Clazosentan in Aneurysmal Subarachnoid Hemorrhage

NCT00940095 | Terminated Phase 3 DMC

• 1 other identifier: AC-054-302
• Study Type: interventional
• Target: 577
• Locations: 27 countries
• Sites: 140

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. 1.Death (all causes).
2. 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. 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. 4.Administration of a valid rescue therapy in the presence of confirmed cerebral vasospasm on angiography (DSA or CTA).

Conditions

Aneurysmal Subarachnoid Hemorrhage

Keywords

Subarachnoid; Aneurysmal; surgical clipping; PIVLAZ; vasospasm; cerebral vasospasm; clazosentan; Actelion; Hemorrhage

Outcome Measures

Primary Outcomes (1)

• Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol

  Within 6 weeks post-aSAH

Secondary Outcomes (1)

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

  Week 12 post-aSAH

Study Arms (3)

Clazosentan 5 mg/h

EXPERIMENTAL

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

Clazosentan 15 mg/h

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Clazosentan 5 m/h DRUG

Continuous intravenous infusion of clazosentan (5 mg/h)

Also known as: ACT-108475 (AXV-034343)

Clazosentan 5 mg/h

Clazosentan 15 mg/h DRUG

Continuous intravenous infusion of clazosentan clazosentan (15 mg/h)

Also known as: ACT-108475 (AXV-034343)

Clazosentan 15 mg/h

Placebo DRUG

Continuous intravenous infusion of placebo-matching clazosentan

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females aged 18 to 75 years (inclusive).
• 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.
• 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 \[GCS\])
• Patients with any thick clot (short axis \> or = 4 mm) on baseline CT scan (investigator's assessment).
• 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.
• 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.

You may not qualify if:

• Subarachnoid hemorrhage (SAH) due to causes other than saccular aneurysm.
• Giant aneurysms (height or width \> or = 25 mm).
• Intraventricular or intracerebral blood, in absence of subarachnoid blood, or or with only a thin clot (short axis \< 4 mm)
• 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)\*.
• Current ruptured aneurysm previously secured (successfully or not) by clipping.
• Coiling material used, which has not been approved by local health authorities.
• Use of liquid embolism aneurysmal treatment or flow diverting device.
• Several aneurysms among which the ruptured one cannot be identified with certainty and which are not all secured during the coiling procedure.
• No end-of-procedure DSA.
• Another securing procedure planned for any aneurysm between randomization and Week 12 post-aSAH.
• Study drug start \>56 hours after the aneurysm rupture.
• Known, at time of screening, that certain follow-up, or protocol-mandated imaging assessments will not be feasible.
• Hypotension (systolic blood pressure \< or = 90 mmHg) refractory to treatment.
• Aspiration pneumonia.
• Pulmonary edema or severe cardiac failure requiring inotropic support at time of randomization.

Sponsors & Collaborators

• Idorsia Pharmaceuticals Ltd.: lead

Study Sites (145)

Glendale Adventist Medical Center

Glendale, California, 91206, United States

Location

UCSF Medical Centre

San Francisco, California, 94143, United States

Location

Stanford Hospital and Clinis

Stanford, California, 94305-5327, United States

Location

Colorado Neurological Institute

Englewood, Colorado, 80110, United States

Location

Yale Univerity School of Medicine

New Haven, Connecticut, 06510, United States

Location

University of South Florida

Tampa, Florida, 33606, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

University of Illnois

Chicago, Illinois, 60612, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Medical Centre

Boston, Massachusetts, 02118, United States

Location

William Beaumont Hospital

Royal Oak, Michigan, 48073, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Barnes_Jewish Hospital

St Louis, Missouri, 63110, United States

Location

Capital Health System Inc. d/b/a The Stroke and Cerebrovascular Center of New Jersey

Trenton, New Jersey, 08638, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

New York Presbyteruan Hospital - Weill Cornell Medical Centre

New York, New York, 10065, United States

Location

State University of New York at Stony Brook

Stony Brook, New York, 11794-8122, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45219, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Oklahoma University Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Oregon Health & Science University

Portland, Oregon, 97219, United States

Location

Thomas Jefferson University School of Medicine

Philadelphia, Pennsylvania, 19107, United States

Location

Temple University Hospital

Philadelphia, Pennsylvania, 19140, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas Southwestern Zale Lipshy Hospital

Dallas, Texas, 75390, United States

Location

Univ. of VA Health System

Charlottesville, Virginia, 22908, United States

Location

Virginia Commonwealth University Medical Centre

Richmond, Virginia, 23284, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 980631, United States

Location

Hospital Aleman

Buenos Aires, C1118AAT, Argentina

Location

Clinica De Sol

Buenos Aires, C1425DQI, Argentina

Location

ENERI

Buenos Aires, C1426ENF, Argentina

Location

Gold Coast Hospital

Southport, Queensland, 4215, Australia

Location

Royal Brisbane & Women's Hosptal

Brisbane, QLD 4029, Australia

Location

Royal Prince Alfred Hosptial

Camperdown, NSW 2050, Australia

Location

Monash Medical Centre

Clayton, VIC 3168, Australia

Location

Princess Alexandra Hospital

Woolloongabba, QLD 4102, Australia

Location

Landeskrankenhaus und Medizinische Universitat

Graz, A-8036, Austria

Location

Medizinsche Universitat Innsbruck

Innsbruck, 6020, Austria

Location

University Fur Neurochirurgie, SALK, Christian Doppler Hospital

Salzburg, 5020, Austria

Location

AKH University of Vienna, Medical Univ. Of Neurosurgery

Vienna, 1090, Austria

Location

UZ Antwerpen

Antwerp, 2650, Belgium

Location

ULB Erasme

Brussels, 1070, Belgium

Location

UZ Brussels

Brussels, 1090, Belgium

Location

UCL Saint-Luc

Brussels, 1200, Belgium

Location

UZ Brussels

Brussels, Belgium

Location

UZ Gent

Ghent, 9000, Belgium

Location

UZ Gasthuisberg

Leuven, 3000, Belgium

Location

Hospital das Clinicas da UFMG

Belo Horizonte, 30110-934, Brazil

Location

Hospital de Clinicas da Universidade Federal do Parana

Curitiba, 80060-900, Brazil

Location

Clinica de Neurologia de

Joinville, 89202-000, Brazil

Location

Hospital de Clínicas de Niteroí

Niteroí, 24020-090, Brazil

Location

Hospital Moinhos de Vento

Porto Alegre, 90035-001, Brazil

Location

Hospital Santa Marcelina

São Paulo, 08270-070, Brazil

Location

Santa Case de Misericordia de Sobral

Sobral, 62010-550, Brazil

Location

University of Calgary - Foothills Medical Center

Calgary, Alberta, T2N 1M9, Canada

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7, Canada

Location

Vancouver Hospital & Health Sciences

Vancouver, British Columbia, V5Z 1M9, Canada

Location

QEII Heath Sciences Center - Halifax Infirmary

Halifax, Nova Scotia, B3H 3A7, Canada

Location

Hamilton General Hospital

Toronto, Ontario, L8L 2X2, Canada

Location

St. Michael's Hospital, University of Toronto

Toronto, Ontario, M5C 3G7, Canada

Location

CHUM Hospital - Notre Dame

Montreal, Quebec, H2L 4M1, Canada

Location

Royal University Hospital

Saskatoon, Saskatchewan, S7N 0W8, Canada

Location

Hopital de I'Enfant-Jesus

Québec, G1J 1Z4, Canada

Location

Hospital Regional de Concepción

Concepción, 4070038, Chile

Location

Institute de Neurocirugia

Santiago, 7500691, Chile

Location

Hospital Clinico Pontificia Universidad Católica de Chile

Santiago, 8330024, Chile

Location

Clinica Davila

Santiago, 8431657, Chile

Location

Hospital Carlos Van Buren

Valparaíso, 2352499, Chile

Location

Fakultni nemocnice Bmo

Brno, 625 00, Czechia

Location

Nemocnice Ceske Budejovice

České Budějovice, 370 87, Czechia

Location

Fakultní nemocnice Ostrava

Ostrava, 169 02, Czechia

Location

Fakultni nemocnice Ostrava

Ostrava, 708 52, Czechia

Location

Nemocnice Na Homolce

Prague, 150 30, Czechia

Location

ÚVN Praha

Prague, 16902, Czechia

Location

Fakultni nemocnice Homoice

Prague, 500 05, Czechia

Location

Masarykova nemocnice Usti n. Labem

Ústí nad Labem, 401 13, Czechia

Location

The Neuroscience Center, Copenhagen University Hospital

Copenhagen, 2100, Denmark

Location

Glostrup Hospital

Glostrup Municipality, 2600, Denmark

Location

Odense University Hospital

Odense, DK 5000, Denmark

Location

Helsinki University Central Hospital

Helsinki, Fin-00029 HUS, Finland

Location

Tampere University Central Hospital (TAYS)

Tampere, 33520, Finland

Location

CHU d'Angers

Angers, 49933, France

Location

Hopital Pellegrin

Bordeaux, 33076, France

Location

Hopital neurologique et Neuro-Chirurgical Pierre Wertheimer

Bron, 69677, France

Location

Hopital Henru Mondor

Créteil, 94010, France

Location

Hopital General

Dijon, 21033, France

Location

Hopital de la Timone - CHU de Marseille

Marseille, 13385, France

Location

Hopital Gui de Chauliac

Montpellier, 34295, France

Location

Hopital central

Nancy, 54035, France

Location

Universitatsklinikum Augsburg Clinic for Diagnostic Radiology and Neuroradiology

Augsburg, 86156, Germany

Location

Charite Universitatsmedzin Berlin

Berlin, D-13353, Germany

Location

Universitatsklinikum Bonn

Bonn, 53105, Germany

Location

University of Bonn Medical Center

Bonn, 53105, Germany

Location

Klinik imd Poliklinik fur Neurochirurgie

Dresden, 1307, Germany

Location

Universitaet Erlangen-Nuerberg Klinik fur Neurologie

Erlangen, 91054, Germany

Location

University Hospital of Essen

Essen, 45122, Germany

Location

Universitatsklinik Frankfurt, Klinik und Poliklinik f. Neurochirurgie

Frankfurt, 60528, Germany

Location

Neuroradiologie der Universitatsklinik Freiburg

Freiburg im Breisgau, D-79106, Germany

Location

Universitatsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Neurochirurggische Universitatsklinik des Heidelberg

Heidelberg, 69120, Germany

Location

Klinik und Poliklinik fur Neurochirurgie

Leipzig, 04103, Germany

Location

Thechnical University - Klinikum rechts der Isar

Munich, 81675, Germany

Location

University Regensburg

Regensburg, 93053, Germany

Location

Queen Mary Hospital

Hong Kong, Hong Kong

Location

Prince od Wales Hospital

Shatin, Hong Kong

Location

Borsod-Abauj-Zemplen County Hospital and University Teaching Hospital

Miskolc, Borsod-Abauj Zemplen county, Hungary

Location

University of Pecs, Faculty of Medicine Neurosurgery Clinic

Pécs, 7623, Hungary

Location

University of Szeged, Faculty of Medicine

Pécs, Hungary

Location

Post Graduate Institute of Medical Education and Research

Chandigarh, 160012, India

Location

CARE Hospital

Hyderabad, 5-4-199, India

Location

King Edward Memorial Hospital

Pune, 411011, India

Location

Rambam Medical Centre

Haifa, 31096, Israel

Location

Hadassah Universtity Medical Center

Jerusalem, 91120, Israel

Location

Sheba Medical Centre

Tel Litwinsky, 52621, Israel

Location

Osepedale Maggiore Bellaria

Bologna, 40139, Italy

Location

Azienda Ospedaliera di Careggi

Florence, 50141, Italy

Location

Azienda Osepedaliera San Giovanni - Addolorata

Rome, 184, Italy

Location

Ospedale Maggiore

Verona, 37126, Italy

Location

Instituto Nacional de Neurologia y Neurocirugia

Mexico City, 14269, Mexico

Location

Hospital Universitario "Dr. Jose Eleuterio Gonzalez" Universidad Autonoma de Nuevo Leon

Monterrey, 64460, Mexico

Location

Elisabeth Ziekenhuis

Tilburg, Netherlands

Location

Haukeland University Hospital, Helse Bergen HF

Bergen, 5021, Norway

Location

Ulleval Univ Hosp

Oslo, 0407, Norway

Location

Universitetssykehuset Nord-Norge

Tromsø, N9038, Norway

Location

Szpital Akademii Medycznej w Gdansku

Gdansk, 80-952, Poland

Location

Samodzielny Publiczny Centralny Szpital Kliniczy w Warszawie

Warsaw, 02-097, Poland

Location

National University Hospital

Singapore, 119074, Singapore

Location

National Neuroscience Institute

Singapore, 308433, Singapore

Location

University Clinical Centre Ljubljana

Ljubljana, 1525, Slovenia

Location

General Hospital Maribor

Maribor, 2000, Slovenia

Location

Hospital Vali d' Hebron

Barcelona, 08035, Spain

Location

Hospital Universitari de Bellvitge

Barcelona, 08907, Spain

Location

Complejo Hospotalario Virgen de las Nieves-Hospital de Rehabilitacion y Traumatologia

Granada, 18012, Spain

Location

Hospital Universitario 12 se Octubre

Madrid, 28041, Spain

Location

Hospital de Son Dureta

Palma de Mallorca, 07014, Spain

Location

Sahlgrenska University Hospital

Gothenburg, 41345, Sweden

Location

Linkoping University Hospital

Linköping, 58185, Sweden

Location

Lund University Hospital

Lund, 22185, Sweden

Location

Kantonsspital Aarau

Aarau, 5001, Switzerland

Location

Universitatsklinik Bern

Bern, 3010, Switzerland

Location

Geneva University Hospital

Geneva, 1211, Switzerland

Location

Universitatsspital Zurich

Zurich, 8091, Switzerland

Location

National Taiwan University Hospital

Taipei, 100, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 112, Taiwan

Location

Related Publications (2)

• 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.

  PMID: 22403047 RESULT

• 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.

  PMID: 31394993 DERIVED

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Vasospasm, Intracranial; Hemorrhage

Interventions

clazosentan

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Sebastien Roux, MD

  Actelion

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2009
• First Posted: July 15, 2009
• Study Start: July 1, 2009
• Primary Completion: October 1, 2010
• Study Completion: January 1, 2011
• Last Updated: July 9, 2018

Record last verified: 2018-07

Locations

AU (4); CA (9); ME (2); CZ (8); DK (3); IL (3); FI (2); SL (2); CH (4); US (29); PL (2); DE (14); FR (8); TW (2); HK (2); BR (7); IN (3); CL (5); SE (3); BE (7); HU (3); IT (4); NL (1); SG (2); ES (5); NO (3); AR (3)