Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping (CONSCIOUS-2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Actelion
ClinicalTrials.gov Identifier:
NCT00558311
First received: November 13, 2007
Last updated: March 9, 2012
Last verified: March 2012
  Purpose

The aim of this study is to demonstrate that clazosentan, administered as a continuous intravenous infusion at 5 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 surgical clipping. 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. 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.

An independent Critical Events Committee (CEC) will adjudicate whether or not patients meet the primary endpoint and its individual morbidity components.


Condition Intervention Phase
Aneurysmal Subarachnoid Hemorrhage
Drug: clazosentan
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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 Surgical Clipping.

Further study details as provided by Actelion:

Primary Outcome Measures:
  • Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol [ Time Frame: Within 6 weeks post-aSAH ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized into good (score > 4) and poor (score ≤ 4) outcome. [ Time Frame: Week 12 post-aSAH ] [ Designated as safety issue: No ]

Enrollment: 1157
Study Start Date: November 2007
Study Completion Date: July 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 A
clazosentan
Drug: clazosentan
Intravenous clazosentan administered by continuous infusion at 5 mg/h for the duration of the treatment
Placebo Comparator: 2 B
placebo
Drug: placebo
Placebo administered by continuous infusion at 5 mg/h for the duration of the treatment.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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]), 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 > or = 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.

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 > or = 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)< or = 90 mmHg) that is refractory to treatment.
  9. Patients with aspiration pneumonia.
  10. Patients with pulmonary edema or 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 > or = 2.5 mg/dL (221 micromol/l) and/or total bilirubin > 3 mg/dL (51.3 micromol/l) measured at the local site laboratory.
  13. Patients receiving i.v. nimodipine, i.v. nicardipine, or fasudil hydrochloride, 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00558311

  Show 117 Study Locations
Sponsors and Collaborators
Actelion
Investigators
Study Director: Sebastien Roux, MD Actelion
  More Information

Additional Information:
No publications provided by Actelion

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT00558311     History of Changes
Other Study ID Numbers: AC-054-301
Study First Received: November 13, 2007
Last Updated: March 9, 2012
Health Authority: Austria: Agency for Health and Food Safety
Belgium: Federal Agency for Medicinal Products and Health Products
Czech Republic: State Institute for Drug Control
Denmark: Danish Medicines Agency
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: German Institute of Medical Documentation and Information
Italy: The Italian Medicines Agency
Norway: Norwegian Medicines Agency
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
Australia: Department of Health and Ageing Therapeutic Goods Administration
Switzerland: Swissmedic
Canada: Health Canada
China: Food and Drug Administration
Colombia: Institutional Review Board
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Actelion:
Aneurysmal
Subarachnoid
Hemorrhage
vasospasm
clazosentan
PIVLAZ
Actelion
surgical clipping

Additional relevant MeSH terms:
Hemorrhage
Subarachnoid Hemorrhage
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on July 26, 2014