Clinical trial NCT00558311: Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping
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 Surgical Clipping.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Aneurysmal Subarachnoid Hemorrhage
Keywords: Aneurysmal
Subarachnoid
Hemorrhage
vasospasm
clazosentan
PIVLAZ
surgical clipping
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2007-11-14
Enrollment: 1157
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 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.


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 \[CTA\]), 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:

1. Patients with subarachnoid hemorrhage (SAH) due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms).
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.

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: Phoenix
country: United States
facility: Barrow Neurosurgical Associates
state: Arizona
city: Englewood
country: United States
facility: Colorado Neurological Institute
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Stony Brook
country: United States
facility: State University of New York at Stony Brook-Health Sciences Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati-Department of Neurosurgery
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center-Department of Neurosurgery
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University-Oregon Stroke Center
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University School of Medicine-Jefferson Hospital for Neuroscience
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia Health System-Department of Neurosurgery
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University-Department of Neurosurgery
state: Virginia
city: Herston
country: Australia
facility: Royal Brisbane Hospital
city: Melbourne
country: Australia
facility: The Alfred Hospital
city: Feldkirch
country: Austria
facility: Landeskrankenhaus
city: Graz
country: Austria
facility: Landeskrankenhaus und Medizinische Universitat Graz
city: Innsbruck
country: Austria
facility: Medizinsche Universitat
city: Salzburg
country: Austria
facility: University Fur Neurochirurgie, SALK, Christian Doppler Hospital
city: Vienna
country: Austria
facility: AKH University of Vienna, Medical University
city: Vienna
country: Austria
facility: Sozialmedizinisches Zentrum Ost (ZMZ-Ost) Donauspital Vienna
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc, Universite Catholique de
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver Hospital
state: British Columbia
city: Toronto
country: Canada
facility: St Michael's Hospital, University
state: Ontario
city: Montreal
country: Canada
facility: CHUM Notre Dame
state: Quebec
city: Calgary
country: Canada
facility: University of Calgary Foothills Medical Center
city: Halifax
country: Canada
facility: QEII Health Science Center
city: Toronto
country: Canada
facility: Toronto Western Hospital, University of Toronto
city: Beijing
country: China
facility: Beijing Tian Tan Hospital
city: Beijing
country: China
facility: XuanWu Hospital Institute of Brain Vascular Disease
city: Guangzhou
country: China
facility: Guangdong Province Chinese Medicine Hospital
city: Guangzhou
country: China
facility: 1st Affilated Hospital of Zhongshan
city: Shanghai
country: China
facility: Shanghai Hua Shan Hospital
city: Wuhan
country: China
facility: Wuhan Tongji Hospital
city: Zagreb
country: Croatia
facility: Clinical Hospital "Dubrava"
city: Zagreb
country: Croatia
facility: Clinical Hospital Dubrava
city: Zagreb
country: Croatia
facility: University Hospital Sestre Milosrdnice
city: Brno
country: Czechia
facility: Faculty Hospital/FN Brno Bohunice
city: Ceske Budejovice
country: Czechia
facility: Nemocnice Ceske Budejovice
city: Prague
country: Czechia
facility: Na Homolce Hospital Prague
city: Prague
country: Czechia
facility: UVN Prague
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital
city: Glostrup
country: Denmark
facility: Copenhagen Country Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Oulu
country: Finland
facility: Oulu University Hospital
city: Tampere
country: Finland
facility: Tampere University Central Hospital
city: Angers
country: France
facility: Pole d'Anesthesie Reanimation, CHU D'Angers
city: Bordeaux
country: France
facility: Hopital Pellegrin
city: Bron
country: France
facility: Hopital Neurologique et Neuro-Chirurgical Pierre Wertheimer
city: Clermont Ferrand
country: France
facility: Chu Hopital Gabriel Montpied
city: Marseille
country: France
facility: Hopital de la Timone
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin-Neurochirurgische Klinik-CVK
city: Bonn
country: Germany
facility: University of Bonn Medical Center
city: Dresden
country: Germany
facility: Klinik und Poliklinik fur Neurochirurgie
city: Erlangen
country: Germany
facility: University of Erlangen-Nurnberg
city: Essen
country: Germany
facility: University of Hospital of Essen
city: Frankfurt
country: Germany
facility: Universitatsklinik Frankfurt, Klinik und Poliklinik fur Neurochirurgie
city: Hamburg
country: Germany
facility: University Hospital of Hamburg
city: Heidelberg
country: Germany
facility: Neurochirurggische Universitatsklinik des Heidelberg
city: Leipzig
country: Germany
facility: Klinik und Poliklinik fur Neurochirurgie
city: Munich
country: Germany
facility: University Munich Groshadern
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: Prince of Wales Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education and Research
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education
city: Hyderabaad
country: India
facility: Nizam's Institute of Medical Sciences
city: New Delhi
country: India
facility: All India Insititute of Medicla Sciences (AIIMS)
city: Pune
country: India
facility: Sahyadri Specialty Hospital
city: Pune
country: India
facility: Sahyadri Hospital
city: Bologna
country: Italy
facility: Ospedale Bellaria-Maggiore Hospital
city: Cesena
country: Italy
facility: Ospedale Maurizio Bufalini
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria di Careggi
city: Milan
country: Italy
facility: Ospedale Niguarda
city: Modena
country: Italy
facility: Nuovo Ospedale Sant' Agostino Estense
city: Padova
country: Italy
facility: Ospedale Civile di Padova
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di
city: Verona
country: Italy
facility: Ospedale Civile Borgo Trento
city: DaeGu
country: Korea, Republic of
facility: Kyungpook National University
city: Daejeon
country: Korea, Republic of
facility: Daejeon Eulji University Hospital
city: Riga
country: Latvia
facility: Riga Eastern Clinical University Hospital
city: Grafton
country: New Zealand
facility: Auckland Hospital
city: Bergen
country: Norway
facility: Haukeland University Hospital Helse Bergen HF
city: Oslo
country: Norway
facility: Ulleval University Hospital
city: Tromsö
country: Norway
facility: Universitetssykehuset Nord-Norge
city: Bialystok
country: Poland
facility: Klinika Neurochirurgii AMB-Neurosurgery Clinic of Medical Academy
city: Bydgoszcz
country: Poland
facility: Kathedra I Klinika Neurochirurghii I Neurotraumatologii Collegium Medicum im. L. Rydygiera w Bydgoszc
city: Gdansk
country: Poland
facility: Katedra Klinika Neurochirurgii Akademii Medycznej w Gdansku
city: Katowice
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Slaskiej Akademii Medycznej w Katowicach
city: Krakow
country: Poland
facility: Oddzial Kliniczny Kliniki Neurochirurgii i Neurotrumatologii Szpitala, Uniwersyteckiego w Krakowie
city: Lodz
country: Poland
facility: Katedra Neurochirurgii, Uniwersytet
city: Lublin
country: Poland
facility: Katedra I Klinika Neurochirurgii i Dzieciecej
city: Warszawa
country: Poland
facility: Katedra IKlinika Neurochirurgii Akademii Medycznej w Warszawie Clinic
city: Moscow
country: Russian Federation
facility: Scientific Research Institute of Neurosurgery by Burdenko
city: Nis
country: Serbia
facility: Clinical Center Nis
city: Novi Sad
country: Serbia
facility: Clinical Center Novi Sad
city: Singapore
country: Singapore
facility: National Neuroscience
city: Maribor
country: Slovenia
facility: General Hospital Maribor
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Barcelona
country: Spain
facility: Vall d'Hebron Hospital
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Palma de Mallorca
country: Spain
facility: Hospital de Son Dureta
city: Goteborg
country: Sweden
facility: Sahlgrenska
city: Lund
country: Sweden
facility: Lund University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital-Uppsala Akademiska Sjukhus
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Bern
country: Switzerland
facility: Universitatsklinik Bern
city: Bern
country: Switzerland
facility: Universitätsklinik Bern Klinik für Neurochirurgie
city: Geneva
country: Switzerland
facility: Geneva University Hospital
city: St Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Zurich
country: Switzerland
facility: Universitatsspital Zurich
city: Ankara
country: Turkey
facility: Ibn-i Sina Hastanesi Ankara & Ankara Universitesi Tip Fakultesi
city: Bornova
country: Turkey
facility: Ege Universitesi Tip Fak Hestanesi
city: Istanbul
country: Turkey
facility: Istanbul Universitesi, Istanbul Tip
city: Dnipropetrovsk
country: Ukraine
facility: Regional Clinical Hospital by Mechnikov
city: Kiev
country: Ukraine
facility: A. P. Romodanov Institute of Neurosurgery
Study officials:
affiliation: Idorsia Pharmaceuticals Ltd.
name: Study Director
role: STUDY_DIRECTOR
References:
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.
citation: 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.
citation: 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.