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

Aneurysmal Subarachnoid Hemorrhage Clinical Trial

— CONSCIOUS-2  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00558311
• Other study ID #: AC-054-301
• Status: Completed
• Phase: Phase 3
• Start date: December 14, 2007
• Est. completion date: July 13, 2010

Study information

• Verified date: February 2020
• 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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1157
• Est. completion date: July 13, 2010
• Est. primary completion date: June 15, 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]), 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.

Related Conditions & MeSH terms

• Aneurysmal Subarachnoid Hemorrhage
• Hemorrhage
• Subarachnoid Hemorrhage

Intervention

Drug:
• Clazosentan
Intravenous clazosentan administered by continuous infusion at 5 mg/h
• Placebo
Placebo administered by continuous infusion matching clazosentan administration

Locations

Country	Name	City	State
Australia	Royal Brisbane Hospital	Herston
Australia	The Alfred Hospital	Melbourne
Austria	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
Belgium	Cliniques Universitaires Saint-Luc, Universite Catholique de	Brussels
Canada	University of Calgary Foothills Medical Center	Calgary
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	QEII Health Science Center	Halifax
Canada	CHUM Notre Dame	Montreal	Quebec
Canada	St Michael's Hospital, University	Toronto	Ontario
Canada	Toronto Western Hospital, University of Toronto	Toronto
Canada	Vancouver Hospital	Vancouver	British Columbia
China	Beijing Tian Tan Hospital	Beijing
China	XuanWu Hospital Institute of Brain Vascular Disease	Beijing
China	1st Affilated Hospital of Zhongshan	Guangzhou
China	Guangdong Province Chinese Medicine Hospital	Guangzhou
China	Shanghai Hua Shan Hospital	Shanghai
China	Wuhan Tongji Hospital	Wuhan
Croatia	Clinical Hospital "Dubrava"	Zagreb
Croatia	Clinical Hospital Dubrava	Zagreb
Croatia	University Hospital Sestre Milosrdnice	Zagreb
Czechia	Faculty Hospital/FN Brno Bohunice	Brno
Czechia	Nemocnice Ceske Budejovice	Ceske Budejovice
Czechia	Na Homolce Hospital Prague	Prague
Czechia	UVN Prague	Prague
Denmark	Copenhagen University Hospital	Copenhagen
Denmark	Copenhagen Country Hospital	Glostrup
Denmark	Odense University Hospital	Odense
Finland	Helsinki University Central Hospital	Helsinki
Finland	Oulu University Hospital	Oulu
Finland	Tampere University Central Hospital	Tampere
France	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
Germany	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	Thechnical University-Klinikum rechts der Isar	Munich
Germany	University Munich Groshadern	Munich
Germany	University Regensburg	Regensburg
Hong Kong	Prince of Wales Hospital	Hong Kong
Hong Kong	Queen Mary Hospital	Hong Kong
India	Post Graduate Institute of Medical Education	Chandigarh
India	Post Graduate Institute of Medical Education and Research	Chandigarh
India	Nizam's Institute of Medical Sciences	Hyderabaad
India	All India Insititute of Medicla Sciences (AIIMS)	New Delhi
India	Sahyadri Hospital	Pune
India	Sahyadri Specialty Hospital	Pune
Italy	Ospedale Bellaria-Maggiore Hospital	Bologna
Italy	Ospedale Maurizio Bufalini	Cesena
Italy	Azienda Ospedaliero-Universitaria di Careggi	Firenze
Italy	Ospedale Niguarda	Milan
Italy	Nuovo Ospedale Sant' Agostino Estense	Modena
Italy	Ospedale Civile di Padova	Padova
Italy	Azienda Ospedaliero-Universitaria di	Parma
Italy	Ospedale Civile Borgo Trento	Verona
Korea, Republic of	Kyungpook National University	DaeGu
Korea, Republic of	Daejeon Eulji University Hospital	Daejeon
Latvia	Riga Eastern Clinical University Hospital	Riga
New Zealand	Auckland Hospital	Grafton
Norway	Haukeland University Hospital Helse Bergen HF	Bergen
Norway	Ulleval University Hospital	Oslo
Norway	Universitetssykehuset Nord-Norge	Tromsö
Poland	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	Warszawa
Russian Federation	Scientific Research Institute of Neurosurgery by Burdenko	Moscow
Serbia	Clinical Center Nis	Nis
Serbia	Clinical Center Novi Sad	Novi Sad
Singapore	National Neuroscience	Singapore
Slovenia	General Hospital Maribor	Maribor
Spain	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
Sweden	Sahlgrenska	Goteborg
Sweden	Lund University Hospital	Lund
Sweden	Uppsala University Hospital-Uppsala Akademiska Sjukhus	Uppsala
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Universitatsklinik Bern	Bern
Switzerland	Universitätsklinik Bern Klinik für Neurochirurgie	Bern
Switzerland	Geneva University Hospital	Geneva
Switzerland	Kantonsspital St. Gallen	St Gallen
Switzerland	Universitatsspital Zurich	Zurich
Turkey	Ibn-i Sina Hastanesi Ankara & Ankara Universitesi Tip Fakultesi	Ankara
Turkey	Ege Universitesi Tip Fak Hestanesi	Bornova
Turkey	Istanbul Universitesi, Istanbul Tip	Istanbul
Ukraine	Regional Clinical Hospital by Mechnikov	Dnipropetrovsk
Ukraine	A. P. Romodanov Institute of Neurosurgery	Kiev
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Virginia Health System-Department of Neurosurgery	Charlottesville	Virginia
United States	University of Cincinnati-Department of Neurosurgery	Cincinnati	Ohio
United States	University Hospitals Case Medical Center-Department of Neurosurgery	Cleveland	Ohio
United States	Colorado Neurological Institute	Englewood	Colorado
United States	Columbia University Medical Center	New York	New York
United States	Thomas Jefferson University School of Medicine-Jefferson Hospital for Neuroscience	Philadelphia	Pennsylvania
United States	Barrow Neurosurgical Associates	Phoenix	Arizona
United States	Oregon Health & Science University-Oregon Stroke Center	Portland	Oregon
United States	Virginia Commonwealth University-Department of Neurosurgery	Richmond	Virginia
United States	State University of New York at Stony Brook-Health Sciences Center	Stony Brook	New York

Sponsors (1)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  China,  Croatia,  Czechia,  Denmark,  Finland,  France,  Germany,  Hong Kong,  India,  Italy,  Korea, Republic of,  Latvia,  New Zealand,  Norway,  Poland,  Russian Federation,  Serbia,  Singapore,  Slovenia,  Spain,  Sweden,  Switzerland,  Turkey,  Ukraine, 

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