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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00940095




Registration number
NCT00940095
Ethics application status
Date submitted
13/07/2009
Date registered
15/07/2009
Date last updated
9/07/2018

Titles & IDs
Public title
Clazosentan in Aneurysmal Subarachnoid Hemorrhage
Scientific title
A Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Efficacy and Safety of Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Endovascular Coiling.
Secondary ID [1] 0 0
AC-054-302
Universal Trial Number (UTN)
Trial acronym
CONSCIOUS-3
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Aneurysmal Subarachnoid Hemorrhage 0 0
Condition category
Condition code
Neurological 0 0 0 0
Other neurological disorders
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Clazosentan 5 m/h
Treatment: Drugs - Clazosentan 15 mg/h
Treatment: Drugs - Placebo

Experimental: Clazosentan 5 mg/h - Continuous intravenous infusion of clazosentan (5 mg/h) started within 56 hours post-aSAH and scheduled to continue until Day 14 post-aSAH, or at least until Day 10 post-aSAH, for patients discharged before Day 14

Experimental: Clazosentan 15 mg/h - Continuous intravenous infusion of clazosentan (15 mg/h) started within 56 hours post-aSAH and scheduled to continue until Day 14 post-aSAH, or at least until Day 10 post-aSAH, for patients discharged before Day 14

Placebo comparator: Placebo - Continuous intravenous infusion of placebo matching clazosentan started within 56 hours post-aSAH and scheduled to continue until Day 14 post-aSAH, or at least until Day 10 post-aSAH, for patients discharged before Day 14


Treatment: Drugs: Clazosentan 5 m/h
Continuous intravenous infusion of clazosentan (5 mg/h)

Treatment: Drugs: Clazosentan 15 mg/h
Continuous intravenous infusion of clazosentan clazosentan (15 mg/h)

Treatment: Drugs: Placebo
Continuous intravenous infusion of placebo-matching clazosentan
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol
Timepoint [1] 0 0
Within 6 weeks post-aSAH
Secondary outcome [1] 0 0
Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized into good (score > 4) and poor (score = 4) outcome.
Timepoint [1] 0 0
Week 12 post-aSAH

Eligibility
Key inclusion criteria
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], investigator's assessment), 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. World Federation of Neurological Surgeons (WFNS) grade I-IV measured prior to the endovascular coiling procedure, and which does not worsen to grade V post-procedure (based on regular Glasgow Coma Scale [GCS])
4. Patients with any thick clot (short axis > or = 4 mm) on baseline CT scan (investigator's assessment).
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.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria :

1. Subarachnoid hemorrhage (SAH) due to causes other than saccular aneurysm.
2. Giant aneurysms (height or width > or = 25 mm).
3. Intraventricular or intracerebral blood, in absence of subarachnoid blood, or or with only a thin clot (short axis < 4 mm)
4. Cerebral vasospasm on angiography (investigator's assessment) prior to endovascular coiling (intraprocedural cerebral vasospasm is not an exclusion criterion).
5. 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 > or = 12 hours post-aneurysm coiling)*.
6. Current ruptured aneurysm previously secured (successfully or not) by clipping.
7. Coiling material used, which has not been approved by local health authorities.
8. Use of liquid embolism aneurysmal treatment or flow diverting device.
9. Several aneurysms among which the ruptured one cannot be identified with certainty and which are not all secured during the coiling procedure.
10. No end-of-procedure DSA.
11. Another securing procedure planned for any aneurysm between randomization and Week 12 post-aSAH.
12. Study drug start >56 hours after the aneurysm rupture.
13. Known, at time of screening, that certain follow-up, or protocol-mandated imaging assessments will not be feasible.
14. Hypotension (systolic blood pressure < or = 90 mmHg) refractory to treatment.
15. Aspiration pneumonia.
16. Pulmonary edema or severe cardiac failure requiring inotropic support at time of randomization.
17. Any severe or unstable concomitant condition or disease (e.g., known significant neurological deficit, cancer, hematological, coronary disease, psychiatric disorder), which would affect assessment of the safety or efficacy of the study drug (investigator's opinion).
18. Significant kidney disease defined by plasma creatinine > or = 2.5 mg/dL (221 micromol/l) and/or liver disease defined by total bilirubin > 2-fold Upper Limit of Normal as measured at local laboratory, and/or known diagnosis or clinical suspicion of liver cirrhosis.
19. Infusion of i.v. nimodipine or i.v. nicardipine must have these drugs discontinued at least 4 hours prior to initiation of study treatment.
20. Infusion of i.v. fasudil within 24-hour period preceding planned start of study drug initiation.
21. Start of statins less than 2 weeks prior to admission must have them discontinued prior to study drug initiation.
22. Infusion of 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.
23. Intake of an investigational product including investigational coil material within 28 days prior to randomization or those who have already participated in current study or CONSCIOUS-2 (AC-054-301).
24. Unlikely event to comply with protocol (e.g., unable to return for follow-up visits).
25. Known hypersensitivity to other endothelin receptor antagonists.26.current alcohol or drug abuse/dependence.

* "Large territorial infarct" refers to infarcts detected during the endovascular coiling 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 reversal of sedation and performance of a GCS examination (verbal scores in intubated patients may be extrapolated from the eye-opening and motor scores using predefined values). If a new major neurological deficit does not improve within 12 hours after the coiling procedure, the patient cannot be included.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/07/2009
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/01/2011
Sample size
Target
Accrual to date
Final
577
Recruitment in Australia
Recruitment state(s)
QLD
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Gold Coast Hospital - Southport
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Royal Brisbane & Women's Hosptal - Brisbane
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Royal Prince Alfred Hosptial - Camperdown
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Monash Medical Centre - Clayton
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Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 0 0
4215 - Southport
Recruitment postcode(s) [2] 0 0
QLD 4029 - Brisbane
Recruitment postcode(s) [3] 0 0
NSW 2050 - Camperdown
Recruitment postcode(s) [4] 0 0
VIC 3168 - Clayton
Recruitment postcode(s) [5] 0 0
QLD 4102 - Woolloongabba
Recruitment outside Australia
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Rome
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Tilburg
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Bergen
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Oslo
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Norway
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Tromso
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Poland
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Gdansk
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Poland
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Warszawa
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Singapore
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Singapore
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Slovenia
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Ljubljana
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Slovenia
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Maribor
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Spain
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Barcelona
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Granada
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Madrid
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Spain
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Palma de Mallorca
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Sweden
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Goteborg
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Linkoping
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Lund
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Switzerland
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Aarau
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Switzerland
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Bern
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Geneva
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Switzerland
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Zurich
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Taiwan
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Taipei

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Idorsia Pharmaceuticals Ltd.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The aim of this study is to demonstrate that clazosentan, administered as a continuous intravenous infusion at either 5 mg/h or 15 mg/h until Day 14 post aneurysmal subarachnoid hemorrhage (aSAH), reduces the incidence of cerebral vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH treated by endovascular coiling.

The primary endpoint of the study is 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.
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.
4. Administration of a valid rescue therapy in the presence of confirmed cerebral vasospasm on angiography (DSA or CTA).

An independent Critical Events Committee (CEC) will adjudicate whether or not patients meet the primary endpoint and its individual morbidity components.
Trial website
https://clinicaltrials.gov/study/NCT00940095
Trial related presentations / publications
Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Nowbakht P, Roux S, Kassell N. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012 Jun;43(6):1463-9. doi: 10.1161/STROKEAHA.111.648980. Epub 2012 Mar 8. Erratum In: Stroke. 2012 Jul;43(7):e68.
Mayer SA, Aldrich EF, Bruder N, Hmissi A, Macdonald RL, Viarasilpa T, Marr A, Roux S, Higashida RT. Thick and Diffuse Subarachnoid Blood as a Treatment Effect Modifier of Clazosentan After Subarachnoid Hemorrhage. Stroke. 2019 Oct;50(10):2738-2744. doi: 10.1161/STROKEAHA.119.025682. Epub 2019 Aug 9.
Public notes

Contacts
Principal investigator
Name 0 0
Sebastien Roux, MD
Address 0 0
Actelion
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00940095