Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping
- Conditions
- Aneurysmal Subarachnoid Hemorrhage
- Interventions
- Drug: Placebo
- Registration Number
- NCT00558311
- Lead Sponsor
- Idorsia Pharmaceuticals Ltd.
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1157
-
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]), 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.
-
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])*
-
Patients with any diffuse clot (long axis > or = 20 mm, or any clot present across both hemispheres) on baseline CT scan.
-
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.
- 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.
-
Patients with subarachnoid hemorrhage (SAH) due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms).
-
Patients with intraventricular or intracerebral blood, in the absence of subarachnoid blood, or with only a local clot.
-
Presence of cerebral vasospasm seen on angiography prior to the clipping procedure.
-
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).*
-
Patients for whom study drug cannot be started within 56 hours after the aneurysm rupture.
-
Patients who have had their aneurysm secured by coiling only.
-
Patients for whom it is known, at the time of screening, that certain follow-up, protocol-mandated imaging assessments will not be feasible.
-
Patients with hypotension (systolic blood pressure (SBP)< or = 90 mmHg) that is refractory to treatment.
-
Patients with aspiration pneumonia.
-
Patients with pulmonary edema or severe cardiac failure requiring inotropic support.
-
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.
-
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.
-
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.
-
Patients receiving statins for less than 2 weeks prior to admission must have them discontinued prior to study drug initiation.
-
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.
-
Patients who have received an investigational product within 28 days prior to randomization or those who have already participated in the current study.
-
Patients unlikely to comply with the protocol (e.g., unable to return for follow-up visits).
-
Known hypersensitivity to other endothelin receptor antagonists.
-
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.
-
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo 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. Clazosentan 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.
- Primary Outcome Measures
Name Time Method Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol Within 6 weeks post-aSAH
- Secondary Outcome Measures
Name Time Method Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized into good (score > 4) and poor (score ≤ 4) outcome. Week 12 post-aSAH
Trial Locations
- Locations (116)
Thechnical University-Klinikum rechts der Isar
🇩🇪Munich, Germany
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
Thomas Jefferson University School of Medicine-Jefferson Hospital for Neuroscience
🇺🇸Philadelphia, Pennsylvania, United States
St Michael's Hospital, University
🇨🇦Toronto, Ontario, Canada
Queen Mary Hospital
🇭🇰Hong Kong, Hong Kong
AKH University of Vienna, Medical University
🇦🇹Vienna, Austria
All India Insititute of Medicla Sciences (AIIMS)
🇮🇳New Delhi, India
Medizinsche Universitat
🇦🇹Innsbruck, Austria
Sozialmedizinisches Zentrum Ost (ZMZ-Ost) Donauspital Vienna
🇦🇹Vienna, Austria
Landeskrankenhaus und Medizinische Universitat Graz
🇦🇹Graz, Austria
A. P. Romodanov Institute of Neurosurgery
🇺🇦Kiev, Ukraine
Vancouver Hospital
🇨🇦Vancouver, British Columbia, Canada
University Fur Neurochirurgie, SALK, Christian Doppler Hospital
🇦🇹Salzburg, Austria
Post Graduate Institute of Medical Education and Research
🇮🇳Chandigarh, India
Nizam's Institute of Medical Sciences
🇮🇳Hyderabaad, India
National Neuroscience
🇸🇬Singapore, Singapore
Barrow Neurosurgical Associates
🇺🇸Phoenix, Arizona, United States
Colorado Neurological Institute
🇺🇸Englewood, Colorado, United States
Landeskrankenhaus
🇦🇹Feldkirch, Austria
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Shanghai Hua Shan Hospital
🇨🇳Shanghai, China
University of Calgary Foothills Medical Center
🇨🇦Calgary, Canada
Faculty Hospital/FN Brno Bohunice
🇨🇿Brno, Czechia
CHUM Notre Dame
🇨🇦Montreal, Quebec, Canada
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
Clinical Hospital "Dubrava"
🇭🇷Zagreb, Croatia
Clinical Hospital Dubrava
🇭🇷Zagreb, Croatia
1st Affilated Hospital of Zhongshan
🇨🇳Guangzhou, China
Na Homolce Hospital Prague
🇨🇿Prague, Czechia
Wuhan Tongji Hospital
🇨🇳Wuhan, China
University Hospital Sestre Milosrdnice
🇭🇷Zagreb, Croatia
Hopital Pellegrin
🇫🇷Bordeaux, France
Nemocnice Ceske Budejovice
🇨🇿Ceske Budejovice, Czechia
Klinik und Poliklinik fur Neurochirurgie
🇩🇪Leipzig, Germany
University Hospital of Hamburg
🇩🇪Hamburg, Germany
Helsinki University Central Hospital
🇫🇮Helsinki, Finland
Hopital de la Timone
🇫🇷Marseille, France
Oulu University Hospital
🇫🇮Oulu, Finland
Tampere University Central Hospital
🇫🇮Tampere, Finland
Azienda Ospedaliero-Universitaria di Careggi
🇮🇹Firenze, Italy
Riga Eastern Clinical University Hospital
🇱🇻Riga, Latvia
Kyungpook National University
🇰🇷DaeGu, Korea, Republic of
Ulleval University Hospital
🇳🇴Oslo, Norway
Haukeland University Hospital Helse Bergen HF
🇳🇴Bergen, Norway
Universitetssykehuset Nord-Norge
🇳🇴Tromsö, Norway
Katedra Klinika Neurochirurgii Akademii Medycznej w Gdansku
🇵🇱Gdansk, Poland
Samodzielny Publiczny Szpital Kliniczny Slaskiej Akademii Medycznej w Katowicach
🇵🇱Katowice, Poland
Klinika Neurochirurgii AMB-Neurosurgery Clinic of Medical Academy
🇵🇱Bialystok, Poland
Katedra IKlinika Neurochirurgii Akademii Medycznej w Warszawie Clinic
🇵🇱Warszawa, Poland
Kathedra I Klinika Neurochirurghii I Neurotraumatologii Collegium Medicum im. L. Rydygiera w Bydgoszc
🇵🇱Bydgoszcz, Poland
Katedra Neurochirurgii, Uniwersytet
🇵🇱Lodz, Poland
Katedra I Klinika Neurochirurgii i Dzieciecej
🇵🇱Lublin, Poland
Geneva University Hospital
🇨🇭Geneva, Switzerland
Universitatsspital Zurich
🇨🇭Zurich, Switzerland
Sahlgrenska
🇸🇪Goteborg, Sweden
Universitätsklinik Bern Klinik für Neurochirurgie
🇨🇭Bern, Switzerland
Kantonsspital St. Gallen
🇨🇭St Gallen, Switzerland
Kantonsspital Aarau
🇨🇭Aarau, Switzerland
Universitatsklinik Bern
🇨🇭Bern, Switzerland
Hopital Neurologique et Neuro-Chirurgical Pierre Wertheimer
🇫🇷Bron, France
Lund University Hospital
🇸🇪Lund, Sweden
Columbia University Medical Center
🇺🇸New York, New York, United States
Ospedale Maurizio Bufalini
🇮🇹Cesena, Italy
Royal Brisbane Hospital
🇦🇺Herston, Australia
The Alfred Hospital
🇦🇺Melbourne, Australia
University of Virginia Health System-Department of Neurosurgery
🇺🇸Charlottesville, Virginia, United States
Oregon Health & Science University-Oregon Stroke Center
🇺🇸Portland, Oregon, United States
Virginia Commonwealth University-Department of Neurosurgery
🇺🇸Richmond, Virginia, United States
Cliniques Universitaires Saint-Luc, Universite Catholique de
🇧🇪Brussels, Belgium
Beijing Tian Tan Hospital
🇨🇳Beijing, China
QEII Health Science Center
🇨🇦Halifax, Canada
Toronto Western Hospital, University of Toronto
🇨🇦Toronto, Canada
XuanWu Hospital Institute of Brain Vascular Disease
🇨🇳Beijing, China
Guangdong Province Chinese Medicine Hospital
🇨🇳Guangzhou, China
UVN Prague
🇨🇿Prague, Czechia
Copenhagen University Hospital
🇩🇰Copenhagen, Denmark
Odense University Hospital
🇩🇰Odense, Denmark
Copenhagen Country Hospital
🇩🇰Glostrup, Denmark
Pole d'Anesthesie Reanimation, CHU D'Angers
🇫🇷Angers, France
Chu Hopital Gabriel Montpied
🇫🇷Clermont Ferrand, France
Charite Universitatsmedizin Berlin-Neurochirurgische Klinik-CVK
🇩🇪Berlin, Germany
University of Bonn Medical Center
🇩🇪Bonn, Germany
University of Erlangen-Nurnberg
🇩🇪Erlangen, Germany
University Munich Groshadern
🇩🇪Munich, Germany
Neurochirurggische Universitatsklinik des Heidelberg
🇩🇪Heidelberg, Germany
Universitatsklinik Frankfurt, Klinik und Poliklinik fur Neurochirurgie
🇩🇪Frankfurt, Germany
University of Hospital of Essen
🇩🇪Essen, Germany
University Regensburg
🇩🇪Regensburg, Germany
Post Graduate Institute of Medical Education
🇮🇳Chandigarh, India
Sahyadri Hospital
🇮🇳Pune, India
Ospedale Bellaria-Maggiore Hospital
🇮🇹Bologna, Italy
Sahyadri Specialty Hospital
🇮🇳Pune, India
Ospedale Niguarda
🇮🇹Milan, Italy
Nuovo Ospedale Sant' Agostino Estense
🇮🇹Modena, Italy
Ospedale Civile di Padova
🇮🇹Padova, Italy
Ospedale Civile Borgo Trento
🇮🇹Verona, Italy
Azienda Ospedaliero-Universitaria di
🇮🇹Parma, Italy
Daejeon Eulji University Hospital
🇰🇷Daejeon, Korea, Republic of
Auckland Hospital
🇳🇿Grafton, New Zealand
Clinical Center Novi Sad
🇷🇸Novi Sad, Serbia
Scientific Research Institute of Neurosurgery by Burdenko
🇷🇺Moscow, Russian Federation
Oddzial Kliniczny Kliniki Neurochirurgii i Neurotrumatologii Szpitala, Uniwersyteckiego w Krakowie
🇵🇱Krakow, Poland
Hospital Del Mar
🇪🇸Barcelona, Spain
Clinical Center Nis
🇷🇸Nis, Serbia
General Hospital Maribor
🇸🇮Maribor, Slovenia
Vall d'Hebron Hospital
🇪🇸Barcelona, Spain
Hospital de Son Dureta
🇪🇸Palma de Mallorca, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Uppsala University Hospital-Uppsala Akademiska Sjukhus
🇸🇪Uppsala, Sweden
Istanbul Universitesi, Istanbul Tip
🇹🇷Istanbul, Turkey
Ibn-i Sina Hastanesi Ankara & Ankara Universitesi Tip Fakultesi
🇹🇷Ankara, Turkey
Ege Universitesi Tip Fak Hestanesi
🇹🇷Bornova, Turkey
Regional Clinical Hospital by Mechnikov
🇺🇦Dnipropetrovsk, Ukraine
Prince of Wales Hospital
🇭🇰Hong Kong, Hong Kong