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

  Hide Study Locations
Locations
United States, Arizona
Barrow Neurosurgical Associates
Phoenix, Arizona, United States, 85013
United States, Colorado
Colorado Neurological Institute
Englewood, Colorado, United States, 80113-2769
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
State University of New York at Stony Brook-Health Sciences Center
Stony Brook, New York, United States, 11794-8122
United States, Ohio
University of Cincinnati-Department of Neurosurgery
Cincinnati, Ohio, United States, 45219
University Hospitals Case Medical Center-Department of Neurosurgery
Cleveland, Ohio, United States, 44106
United States, Oregon
Oregon Health & Science University-Oregon Stroke Center
Portland, Oregon, United States, 97239
United States, Pennsylvania
Thomas Jefferson University School of Medicine-Jefferson Hospital for Neuroscience
Philadelphia, Pennsylvania, United States, 19107
United States, Virginia
University of Virginia Health System-Department of Neurosurgery
Charlottesville, Virginia, United States, 22908
Virginia Commonwealth University-Department of Neurosurgery
Richmond, Virginia, United States, 23284
Australia
Royal Brisbane Hospital
Herston, Australia, 4029
The Alfred Hospital
Melbourne, Australia, VIC 3004
Austria
Landeskrankenhaus
Feldkirch, Austria, 6807
Landeskrankenhaus und Medizinische Universitat Graz
Graz, Austria, 8036
Medizinsche Universitat
Innsbruck, Austria, 6020
University Fur Neurochirurgie, SALK, Christian Doppler Hospital
Salzburg, Austria, 5020
AKH University of Vienna, Medical University
Vienna, Austria, 1090
Sozialmedizinisches Zentrum Ost (ZMZ-Ost) Donauspital Vienna
Vienna, Austria, 1220
Belgium
Cliniques Universitaires Saint-Luc, Universite Catholique de
Brussels, Belgium, 1200
Canada, Alberta
University of Alberta Hospital
Edmonton, Alberta, Canada, T6G2B7
Canada, British Columbia
Vancouver Hospital
Vancouver, British Columbia, Canada, V5Z 1 M9BC
Canada, Ontario
St Michael's Hospital, University
Toronto, Ontario, Canada, M5C367
Canada, Quebec
CHUM Notre Dame
Montreal, Quebec, Canada, H2L4M1
Canada
University of Calgary Foothills Medical Center
Calgary, Canada, T2N2T9AB
QEII Health Science Center
Halifax, Canada, B3H3A7
Toronto Western Hospital, University of Toronto
Toronto, Canada, M5T2S8
China
Beijing Tian Tan Hospital
Beijing, China, 100050
XuanWu Hospital Institute of Brain Vascular Disease
Beijing, China, 100053 PR
Guangdong Province Chinese Medicine Hospital
Guangzhou, China, 51000
1st Affilated Hospital of Zhongshan
Guangzhou, China, 510080
Shanghai Hua Shan Hospital
Shanghai, China, 200040
Wuhan Tongji Hospital
Wuhan, China, 430030
Croatia
Clinical Hospital Dubrava
Zagreb, Croatia, 1000
University Hospital Sestre Milosrdnice
Zagreb, Croatia, 1000
Clinical Hospital "Dubrava"
Zagreb, Croatia, 10000
Czech Republic
Faculty Hospital/FN Brno Bohunice
Brno, Czech Republic, 62500
Nemocnice Ceske Budejovice
Ceske Budejovice, Czech Republic, 37087
UVN Prague
Prague, Czech Republic, 16902
Na Homolce Hospital Prague
Prague, Czech Republic, 15030
Denmark
Copenhagen University Hospital
Copenhagen, Denmark, 2100
Copenhagen Country Hospital
Glostrup, Denmark, 2600
Odense University Hospital
Odense, Denmark, 5000
Finland
Helsinki University Central Hospital
Helsinki, Finland, Fin-00029HUS
Oulu University Hospital
Oulu, Finland, 90029OYS
Tampere University Central Hospital
Tampere, Finland, 33521
France
Pole d'Anesthesie Reanimation, CHU D'Angers
Angers, France, 49933
Hopital Pellegrin
Bordeaux, France, 33076
Hopital Neurologique et Neuro-Chirurgical Pierre Wertheimer
Bron, France, 69677
Chu Hopital Gabriel Montpied
Clermont Ferrand, France, 63003
Hopital de la Timone
Marseille, France, 13385
Germany
Charite Universitatsmedizin Berlin-Neurochirurgische Klinik-CVK
Berlin, Germany, D-13353
University of Bonn Medical Center
Bonn, Germany, 53105
Klinik und Poliklinik fur Neurochirurgie
Dresden, Germany, 01307
University of Erlangen-Nurnberg
Erlangen, Germany, 91054
University of Hospital of Essen
Essen, Germany, 45147
Universitatsklinik Frankfurt, Klinik und Poliklinik fur Neurochirurgie
Frankfurt, Germany, 60528
University Hospital of Hamburg
Hamburg, Germany, 20246
Neurochirurggische Universitatsklinik des Heidelberg
Heidelberg, Germany, 69120
Klinik und Poliklinik fur Neurochirurgie
Leipzig, Germany, 04103
University Munich Groshadern
Munich, Germany, 81377
Thechnical University-Klinikum rechts der Isar
Munich, Germany, 81675
University Regensburg
Regensburg, Germany, 93053
Hong Kong
Prince of Wales Hospital
Hong Kong, Hong Kong, NT
Queen Mary Hospital
Hong Kong, Hong Kong
India
Post Graduate Institute of Medical Education
Chandigarh, India, 160012
Post Graduate Institute of Medical Education and Research
Chandigarh, India, 160012
Nizam's Institute of Medical Sciences
Hyderabaad, India, 500482
All India Insititute of Medicla Sciences (AIIMS)
New Delhi, India, 110011
Sahyadri Hospital
Pune, India, 411005
Sahyadri Specialty Hospital
Pune, India, 411 004
Italy
Ospedale Bellaria-Maggiore Hospital
Bologna, Italy, 40139
Ospedale Maurizio Bufalini
Cesena, Italy, 47023
Azienda Ospedaliero-Universitaria di Careggi
Firenze, Italy, 50141
Ospedale Niguarda
Milan, Italy, 20162
Nuovo Ospedale Sant' Agostino Estense
Modena, Italy, 41100
Ospedale Civile di Padova
Padova, Italy, 35128
Azienda Ospedaliero-Universitaria di
Parma, Italy, 43100
Ospedale Civile Borgo Trento
Verona, Italy, 37126
Korea, Republic of
Kyungpook National University
DaeGu, Korea, Republic of, 700-721
Daejeon Eulji University Hospital
Daejeon, Korea, Republic of, 302-799
Latvia
Riga Eastern Clinical University Hospital
Riga, Latvia, LV-1038
New Zealand
Auckland Hospital
Grafton, New Zealand, Auckland
Norway
Haukeland University Hospital Helse Bergen HF
Bergen, Norway, 5021
Ulleval University Hospital
Oslo, Norway, 0407
Universitetssykehuset Nord-Norge
Tromsö, Norway, N9038
Poland
Klinika Neurochirurgii AMB-Neurosurgery Clinic of Medical Academy
Bialystok, Poland
Kathedra I Klinika Neurochirurghii I Neurotraumatologii Collegium Medicum im. L. Rydygiera w Bydgoszc
Bydgoszcz, Poland, 85-094
Katedra Klinika Neurochirurgii Akademii Medycznej w Gdansku
Gdansk, Poland, 80211
Samodzielny Publiczny Szpital Kliniczny Slaskiej Akademii Medycznej w Katowicach
Katowice, Poland, 40-752
Oddzial Kliniczny Kliniki Neurochirurgii i Neurotrumatologii Szpitala, Uniwersyteckiego w Krakowie
Krakow, Poland, 31-503
Katedra Neurochirurgii, Uniwersytet
Lodz, Poland, 90-153
Katedra I Klinika Neurochirurgii i Dzieciecej
Lublin, Poland, 20-090
Katedra IKlinika Neurochirurgii Akademii Medycznej w Warszawie Clinic
Warszawa, Poland, 02-097
Russian Federation
Scientific Research Institute of Neurosurgery by Burdenko
Moscow, Russian Federation, 125 047
Serbia
Clinical Center Nis
Nis, Serbia, 18000
Clinical Center Novi Sad
Novisad, Serbia, 21000
Singapore
National Neuroscience
Singapore, Singapore, 308433
Slovenia
General Hospital Maribor
Maribor, Slovenia, 2000
Spain
Hospital Del Mar
Barcelona, Spain, 08003
Vall d'Hebron Hospital
Barcelona, Spain, 08035
Hospital Universitario 12 de Octubre
Madrid, Spain, 28041
Hospital de Son Dureta
Palma de Mallorca, Spain, 07014
Sweden
Sahlgrenska
Goteborg, Sweden, 41345
Lund University Hospital
Lund, Sweden, 22185
Uppsala University Hospital-Uppsala Akademiska Sjukhus
Uppsala, Sweden, 75185
Switzerland
Kantonsspital Aarau
Aarau, Switzerland, 5001
Universitätsklinik Bern Klinik für Neurochirurgie
Bern, Switzerland, 3010
Universitatsklinik Bern
Bern, Switzerland, 3010
Geneva University Hospital
Geneva, Switzerland, 1211
Kantonsspital St. Gallen
St Gallen, Switzerland, 9007
Universitatsspital Zurich
Zurich, Switzerland, 8091
Turkey
Ibn-i Sina Hastanesi Ankara & Ankara Universitesi Tip Fakultesi
Ankara, Turkey, 06100
Ege Universitesi Tip Fak Hestanesi
Bornova-Izmir, Turkey, 35100
Istanbul Universitesi, Istanbul Tip
Istanbul, Turkey, 34390
Ukraine
Regional Clinical Hospital by Mechnikov
Dnipropetrovsk, Ukraine, 49,005
A. P. Romodanov Institute of Neurosurgery
Kiev, Ukraine, 04 050
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 August 28, 2014