Clazosentan in Aneurysmal Subarachnoid Hemorrhage (CONSCIOUS-3)

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.

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.

Study Overview

• Status: Terminated
• Conditions: Aneurysmal Subarachnoid Hemorrhage
• Intervention / Treatment: Drug: Clazosentan 5 m/h; Drug: Clazosentan 15 mg/h; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 577
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1118AAT
    • Hospital Aleman
  • Buenos Aires, Argentina, C1425DQI
    • Clinica De Sol
  • Buenos Aires, Argentina, C1426ENF
    • ENERI
• Australia
  • Brisbane, Australia, QLD 4029
    • Royal Brisbane & Women's Hosptal
  • Camperdown, Australia, NSW 2050
    • Royal Prince Alfred Hosptial
  • Clayton, Australia, VIC 3168
    • Monash Medical Centre
  • Woolloongabba, Australia, QLD 4102
    • Princess Alexandra Hospital
  • Queensland
    • Southport, Queensland, Australia, 4215
      • Gold Coast Hospital
• Austria
  • Graz, Austria, A-8036
    • Landeskrankenhaus und Medizinische Universitat
  • Innsbruck, Austria, 6020
    • Medizinsche Universitat Innsbruck
  • Salzburg, Austria, 5020
    • University Fur Neurochirurgie, SALK, Christian Doppler Hospital
  • Vienna, Austria, 1090
    • AKH University of Vienna, Medical Univ. Of Neurosurgery
• Belgium
  • Antwerp, Belgium, 2650
    • UZ Antwerpen
  • Brussels, Belgium, 1090
    • UZ Brussels
  • Brussels, Belgium, 1070
    • ULB Erasme
  • Brussels, Belgium
    • UZ Brussels
  • Brussels, Belgium, 1200
    • UCL Saint-Luc
  • Gent, Belgium, 9000
    • UZ Gent
  • Leuven, Belgium, 3000
    • UZ Gasthuisberg
• Brazil
  • Belo Horizonte, Brazil, 30110-934
    • Hospital das Clinicas da Ufmg
  • Curitiba, Brazil, 80060-900
    • Hospital de Clínicas da Universidade Federal do Paraná
  • Joinville, Brazil, 89202-000
    • Clinica de Neurologia de
  • Niteroí, Brazil, 24020-090
    • Hospital de Clínicas de Niteroí
  • Porto Alegre, Brazil, 90035-001
    • Hospital Moinhos de Vento
  • Sao Paulo, Brazil, 08270-070
    • Hospital Santa Marcelina
  • Sobral, Brazil, 62010-550
    • Santa Case de Misericordia de Sobral
• Canada
  • Quebec, Canada, G1J 1Z4
    • Hopital de I'Enfant-Jesus
  • Alberta
    • Calgary, Alberta, Canada, T2N 1M9
      • University of Calgary - Foothills Medical Center
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver Hospital & Health Sciences
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • QEII Heath Sciences Center - Halifax Infirmary
  • Ontario
    • Toronto, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital
    • Toronto, Ontario, Canada, M5C 3G7
      • St. Michael's Hospital, University of Toronto
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM Hospital - Notre Dame
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Royal University Hospital
• Chile
  • Concepcion, Chile, 4070038
    • Hospital Regional de Concepcion
  • Santiago, Chile, 7500691
    • Institute de Neurocirugia
  • Santiago, Chile, 8330024
    • Hospital Clínico Pontificia Universidad Católica de Chile
  • Santiago, Chile, 8431657
    • Clínica Dávila
  • Valparaiso, Chile, 2352499
    • Hospital Carlos Van Buren
• Czechia
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Bmo
  • Ceske Budejovice, Czechia, 370 87
    • Nemocnice Ceske Budejovice
  • Ostrava, Czechia, 708 52
    • Fakultni nemocnice Ostrava
  • Ostrava, Czechia, 169 02
    • Fakultni nemocnice Ostrava
  • Praha, Czechia, 150 30
    • Nemocnice Na Homolce
  • Praha, Czechia, 16902
    • ÚVN Praha
  • Praha, Czechia, 500 05
    • Fakultni nemocnice Homoice
  • Usti nad Labem, Czechia, 401 13
    • Masarykova nemocnice Usti n. Labem
• Denmark
  • Copenhagen, Denmark, 2100
    • The Neuroscience Center, Copenhagen University Hospital
  • Glostrup, Denmark, 2600
    • Glostrup Hospital
  • Odense, Denmark, DK 5000
    • Odense University Hospital
• Finland
  • Helsinki, Finland, FIN-00029 HUS
    • Helsinki University Central Hospital
  • Tampere, Finland, 33520
    • Tampere University Central Hospital (TAYS)
• France
  • Angers Cedex 9, France, 49933
    • CHU d'Angers
  • Bordeaux cedex, France, 33076
    • Hopital Pellegrin
  • Bron, France, 69677
    • Hopital Neurologique et Neuro-Chirurgical Pierre Wertheimer
  • Creteil, France, 94010
    • Hopital Henru Mondor
  • Dijon, France, 21033
    • Hôpital Général
  • Marseille cedex 5, France, 13385
    • Hopital de la Timone - CHU de Marseille
  • Montpellier, France, 34295
    • Hopital Gui de Chauliac
  • Nancy, France, 54035
    • Hôpital Central
• Germany
  • Augsburg, Germany, 86156
    • Universitatsklinikum Augsburg Clinic for Diagnostic Radiology and Neuroradiology
  • Berlin, Germany, D-13353
    • Charite Universitatsmedzin Berlin
  • Bonn, Germany, 53105
    • Universitätsklinikum Bonn
  • Bonn, Germany, 53105
    • University of Bonn Medical Center
  • Dresden, Germany, 1307
    • Klinik imd Poliklinik fur Neurochirurgie
  • Erlangen, Germany, 91054
    • Universitaet Erlangen-Nuerberg Klinik fur Neurologie
  • Essen, Germany, 45122
    • University Hospital of Essen
  • Frankfurt, Germany, 60528
    • Universitatsklinik Frankfurt, Klinik und Poliklinik f. Neurochirurgie
  • Freiburg, Germany, D-79106
    • Neuroradiologie der Universitatsklinik Freiburg
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Heidelberg, Germany, 69120
    • Neurochirurggische Universitatsklinik des Heidelberg
  • Leipzig, Germany, 04103
    • Klinik und Poliklinik für Neurochirurgie
  • Munich, Germany, 81675
    • Thechnical University - Klinikum rechts der Isar
  • Regensburg, Germany, 93053
    • University Regensburg
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
  • Shatin, Hong Kong
    • Prince od Wales Hospital
• Hungary
  • Pecs, Hungary, 7623
    • University of Pecs, Faculty of Medicine Neurosurgery Clinic
  • Pecs, Hungary
    • University of Szeged, Faculty of Medicine
  • Borsod Abauj-Zemplen
    • Miskolc, Borsod Abauj-Zemplen, Hungary
      • Borsod-Abauj-Zemplen County Hospital and University Teaching Hospital
  • Borsod-Abauj-Zemplen
    • Miskolc, Borsod-Abauj-Zemplen, Hungary
      • Borsod-Abauj-Zemplen County Hospital and University Teaching Hospital
• India
  • Chandigarh, India, 160012
    • Post Graduate Institute of Medical Education and Research
  • Hyderabad, India, 5-4-199
    • Care Hospital
  • Pune, India, 411011
    • King Edward Memorial Hospital
• Israel
  • Haifa, Israel, 31096
    • Rambam Medical Centre
  • Jerusalem, Israel, 91120
    • Hadassah Universtity Medical Center
  • Tel Hashomer, Israel, 52621
    • Sheba Medical Centre
• Italy
  • Bologna, Italy, 40139
    • Osepedale Maggiore Bellaria
  • Firenze, Italy, 50141
    • Azienda Ospedaliera di Careggi
  • Rome, Italy, 184
    • Azienda Osepedaliera San Giovanni - Addolorata
  • Verona, Italy, 37126
    • Ospedale Maggiore
• Mexico
  • Mexico City, Mexico, 14269
    • Instituto Nacional de Neurologia y Neurocirugia
  • Monterrey, Mexico, 64460
    • Hospital Universitario "Dr. José Eleuterio González" Universidad Autónoma de Nuevo León
• Netherlands
  • Tilburg, Netherlands
    • Elisabeth Ziekenhuis
• Norway
  • Bergen, Norway, 5021
    • Haukeland University Hospital, Helse Bergen HF
  • Oslo, Norway, 0407
    • Ulleval Univ Hosp
  • Tromso, Norway, N9038
    • Universitetssykehuset Nord-Norge
• Poland
  • Gdansk, Poland, 80-952
    • Szpital Akademii Medycznej w Gdansku
  • Warszawa, Poland, 02-097
    • Samodzielny Publiczny Centralny Szpital Kliniczy w Warszawie
• Singapore
  • Singapore, Singapore, 119074
    • National University Hospital
  • Singapore, Singapore, 308433
    • National Neuroscience Institute
• Slovenia
  • Ljubljana, Slovenia, 1525
    • University Clinical Centre Ljubljana
  • Maribor, Slovenia, 2000
    • General Hospital Maribor
• Spain
  • Barcelona, Spain, 08907
    • Hospital Universitari de Bellvitge
  • Barcelona, Spain, 08035
    • Hospital Vali d' Hebron
  • Granada, Spain, 18012
    • Complejo Hospotalario Virgen de las Nieves-Hospital de Rehabilitacion y Traumatologia
  • Madrid, Spain, 28041
    • Hospital Universitario 12 se Octubre
  • Palma de Mallorca, Spain, 07014
    • Hospital de Son Dureta
• Sweden
  • Goteborg, Sweden, 41345
    • Sahlgrenska University Hospital
  • Linkoping, Sweden, 58185
    • Linkoping University Hospital
  • Lund, Sweden, 22185
    • Lund University Hospital
• Switzerland
  • Aarau, Switzerland, 5001
    • Kantonsspital Aarau
  • Bern, Switzerland, 3010
    • Universitätsklinik Bern
  • Geneva, Switzerland, 1211
    • Geneva University Hospital
  • Zurich, Switzerland, 8091
    • Universitatsspital Zurich
• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
• United States
  • California
    • Glendale, California, United States, 91206
      • Glendale Adventist Medical Center
    • San Francisco, California, United States, 94143
      • UCSF Medical Centre
    • Stanford, California, United States, 94305-5327
      • Stanford Hospital and Clinis
  • Colorado
    • Englewood, Colorado, United States, 80110
      • Colorado Neurological Institute
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale Univerity School of Medicine
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60612
      • University of Illnois
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Centre
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Barnes_Jewish Hospital
  • New Jersey
    • Trenton, New Jersey, United States, 08638
      • Capital Health System Inc. d/b/a The Stroke and Cerebrovascular Center of New Jersey
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • New York Presbyteruan Hospital - Weill Cornell Medical Centre
    • Stony Brook, New York, United States, 11794-8122
      • State University of New York at Stony Brook
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97219
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University School of Medicine
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Zale Lipshy Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Univ. of VA Health System
    • Richmond, Virginia, United States, 23284
      • Virginia Commonwealth University Medical Centre
    • Richmond, Virginia, United States, 980631
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Clazosentan 5 m/h; Continuous intravenous infusion of clazosentan (5 mg/h); Other Names: ACT-108475 (AXV-034343)
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	Drug: Clazosentan 15 mg/h; Continuous intravenous infusion of clazosentan clazosentan (15 mg/h); Other Names: ACT-108475 (AXV-034343)
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	Drug: Placebo; Continuous intravenous infusion of placebo-matching clazosentan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol	Within 6 weeks post-aSAH

Secondary Outcome Measures

Outcome Measure	Time Frame
Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized into good (score > 4) and poor (score ≤ 4) outcome.	Week 12 post-aSAH

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.
• Investigators: Study Director: Sebastien Roux, MD, Actelion

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: July 13, 2009
• First Submitted That Met QC Criteria: July 14, 2009
• First Posted (Estimate): July 15, 2009

Study Record Updates

• Last Update Posted (Actual): July 9, 2018
• Last Update Submitted That Met QC Criteria: July 6, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: vasospasm; Hemorrhage; cerebral vasospasm; clazosentan; Subarachnoid; Aneurysmal; surgical clipping; PIVLAZ; Actelion
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage
• Other Study ID Numbers: AC-054-302