Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping

NCT00558311 | Completed Phase 3 DMC

• 1 other identifier: AC-054-301
• Study Type: interventional
• Target: 1,157
• Locations: 27 countries
• Sites: 109

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. 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.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.

Conditions

Aneurysmal Subarachnoid Hemorrhage

Keywords

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

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 (2)

Clazosentan

EXPERIMENTAL

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.

Drug: Clazosentan

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Clazosentan DRUG

Intravenous clazosentan administered by continuous infusion at 5 mg/h

Clazosentan

Placebo DRUG

Placebo administered by continuous infusion matching clazosentan administration

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 \[CTA\]), 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Idorsia Pharmaceuticals Ltd.: lead

Study Sites (117)

Barrow Neurosurgical Associates

Phoenix, Arizona, 85013, United States

Location

Colorado Neurological Institute

Englewood, Colorado, 80113-2769, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

State University of New York at Stony Brook-Health Sciences Center

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

Location

University of Cincinnati-Department of Neurosurgery

Cincinnati, Ohio, 45219, United States

Location

University Hospitals Case Medical Center-Department of Neurosurgery

Cleveland, Ohio, 44106, United States

Location

Oregon Health & Science University-Oregon Stroke Center

Portland, Oregon, 97239, United States

Location

Thomas Jefferson University School of Medicine-Jefferson Hospital for Neuroscience

Philadelphia, Pennsylvania, 19107, United States

Location

University of Virginia Health System-Department of Neurosurgery

Charlottesville, Virginia, 22908, United States

Location

Virginia Commonwealth University-Department of Neurosurgery

Richmond, Virginia, 23284, United States

Location

Royal Brisbane Hospital

Herston, 4029, Australia

Location

The Alfred Hospital

Melbourne, VIC 3004, Australia

Location

Landeskrankenhaus

Feldkirch, 6807, Austria

Location

Landeskrankenhaus und Medizinische Universitat Graz

Graz, 8036, Austria

Location

Medizinsche Universitat

Innsbruck, 6020, Austria

Location

University Fur Neurochirurgie, SALK, Christian Doppler Hospital

Salzburg, 5020, Austria

Location

AKH University of Vienna, Medical University

Vienna, 1090, Austria

Location

Sozialmedizinisches Zentrum Ost (ZMZ-Ost) Donauspital Vienna

Vienna, 1220, Austria

Location

Cliniques Universitaires Saint-Luc, Universite Catholique de

Brussels, 1200, Belgium

Location

University of Alberta Hospital

Edmonton, Alberta, T6G2B7, Canada

Location

Vancouver Hospital

Vancouver, British Columbia, V5Z 1 M9BC, Canada

Location

St Michael's Hospital, University

Toronto, Ontario, M5C367, Canada

Location

CHUM Notre Dame

Montreal, Quebec, H2L4M1, Canada

Location

University of Calgary Foothills Medical Center

Calgary, T2N2T9AB, Canada

Location

QEII Health Science Center

Halifax, B3H3A7, Canada

Location

Toronto Western Hospital, University of Toronto

Toronto, M5T2S8, Canada

Location

Beijing Tian Tan Hospital

Beijing, 100050, China

Location

XuanWu Hospital Institute of Brain Vascular Disease

Beijing, 100053 PR, China

Location

Guangdong Province Chinese Medicine Hospital

Guangzhou, 51000, China

Location

1st Affilated Hospital of Zhongshan

Guangzhou, 510080, China

Location

Shanghai Hua Shan Hospital

Shanghai, 200040, China

Location

Wuhan Tongji Hospital

Wuhan, 430030, China

Location

Clinical Hospital "Dubrava"

Zagreb, 10000, Croatia

Location

Clinical Hospital Dubrava

Zagreb, 1000, Croatia

Location

University Hospital Sestre Milosrdnice

Zagreb, 1000, Croatia

Location

Faculty Hospital/FN Brno Bohunice

Brno, 62500, Czechia

Location

Nemocnice Ceske Budejovice

České Budějovice, 37087, Czechia

Location

Na Homolce Hospital Prague

Prague, 15030, Czechia

Location

UVN Prague

Prague, 16902, Czechia

Location

Copenhagen University Hospital

Copenhagen, 2100, Denmark

Location

Copenhagen Country Hospital

Glostrup Municipality, 2600, Denmark

Location

Odense University Hospital

Odense, 5000, Denmark

Location

Helsinki University Central Hospital

Helsinki, Fin-00029HUS, Finland

Location

Oulu University Hospital

Oulu, 90029OYS, Finland

Location

Tampere University Central Hospital

Tampere, 33521, Finland

Location

Pole d'Anesthesie Reanimation, CHU D'Angers

Angers, 49933, France

Location

Hopital Pellegrin

Bordeaux, 33076, France

Location

Hopital Neurologique et Neuro-Chirurgical Pierre Wertheimer

Bron, 69677, France

Location

Chu Hopital Gabriel Montpied

Clermont-Ferrand, 63003, France

Location

Hopital de la Timone

Marseille, 13385, France

Location

Charite Universitatsmedizin Berlin-Neurochirurgische Klinik-CVK

Berlin, D-13353, Germany

Location

University of Bonn Medical Center

Bonn, 53105, Germany

Location

Klinik und Poliklinik fur Neurochirurgie

Dresden, 01307, Germany

Location

University of Erlangen-Nurnberg

Erlangen, 91054, Germany

Location

University of Hospital of Essen

Essen, 45147, Germany

Location

Universitatsklinik Frankfurt, Klinik und Poliklinik fur Neurochirurgie

Frankfurt, 60528, Germany

Location

University Hospital of Hamburg

Hamburg, 20246, Germany

Location

Neurochirurggische Universitatsklinik des Heidelberg

Heidelberg, 69120, Germany

Location

Klinik und Poliklinik fur Neurochirurgie

Leipzig, 04103, Germany

Location

University Munich Groshadern

Munich, 81377, Germany

Location

Thechnical University-Klinikum rechts der Isar

Munich, 81675, Germany

Location

University Regensburg

Regensburg, 93053, Germany

Location

Prince of Wales Hospital

Hong Kong, NT, Hong Kong

Location

Queen Mary Hospital

Hong Kong, Hong Kong

Location

Post Graduate Institute of Medical Education and Research

Chandigarh, 160012, India

Location

Post Graduate Institute of Medical Education

Chandigarh, 160012, India

Location

Nizam's Institute of Medical Sciences

Hyderabaad, 500482, India

Location

All India Insititute of Medicla Sciences (AIIMS)

New Delhi, 110011, India

Location

Sahyadri Specialty Hospital

Pune, 411 004, India

Location

Sahyadri Hospital

Pune, 411005, India

Location

Ospedale Bellaria-Maggiore Hospital

Bologna, 40139, Italy

Location

Ospedale Maurizio Bufalini

Cesena, 47023, Italy

Location

Azienda Ospedaliero-Universitaria di Careggi

Florence, 50141, Italy

Location

Ospedale Niguarda

Milan, 20162, Italy

Location

Nuovo Ospedale Sant' Agostino Estense

Modena, 41100, Italy

Location

Ospedale Civile di Padova

Padua, 35128, Italy

Location

Azienda Ospedaliero-Universitaria di

Parma, 43100, Italy

Location

Ospedale Civile Borgo Trento

Verona, 37126, Italy

Location

Riga Eastern Clinical University Hospital

Riga, LV-1038, Latvia

Location

Auckland Hospital

Grafton, Auckland, New Zealand

Location

Haukeland University Hospital Helse Bergen HF

Bergen, 5021, Norway

Location

Ulleval University Hospital

Oslo, 0407, Norway

Location

Universitetssykehuset Nord-Norge

Tromsø, N9038, Norway

Location

Klinika Neurochirurgii AMB-Neurosurgery Clinic of Medical Academy

Bialystok, Poland

Location

Kathedra I Klinika Neurochirurghii I Neurotraumatologii Collegium Medicum im. L. Rydygiera w Bydgoszc

Bydgoszcz, 85-094, Poland

Location

Katedra Klinika Neurochirurgii Akademii Medycznej w Gdansku

Gdansk, 80211, Poland

Location

Samodzielny Publiczny Szpital Kliniczny Slaskiej Akademii Medycznej w Katowicach

Katowice, 40-752, Poland

Location

Oddzial Kliniczny Kliniki Neurochirurgii i Neurotrumatologii Szpitala, Uniwersyteckiego w Krakowie

Krakow, 31-503, Poland

Location

Katedra Neurochirurgii, Uniwersytet

Lodz, 90-153, Poland

Location

Katedra I Klinika Neurochirurgii i Dzieciecej

Lublin, 20-090, Poland

Location

Katedra IKlinika Neurochirurgii Akademii Medycznej w Warszawie Clinic

Warsaw, 02-097, Poland

Location

Scientific Research Institute of Neurosurgery by Burdenko

Moscow, 125 047, Russia

Location

Clinical Center Nis

Niš, 18000, Serbia

Location

Clinical Center Novi Sad

Novi Sad, 21000, Serbia

Location

National Neuroscience

Singapore, 308433, Singapore

Location

General Hospital Maribor

Maribor, 2000, Slovenia

Location

Kyungpook National University

Daegu, 700-721, South Korea

Location

Daejeon Eulji University Hospital

Daejeon, 302-799, South Korea

Location

Hospital Del Mar

Barcelona, 08003, Spain

Location

Vall d'Hebron Hospital

Barcelona, 08035, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital de Son Dureta

Palma de Mallorca, 07014, Spain

Location

Sahlgrenska

Gothenburg, 41345, Sweden

Location

Lund University Hospital

Lund, 22185, Sweden

Location

Uppsala University Hospital-Uppsala Akademiska Sjukhus

Uppsala, 75185, Sweden

Location

Kantonsspital Aarau

Aarau, 5001, Switzerland

Location

Universitatsklinik Bern

Bern, 3010, Switzerland

Location

Universitätsklinik Bern Klinik für Neurochirurgie

Bern, 3010, Switzerland

Location

Geneva University Hospital

Geneva, 1211, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, 9007, Switzerland

Location

Universitatsspital Zurich

Zurich, 8091, Switzerland

Location

Ibn-i Sina Hastanesi Ankara & Ankara Universitesi Tip Fakultesi

Ankara, 06100, Turkey (Türkiye)

Location

Ege Universitesi Tip Fak Hestanesi

Bornova, 35100, Turkey (Türkiye)

Location

Istanbul Universitesi, Istanbul Tip

Istanbul, 34390, Turkey (Türkiye)

Location

Regional Clinical Hospital by Mechnikov

Dnipropetrovsk, 49,005, Ukraine

Location

A. P. Romodanov Institute of Neurosurgery

Kiev, 04 050, Ukraine

Location

Related Publications (3)

• 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

• 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.

  PMID: 22890639 DERIVED

• 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.

  PMID: 21640651 DERIVED

MeSH Terms

Conditions

Subarachnoid Hemorrhage; 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

• Study Director

  Idorsia Pharmaceuticals Ltd.

  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: November 13, 2007
• First Posted: November 14, 2007
• Study Start: December 14, 2007
• Primary Completion: June 15, 2010
• Study Completion: July 13, 2010
• Last Updated: February 17, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (4); LA (1); IT (8); FI (3); NO (3); AU (2); SG (1); CN (6); KR (2); PL (8); CR (3); ES (4); CH (6); SE (3); CA (7); DK (3); SL (1); US (11); FR (5); DE (12); RU (1); HK (2); IN (6); BE (1); NZ (1); UA (2); TU (3)