Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping (CONSCIOUS-2)

February 12, 2020 updated by: Idorsia Pharmaceuticals Ltd.

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.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

1157

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
      • Herston, Australia, 4029
        • Royal Brisbane Hospital
      • Melbourne, Australia, VIC 3004
        • The Alfred Hospital
  • Austria
      • Feldkirch, Austria, 6807
        • Landeskrankenhaus
      • Graz, Austria, 8036
        • Landeskrankenhaus und Medizinische Universitat Graz
      • Innsbruck, Austria, 6020
        • Medizinsche Universitat
      • Salzburg, Austria, 5020
        • University Fur Neurochirurgie, SALK, Christian Doppler Hospital
      • Vienna, Austria, 1090
        • AKH University of Vienna, Medical University
      • Vienna, Austria, 1220
        • Sozialmedizinisches Zentrum Ost (ZMZ-Ost) Donauspital Vienna
  • Belgium
      • Brussels, Belgium, 1200
        • Cliniques Universitaires Saint-Luc, Universite Catholique de
  • Canada
      • Calgary, Canada, T2N2T9AB
        • University of Calgary Foothills Medical Center
      • Halifax, Canada, B3H3A7
        • Qeii Health Science Center
      • Toronto, Canada, M5T2S8
        • Toronto Western Hospital, University of Toronto
    • Alberta
      • Edmonton, Alberta, Canada, T6G2B7
        • University of Alberta Hospital
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 1 M9BC
        • Vancouver Hospital
    • Ontario
      • Toronto, Ontario, Canada, M5C367
        • St Michael's Hospital, University
    • Quebec
      • Montreal, Quebec, Canada, H2L4M1
        • CHUM Notre Dame
  • China
      • Beijing, China, 100050
        • Beijing Tian Tan Hospital
      • Beijing, China, 100053 PR
        • XuanWu Hospital Institute of Brain Vascular Disease
      • Guangzhou, China, 51000
        • Guangdong Province Chinese Medicine Hospital
      • Guangzhou, China, 510080
        • 1st Affilated Hospital of Zhongshan
      • Shanghai, China, 200040
        • Shanghai Hua Shan Hospital
      • Wuhan, China, 430030
        • Wuhan TongJi Hospital
  • Croatia
      • Zagreb, Croatia, 10000
        • Clinical Hospital "Dubrava"
      • Zagreb, Croatia, 1000
        • Clinical Hospital Dubrava
      • Zagreb, Croatia, 1000
        • University Hospital Sestre Milosrdnice
  • Czechia
      • Brno, Czechia, 62500
        • Faculty Hospital/FN Brno Bohunice
      • Ceske Budejovice, Czechia, 37087
        • Nemocnice Ceske Budejovice
      • Prague, Czechia, 15030
        • Na Homolce Hospital Prague
      • Prague, Czechia, 16902
        • UVN Prague
  • Denmark
      • Copenhagen, Denmark, 2100
        • Copenhagen University Hospital
      • Glostrup, Denmark, 2600
        • Copenhagen Country Hospital
      • Odense, Denmark, 5000
        • Odense University Hospital
  • Finland
      • Helsinki, Finland, Fin-00029HUS
        • Helsinki University Central Hospital
      • Oulu, Finland, 90029OYS
        • Oulu University Hospital
      • Tampere, Finland, 33521
        • Tampere University Central Hospital
  • France
      • Angers, France, 49933
        • Pole d'Anesthesie Reanimation, CHU D'Angers
      • Bordeaux, France, 33076
        • Hôpital Pellegrin
      • Bron, France, 69677
        • Hopital Neurologique et Neuro-Chirurgical Pierre Wertheimer
      • Clermont Ferrand, France, 63003
        • CHU Hopital Gabriel Montpied
      • Marseille, France, 13385
        • Hôpital de la timone
  • Germany
      • Berlin, Germany, D-13353
        • Charite Universitatsmedizin Berlin-Neurochirurgische Klinik-CVK
      • Bonn, Germany, 53105
        • University of Bonn Medical Center
      • Dresden, Germany, 01307
        • Klinik und Poliklinik für Neurochirurgie
      • Erlangen, Germany, 91054
        • University of Erlangen-Nürnberg
      • Essen, Germany, 45147
        • University of Hospital of Essen
      • Frankfurt, Germany, 60528
        • Universitatsklinik Frankfurt, Klinik und Poliklinik fur Neurochirurgie
      • Hamburg, Germany, 20246
        • University Hospital of Hamburg
      • Heidelberg, Germany, 69120
        • Neurochirurggische Universitatsklinik des Heidelberg
      • Leipzig, Germany, 04103
        • Klinik und Poliklinik für Neurochirurgie
      • Munich, Germany, 81377
        • University Munich Groshadern
      • Munich, Germany, 81675
        • Thechnical University-Klinikum rechts der Isar
      • Regensburg, Germany, 93053
        • University Regensburg
  • Hong Kong
      • Hong Kong, Hong Kong
        • Queen Mary Hospital
      • Hong Kong, Hong Kong, NT
        • Prince of Wales Hospital
  • India
      • Chandigarh, India, 160012
        • Post Graduate Institute of Medical Education and Research
      • Chandigarh, India, 160012
        • Post Graduate Institute of Medical Education
      • Hyderabaad, India, 500482
        • Nizam's Institute of medical Sciences
      • New Delhi, India, 110011
        • All India Insititute of Medicla Sciences (AIIMS)
      • Pune, India, 411 004
        • Sahyadri Specialty Hospital
      • Pune, India, 411005
        • Sahyadri Hospital
  • Italy
      • Bologna, Italy, 40139
        • Ospedale Bellaria-Maggiore Hospital
      • Cesena, Italy, 47023
        • Ospedale Maurizio Bufalini
      • Firenze, Italy, 50141
        • Azienda Ospedaliero-Universitaria di Careggi
      • Milan, Italy, 20162
        • Ospedale Niguarda
      • Modena, Italy, 41100
        • Nuovo Ospedale Sant' Agostino Estense
      • Padova, Italy, 35128
        • Ospedale Civile di Padova
      • Parma, Italy, 43100
        • Azienda Ospedaliero-Universitaria di
      • Verona, Italy, 37126
        • Ospedale Civile Borgo Trento
  • Korea, Republic of
      • DaeGu, Korea, Republic of, 700-721
        • Kyungpook National University
      • Daejeon, Korea, Republic of, 302-799
        • Daejeon Eulji University Hospital
  • Latvia
      • Riga, Latvia, LV-1038
        • Riga Eastern Clinical University Hospital
  • New Zealand
      • Grafton, New Zealand, Auckland
        • Auckland Hospital
  • Norway
      • Bergen, Norway, 5021
        • Haukeland University Hospital Helse Bergen HF
      • Oslo, Norway, 0407
        • Ullevål University Hospital
      • Tromsö, Norway, N9038
        • Universitetssykehuset Nord-Norge
  • Poland
      • Bialystok, Poland
        • Klinika Neurochirurgii AMB-Neurosurgery Clinic of Medical Academy
      • Bydgoszcz, Poland, 85-094
        • Kathedra I Klinika Neurochirurghii I Neurotraumatologii Collegium Medicum im. L. Rydygiera w Bydgoszc
      • Gdansk, Poland, 80211
        • Katedra Klinika Neurochirurgii Akademii Medycznej w Gdansku
      • Katowice, Poland, 40-752
        • Samodzielny Publiczny Szpital Kliniczny Slaskiej Akademii Medycznej w Katowicach
      • Krakow, Poland, 31-503
        • Oddzial Kliniczny Kliniki Neurochirurgii i Neurotrumatologii Szpitala, Uniwersyteckiego w Krakowie
      • Lodz, Poland, 90-153
        • Katedra Neurochirurgii, Uniwersytet
      • Lublin, Poland, 20-090
        • Katedra I Klinika Neurochirurgii i Dzieciecej
      • Warszawa, Poland, 02-097
        • Katedra IKlinika Neurochirurgii Akademii Medycznej w Warszawie Clinic
  • Russian Federation
      • Moscow, Russian Federation, 125 047
        • Scientific Research Institute of Neurosurgery by Burdenko
  • Serbia
      • Nis, Serbia, 18000
        • Clinical Center Niš
      • Novi Sad, Serbia, 21000
        • Clinical Center Novi Sad
  • Singapore
      • Singapore, Singapore, 308433
        • National Neuroscience
  • Slovenia
      • Maribor, Slovenia, 2000
        • General Hospital Maribor
  • Spain
      • Barcelona, Spain, 08003
        • Hospital del Mar
      • Barcelona, Spain, 08035
        • Vall d'Hebron Hospital
      • Madrid, Spain, 28041
        • Hospital Universitario 12 de Octubre
      • Palma de Mallorca, Spain, 07014
        • Hospital de Son Dureta
  • Sweden
      • Goteborg, Sweden, 41345
        • Sahlgrenska
      • Lund, Sweden, 22185
        • Lund University Hospital
      • Uppsala, Sweden, 75185
        • Uppsala University Hospital-Uppsala Akademiska Sjukhus
  • Switzerland
      • Aarau, Switzerland, 5001
        • Kantonsspital Aarau
      • Bern, Switzerland, 3010
        • Universitätsklinik Bern
      • Bern, Switzerland, 3010
        • Universitätsklinik Bern Klinik für Neurochirurgie
      • Geneva, Switzerland, 1211
        • Geneva University Hospital
      • St Gallen, Switzerland, 9007
        • Kantonsspital St. Gallen
      • Zurich, Switzerland, 8091
        • UniversitätsSpital Zürich
  • Turkey
      • Ankara, Turkey, 06100
        • Ibn-i Sina Hastanesi Ankara & Ankara Universitesi Tip Fakultesi
      • Bornova, Turkey, 35100
        • Ege Universitesi Tip Fak Hestanesi
      • Istanbul, Turkey, 34390
        • Istanbul Universitesi, Istanbul Tip
  • Ukraine
      • Dnipropetrovsk, Ukraine, 49,005
        • Regional Clinical Hospital by Mechnikov
      • Kiev, Ukraine, 04 050
        • A. P. Romodanov Institute of Neurosurgery
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85013
        • Barrow Neurosurgical Associates
    • Colorado
      • Englewood, Colorado, United States, 80113-2769
        • Colorado Neurological Institute
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center
      • Stony Brook, New York, United States, 11794-8122
        • State University of New York at Stony Brook-Health Sciences Center
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • University of Cincinnati-Department of Neurosurgery
      • Cleveland, Ohio, United States, 44106
        • University Hospitals Case Medical Center-Department of Neurosurgery
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health & Science University-Oregon Stroke Center
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Thomas Jefferson University School of Medicine-Jefferson Hospital for Neuroscience
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • University of Virginia Health System-Department of Neurosurgery
      • Richmond, Virginia, United States, 23284
        • Virginia Commonwealth University-Department of Neurosurgery

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: Clazosentan
Intravenous clazosentan administered by continuous infusion at 5 mg/h
Placebo Comparator: 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.
Drug: Placebo
Placebo administered by continuous infusion matching clazosentan administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Cerebral vasospasm-related morbidity and mortality of all-causes as defined by the protocol
Time Frame: Within 6 weeks post-aSAH
Within 6 weeks post-aSAH

Secondary Outcome Measures

Outcome Measure
Time Frame
Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized into good (score > 4) and poor (score ≤ 4) outcome.
Time Frame: Week 12 post-aSAH
Week 12 post-aSAH

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Idorsia Pharmaceuticals Ltd.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 14, 2007

Primary Completion (Actual)

June 15, 2010

Study Completion (Actual)

July 13, 2010

Study Registration Dates

First Submitted

November 13, 2007

First Submitted That Met QC Criteria

November 13, 2007

First Posted (Estimate)

November 14, 2007

Study Record Updates

Last Update Posted (Actual)

February 17, 2020

Last Update Submitted That Met QC Criteria

February 12, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AC-054-301

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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