Clinical trial NCT00940095: Clazosentan in Aneurysmal Subarachnoid Hemorrhage
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 Endovascular Coiling.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Aneurysmal Subarachnoid Hemorrhage
Keywords: Subarachnoid
Aneurysmal
surgical clipping
PIVLAZ
vasospasm
cerebral vasospasm
clazosentan
Actelion
Hemorrhage
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2009-07-15
Enrollment: 577
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

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.

Primary outcomes:
measure: Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol
timeFrame: Within 6 weeks post-aSAH
Secondary outcomes:
measure: Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized into good (score > 4) and poor (score ≤ 4) outcome.
timeFrame: Week 12 post-aSAH
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Glendale Adventist Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Centre
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinis
state: California
city: Englewood
country: United States
facility: Colorado Neurological Institute
state: Colorado
city: New Haven
country: United States
facility: Yale Univerity School of Medicine
state: Connecticut
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Illnois
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Centre
state: Massachusetts
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Barnes_Jewish Hospital
state: Missouri
city: Trenton
country: United States
facility: Capital Health System Inc. d/b/a The Stroke and Cerebrovascular Center of New Jersey
state: New Jersey
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyteruan Hospital - Weill Cornell Medical Centre
state: New York
city: Stony Brook
country: United States
facility: State University of New York at Stony Brook
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University School of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Zale Lipshy Hospital
state: Texas
city: Charlottesville
country: United States
facility: Univ. of VA Health System
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Centre
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Buenos Aires
country: Argentina
facility: Hospital Aleman
city: Buenos Aires
country: Argentina
facility: Clinica De Sol
city: Buenos Aires
country: Argentina
facility: ENERI
city: Southport
country: Australia
facility: Gold Coast Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Royal Brisbane & Women's Hosptal
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hosptial
city: Clayton
country: Australia
facility: Monash Medical Centre
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
city: Graz
country: Austria
facility: Landeskrankenhaus und Medizinische Universitat
city: Innsbruck
country: Austria
facility: Medizinsche Universitat Innsbruck
city: Salzburg
country: Austria
facility: University Fur Neurochirurgie, SALK, Christian Doppler Hospital
city: Vienna
country: Austria
facility: AKH University of Vienna, Medical Univ. Of Neurosurgery
city: Antwerp
country: Belgium
facility: UZ Antwerpen
city: Brussels
country: Belgium
facility: ULB Erasme
city: Brussels
country: Belgium
facility: UZ Brussels
city: Brussels
country: Belgium
facility: UCL Saint-Luc
city: Brussels
country: Belgium
facility: UZ Brussels
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Gasthuisberg
city: Belo Horizonte
country: Brazil
facility: Hospital das Clinicas da UFMG
city: Curitiba
country: Brazil
facility: Hospital de Clinicas da Universidade Federal do Parana
city: Joinville
country: Brazil
facility: Clinica de Neurologia de
city: Niteroí
country: Brazil
facility: Hospital de Clínicas de Niteroí
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
city: Sao Paulo
country: Brazil
facility: Hospital Santa Marcelina
city: Sobral
country: Brazil
facility: Santa Case de Misericordia de Sobral
city: Calgary
country: Canada
facility: University of Calgary - Foothills Medical Center
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver Hospital & Health Sciences
state: British Columbia
city: Halifax
country: Canada
facility: QEII Heath Sciences Center - Halifax Infirmary
state: Nova Scotia
city: Toronto
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital, University of Toronto
state: Ontario
city: Montreal
country: Canada
facility: CHUM Hospital - Notre Dame
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
city: Quebec
country: Canada
facility: Hopital de I'Enfant-Jesus
city: Concepcion
country: Chile
facility: Hospital Regional de Concepción
city: Santiago
country: Chile
facility: Institute de Neurocirugia
city: Santiago
country: Chile
facility: Hospital Clinico Pontificia Universidad Católica de Chile
city: Santiago
country: Chile
facility: Clinica Davila
city: Valparaiso
country: Chile
facility: Hospital Carlos Van Buren
city: Brno
country: Czechia
facility: Fakultni nemocnice Bmo
city: Ceske Budejovice
country: Czechia
facility: Nemocnice Ceske Budejovice
city: Ostrava
country: Czechia
facility: Fakultní nemocnice Ostrava
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Praha
country: Czechia
facility: Nemocnice Na Homolce
city: Praha
country: Czechia
facility: ÚVN Praha
city: Praha
country: Czechia
facility: Fakultni nemocnice Homoice
city: Usti nad Labem
country: Czechia
facility: Masarykova nemocnice Usti n. Labem
city: Copenhagen
country: Denmark
facility: The Neuroscience Center, Copenhagen University Hospital
city: Glostrup
country: Denmark
facility: Glostrup Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Tampere
country: Finland
facility: Tampere University Central Hospital (TAYS)
city: Angers Cedex 9
country: France
facility: CHU d'Angers
city: Bordeaux cedex
country: France
facility: Hopital Pellegrin
city: Bron
country: France
facility: Hopital neurologique et Neuro-Chirurgical Pierre Wertheimer
city: Creteil
country: France
facility: Hopital Henru Mondor
city: Dijon
country: France
facility: Hopital General
city: Marseille cedex 5
country: France
facility: Hopital de la Timone - CHU de Marseille
city: Montpellier
country: France
facility: Hopital Gui de Chauliac
city: Nancy
country: France
facility: Hopital central
city: Augsburg
country: Germany
facility: Universitatsklinikum Augsburg Clinic for Diagnostic Radiology and Neuroradiology
city: Berlin
country: Germany
facility: Charite Universitatsmedzin Berlin
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Bonn
country: Germany
facility: University of Bonn Medical Center
city: Dresden
country: Germany
facility: Klinik imd Poliklinik fur Neurochirurgie
city: Erlangen
country: Germany
facility: Universitaet Erlangen-Nuerberg Klinik fur Neurologie
city: Essen
country: Germany
facility: University Hospital of Essen
city: Frankfurt
country: Germany
facility: Universitatsklinik Frankfurt, Klinik und Poliklinik f. Neurochirurgie
city: Freiburg
country: Germany
facility: Neuroradiologie der Universitatsklinik Freiburg
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Neurochirurggische Universitatsklinik des Heidelberg
city: Leipzig
country: Germany
facility: Klinik und Poliklinik fur Neurochirurgie
city: Munich
country: Germany
facility: Thechnical University - Klinikum rechts der Isar
city: Regensburg
country: Germany
facility: University Regensburg
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Shatin
country: Hong Kong
facility: Prince od Wales Hospital
city: Miskolc
country: Hungary
facility: Borsod-Abauj-Zemplen County Hospital and University Teaching Hospital
state: Borsod Abauj-Zemplen
city: Miskolc
country: Hungary
facility: Borsod-Abauj-Zemplen County Hospital and University Teaching Hospital
state: Borsod-Abauj-Zemplen
city: Pecs
country: Hungary
facility: University of Pecs, Faculty of Medicine Neurosurgery Clinic
city: Pecs
country: Hungary
facility: University of Szeged, Faculty of Medicine
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education and Research
city: Hyderabad
country: India
facility: CARE Hospital
city: Pune
country: India
facility: King Edward Memorial Hospital
city: Haifa
country: Israel
facility: Rambam Medical Centre
city: Jerusalem
country: Israel
facility: Hadassah Universtity Medical Center
city: Tel Hashomer
country: Israel
facility: Sheba Medical Centre
city: Bologna
country: Italy
facility: Osepedale Maggiore Bellaria
city: Firenze
country: Italy
facility: Azienda Ospedaliera di Careggi
city: Rome
country: Italy
facility: Azienda Osepedaliera San Giovanni - Addolorata
city: Verona
country: Italy
facility: Ospedale Maggiore
city: Mexico City
country: Mexico
facility: Instituto Nacional de Neurologia y Neurocirugia
city: Monterrey
country: Mexico
facility: Hospital Universitario "Dr. Jose Eleuterio Gonzalez" Universidad Autonoma de Nuevo Leon
city: Tilburg
country: Netherlands
facility: Elisabeth Ziekenhuis
city: Bergen
country: Norway
facility: Haukeland University Hospital, Helse Bergen HF
city: Oslo
country: Norway
facility: Ulleval Univ Hosp
city: Tromso
country: Norway
facility: Universitetssykehuset Nord-Norge
city: Gdansk
country: Poland
facility: Szpital Akademii Medycznej w Gdansku
city: Warszawa
country: Poland
facility: Samodzielny Publiczny Centralny Szpital Kliniczy w Warszawie
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: National Neuroscience Institute
city: Ljubljana
country: Slovenia
facility: University Clinical Centre Ljubljana
city: Maribor
country: Slovenia
facility: General Hospital Maribor
city: Barcelona
country: Spain
facility: Hospital Vali d' Hebron
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Granada
country: Spain
facility: Complejo Hospotalario Virgen de las Nieves-Hospital de Rehabilitacion y Traumatologia
city: Madrid
country: Spain
facility: Hospital Universitario 12 se Octubre
city: Palma de Mallorca
country: Spain
facility: Hospital de Son Dureta
city: Goteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Linkoping
country: Sweden
facility: Linkoping University Hospital
city: Lund
country: Sweden
facility: Lund University Hospital
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Bern
country: Switzerland
facility: Universitatsklinik Bern
city: Geneva
country: Switzerland
facility: Geneva University Hospital
city: Zurich
country: Switzerland
facility: Universitatsspital Zurich
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
Study officials:
affiliation: Actelion
name: Sebastien Roux, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.