Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping
NCT ID: NCT00558311
Last Updated: 2020-02-17
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE3
1157 participants
INTERVENTIONAL
2007-12-14
2010-07-13
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Clazosentan
A continuous intravenous infusion of clazosentan was started within 56 hours post-aSAH and was scheduled to continue during the hospitalization until Day 14 post-aSAH, or at least until Day 10.
Clazosentan
Intravenous clazosentan administered by continuous infusion at 5 mg/h
Placebo
A continuous intravenous infusion of placebo-matching clazosentan was started within 56 hours post-aSAH and was scheduled to continue during the hospitalization until Day 14 post-aSAH, or at least until Day 10.
Placebo
Placebo administered by continuous infusion matching clazosentan administration
Interventions
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Clazosentan
Intravenous clazosentan administered by continuous infusion at 5 mg/h
Placebo
Placebo administered by continuous infusion matching clazosentan administration
Eligibility Criteria
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Inclusion Criteria
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
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.
18 Years
75 Years
ALL
No
Sponsors
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Idorsia Pharmaceuticals Ltd.
INDUSTRY
Responsible Party
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Principal Investigators
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Study Director
Role: STUDY_DIRECTOR
Idorsia Pharmaceuticals Ltd.
Locations
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Barrow Neurosurgical Associates
Phoenix, Arizona, United States
Colorado Neurological Institute
Englewood, Colorado, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Columbia University Medical Center
New York, New York, United States
State University of New York at Stony Brook-Health Sciences Center
Stony Brook, New York, United States
University of Cincinnati-Department of Neurosurgery
Cincinnati, Ohio, United States
University Hospitals Case Medical Center-Department of Neurosurgery
Cleveland, Ohio, United States
Oregon Health & Science University-Oregon Stroke Center
Portland, Oregon, United States
Thomas Jefferson University School of Medicine-Jefferson Hospital for Neuroscience
Philadelphia, Pennsylvania, United States
University of Virginia Health System-Department of Neurosurgery
Charlottesville, Virginia, United States
Virginia Commonwealth University-Department of Neurosurgery
Richmond, Virginia, United States
Royal Brisbane Hospital
Herston, , Australia
The Alfred Hospital
Melbourne, , Australia
Landeskrankenhaus
Feldkirch, , Austria
Landeskrankenhaus und Medizinische Universitat Graz
Graz, , Austria
Medizinsche Universitat
Innsbruck, , Austria
University Fur Neurochirurgie, SALK, Christian Doppler Hospital
Salzburg, , Austria
AKH University of Vienna, Medical University
Vienna, , Austria
Sozialmedizinisches Zentrum Ost (ZMZ-Ost) Donauspital Vienna
Vienna, , Austria
Cliniques Universitaires Saint-Luc, Universite Catholique de
Brussels, , Belgium
University of Alberta Hospital
Edmonton, Alberta, Canada
Vancouver Hospital
Vancouver, British Columbia, Canada
St Michael's Hospital, University
Toronto, Ontario, Canada
CHUM Notre Dame
Montreal, Quebec, Canada
University of Calgary Foothills Medical Center
Calgary, , Canada
QEII Health Science Center
Halifax, , Canada
Toronto Western Hospital, University of Toronto
Toronto, , Canada
Beijing Tian Tan Hospital
Beijing, , China
XuanWu Hospital Institute of Brain Vascular Disease
Beijing, , China
Guangdong Province Chinese Medicine Hospital
Guangzhou, , China
1st Affilated Hospital of Zhongshan
Guangzhou, , China
Shanghai Hua Shan Hospital
Shanghai, , China
Wuhan Tongji Hospital
Wuhan, , China
Clinical Hospital "Dubrava"
Zagreb, , Croatia
Clinical Hospital Dubrava
Zagreb, , Croatia
University Hospital Sestre Milosrdnice
Zagreb, , Croatia
Faculty Hospital/FN Brno Bohunice
Brno, , Czechia
Nemocnice Ceske Budejovice
České Budějovice, , Czechia
Na Homolce Hospital Prague
Prague, , Czechia
UVN Prague
Prague, , Czechia
Copenhagen University Hospital
Copenhagen, , Denmark
Copenhagen Country Hospital
Glostrup Municipality, , Denmark
Odense University Hospital
Odense, , Denmark
Helsinki University Central Hospital
Helsinki, , Finland
Oulu University Hospital
Oulu, , Finland
Tampere University Central Hospital
Tampere, , Finland
Pole d'Anesthesie Reanimation, CHU D'Angers
Angers, , France
Hopital Pellegrin
Bordeaux, , France
Hopital Neurologique et Neuro-Chirurgical Pierre Wertheimer
Bron, , France
Chu Hopital Gabriel Montpied
Clermont-Ferrand, , France
Hopital de la Timone
Marseille, , France
Charite Universitatsmedizin Berlin-Neurochirurgische Klinik-CVK
Berlin, , Germany
University of Bonn Medical Center
Bonn, , Germany
Klinik und Poliklinik fur Neurochirurgie
Dresden, , Germany
University of Erlangen-Nurnberg
Erlangen, , Germany
University of Hospital of Essen
Essen, , Germany
Universitatsklinik Frankfurt, Klinik und Poliklinik fur Neurochirurgie
Frankfurt, , Germany
University Hospital of Hamburg
Hamburg, , Germany
Neurochirurggische Universitatsklinik des Heidelberg
Heidelberg, , Germany
Klinik und Poliklinik fur Neurochirurgie
Leipzig, , Germany
University Munich Groshadern
Munich, , Germany
Thechnical University-Klinikum rechts der Isar
Munich, , Germany
University Regensburg
Regensburg, , Germany
Prince of Wales Hospital
Hong Kong, , Hong Kong
Queen Mary Hospital
Hong Kong, , Hong Kong
Post Graduate Institute of Medical Education and Research
Chandigarh, , India
Post Graduate Institute of Medical Education
Chandigarh, , India
Nizam's Institute of Medical Sciences
Hyderabaad, , India
All India Insititute of Medicla Sciences (AIIMS)
New Delhi, , India
Sahyadri Specialty Hospital
Pune, , India
Sahyadri Hospital
Pune, , India
Ospedale Bellaria-Maggiore Hospital
Bologna, , Italy
Ospedale Maurizio Bufalini
Cesena, , Italy
Azienda Ospedaliero-Universitaria di Careggi
Florence, , Italy
Ospedale Niguarda
Milan, , Italy
Nuovo Ospedale Sant' Agostino Estense
Modena, , Italy
Ospedale Civile di Padova
Padua, , Italy
Azienda Ospedaliero-Universitaria di
Parma, , Italy
Ospedale Civile Borgo Trento
Verona, , Italy
Riga Eastern Clinical University Hospital
Riga, , Latvia
Auckland Hospital
Grafton, , New Zealand
Haukeland University Hospital Helse Bergen HF
Bergen, , Norway
Ulleval University Hospital
Oslo, , Norway
Universitetssykehuset Nord-Norge
Tromsø, , Norway
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
Katedra Klinika Neurochirurgii Akademii Medycznej w Gdansku
Gdansk, , Poland
Samodzielny Publiczny Szpital Kliniczny Slaskiej Akademii Medycznej w Katowicach
Katowice, , Poland
Oddzial Kliniczny Kliniki Neurochirurgii i Neurotrumatologii Szpitala, Uniwersyteckiego w Krakowie
Krakow, , Poland
Katedra Neurochirurgii, Uniwersytet
Lodz, , Poland
Katedra I Klinika Neurochirurgii i Dzieciecej
Lublin, , Poland
Katedra IKlinika Neurochirurgii Akademii Medycznej w Warszawie Clinic
Warsaw, , Poland
Scientific Research Institute of Neurosurgery by Burdenko
Moscow, , Russia
Clinical Center Nis
Niš, , Serbia
Clinical Center Novi Sad
Novi Sad, , Serbia
National Neuroscience
Singapore, , Singapore
General Hospital Maribor
Maribor, , Slovenia
Kyungpook National University
Daegu, , South Korea
Daejeon Eulji University Hospital
Daejeon, , South Korea
Hospital Del Mar
Barcelona, , Spain
Vall d'Hebron Hospital
Barcelona, , Spain
Hospital Universitario 12 de Octubre
Madrid, , Spain
Hospital de Son Dureta
Palma de Mallorca, , Spain
Sahlgrenska
Gothenburg, , Sweden
Lund University Hospital
Lund, , Sweden
Uppsala University Hospital-Uppsala Akademiska Sjukhus
Uppsala, , Sweden
Kantonsspital Aarau
Aarau, , Switzerland
Universitatsklinik Bern
Bern, , Switzerland
Universitätsklinik Bern Klinik für Neurochirurgie
Bern, , Switzerland
Geneva University Hospital
Geneva, , Switzerland
Kantonsspital St. Gallen
Sankt Gallen, , Switzerland
Universitatsspital Zurich
Zurich, , Switzerland
Ibn-i Sina Hastanesi Ankara & Ankara Universitesi Tip Fakultesi
Ankara, , Turkey (Türkiye)
Ege Universitesi Tip Fak Hestanesi
Bornova, , Turkey (Türkiye)
Istanbul Universitesi, Istanbul Tip
Istanbul, , Turkey (Türkiye)
Regional Clinical Hospital by Mechnikov
Dnipropetrovsk, , Ukraine
A. P. Romodanov Institute of Neurosurgery
Kiev, , Ukraine
Countries
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References
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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.
Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N. Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2). Acta Neurochir Suppl. 2013;115:27-31. doi: 10.1007/978-3-7091-1192-5_7.
Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011 Jul;10(7):618-25. doi: 10.1016/S1474-4422(11)70108-9. Epub 2011 Jun 2.
Other Identifiers
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AC-054-301
Identifier Type: -
Identifier Source: org_study_id
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