Clazosentan in Aneurysmal Subarachnoid Hemorrhage

Aneurysmal Subarachnoid Hemorrhage Clinical Trial

— CONSCIOUS-3  

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00940095
• Other study ID #: AC-054-302
• Status: Terminated
• Phase: Phase 3
• Start date: July 1, 2009
• Est. completion date: January 1, 2011

Study information

• Verified date: July 2018
• Source: Idorsia Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 577
• Est. completion date: January 1, 2011
• Est. primary completion date: October 1, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Aneurysmal Subarachnoid Hemorrhage
• Hemorrhage
• Subarachnoid Hemorrhage

Intervention

Drug:
• Clazosentan 5 m/h
Continuous intravenous infusion of clazosentan (5 mg/h)
• Clazosentan 15 mg/h
Continuous intravenous infusion of clazosentan clazosentan (15 mg/h)
• Placebo
Continuous intravenous infusion of placebo-matching clazosentan

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  Czechia,  Denmark,  Finland,  France,  Germany,  Hong Kong,  Hungary,  India,  Israel,  Italy,  Mexico,  Netherlands,  Norway,  Poland,  Singapore,  Slovenia,  Spain,  Sweden,  Switzerland,  Taiwan, 

References & Publications (1)

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. S — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol		Within 6 weeks post-aSAH
Secondary	Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized into good (score > 4) and poor (score = 4) outcome.		Week 12 post-aSAH