Conditions: Aneurysmal Subarachnoid Hemorrhage
MedDRA version: 21.1Level: PTClassification code 10039330Term: Ruptured cerebral aneurysmSystem Organ Class: 10029205 - Nervous system disorders
MedDRA version: 21.1Level: PTClassification code 10042316Term: Subarachnoid haemorrhageSystem Organ Class: 10029205 - Nervous system disorders
Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Registration Number: EUCTR2018-000241-39-BE

Lead Sponsor: Idorsia Pharmaceuticals Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 400

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. 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.

6. A) Presence of a cerebral CT scan, performed at least 8 hours post-aneurysm-securing procedure and within 24 hours prior to randomization
6. B) Absence of a significant (e.g., symptomatic or large) new or worsened cerebral infarct or re-bleeding of the repaired aneurysm on the post-procedure CT scan.

7. A woman of childbearing potential is eligible only if the pregnancy test performed during the screening period is negative.
Agreement must be obtained to take the necessary precautions to avoid pregnancy from hospital discharge until 30 days post-study drug discontinuation.
If breastfeeding, agreement must be obtained to refrain for the duration of the treatment with study drug and until 30 days post-study drug discontinuation.

8.Males are eligible for study participation only if they agree to take the necessary precautions to avoid pregnancy in a female partner from hospital discharge until 30 days post-study drug discontinuation.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 250
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 150

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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: - To determine the efficacy of clazosentan in preventing clinical deterioration due to DCI, in subjects with aSAH.;Secondary Objective: - 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<br>- To evaluate the effect of clazosentan on long-term clinical outcome, cognition, and health-related quality of life (QoL) at Week 12 and QoL at week 24 post-aSAH.<br>- To evaluate the safety and tolerability of clazosentan in the selected population up to 24 hours post-study drug discontinuation.<br>;Primary end point(s): - Occurrence of clinical deterioration due to DCI from study drug initiation up to 14 days post-study drug initiation;Timepoint(s) of evaluation of this end point: From study drug initiation up to 14 days post-study drug initiation

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1- Main secondary endpoint:<br>Occurrence of all-cause new or worsened cerebral infarction = 5 cm3 (total volume) at Day 16 post study drug initiation<br><br>2- Other secondary endpoint:<br>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);Timepoint(s) of evaluation of this end point: 1- At Day 16 post study drug initiation<br>2- At Week 12 post-aSAH

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