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    The EU Clinical Trials Register currently displays   42732   clinical trials with a EudraCT protocol, of which   7035   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2007-002584-27
    Sponsor's Protocol Code Number:AC-054-301
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-09-18
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFinland - Fimea
    A.2EudraCT number2007-002584-27
    A.3Full title of the trial
    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.
    A.3.2Name or abbreviated title of the trial where available
    CONSCIOUS 2
    A.4.1Sponsor's protocol code numberAC-054-301
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorActelion Pharmaceuticals Ltd.
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/03/182
    D.3 Description of the IMP
    D.3.1Product nameClazosentan
    D.3.2Product code AXV-034343
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNClazosentan
    D.3.9.1CAS number 180384-56-9
    D.3.9.2Current sponsor codeAXV-034343
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number to 25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboIntravenous infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Indication: Aneurysmal subarachnoid hemorrhage
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10042318
    E.1.2Term Subarachnoid haemorrhage NOS
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that clazosentan reduces the incidence of cerebral vasospasm-related morbidity and all-cause mortality within 6 weeks post aneurysmal subarachnoid hemorrhage (aSAH) treated by surgical clipping.
    E.2.2Secondary objectives of the trial
    ·To demonstrate that clazosentan improves clinical outcome at Week 12 post-aSAH treated by surgical clipping, as measured by the dichotomized Glasgow Outcome Scale (extended version [GOSE]).

    ·To evaluate the impact of clazosentan on total infarct volume at Week 6 post-aSAH treated by surgical clipping, and on each individual component of the primary endpoint.
    ·To evaluate the safety and tolerability of clazosentan.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 >= 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 least 12 hours post-procedure, but prior to randomization, ruling out any large procedure-related infarct.
    E.4Principal 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 >= 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) <= 90 mmHg) that is refractory to treatment.
    9. Patients with aspiration pneumonia or pulmonary edema.
    10. Patients with 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 disease, as defined by plasma creatinine >= 2.5 mg/dL (221 µmol/l), and/or liver disease, as defined by total bilirubin > 2 fold the Upper Limit of Normal (ULN) as measured at the local laboratory, and/or known diagnosis or clinical suspicion of liver cirrhosis.
    13. Patients receiving i.v. nimodipine or i.v. nicardipine 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
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy 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 (e.g., lesions arising from intra-cerebral hemorrhage, the aneurysm clipping, the primary injury, or ventricular drain encephalomalacia).*
    In this context, new cerebral infarct(s) are those that were not present at baseline and cerebral infarcts that were present at baseline but substantially worsened within 6 weeks post-aSAH, as confirmed by the CEC clinicians.

    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 (e.g., hydrocephalus, seizure, etc.) .
    a) DIND is defined in patients in whom the neurological scales are assessable as:
    •A decrease of at least two points on the modified Glasgow Coma Scale (mGCS), or an increase of at least two points on the abbreviated National Institutes of Health Stroke Scale (abbrev. NIHSS), lasting for at least 2 hours.
    b) DIND is defined in patients in whom the neurological scales are not assessable as:
    •A valid rescue therapy started for a justifiable reason.
    The assessment of the contribution of cerebral vasospasm to DIND is based on (but not limited to) the presence of cerebral vasospasm on CTA or DSA.
    A valid rescue therapy is defined under endpoint component number 4 (below).
    A justifiable reason for start of rescue therapy may include, but is not limited to, an angiogram positive for vasospasm, suspicion of vasospasm on TCD or perfusion CT, clinical signs suggestive of vasospasm such as unexplained fever or increased white blood cell count.

    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*.
    Vasospasm is considered to be present in a cerebral artery when narrowing of at least 1/3 of the vessel diameter is observed. Whether or not the overall angiogram is considered to be positive for vasospasm is left to the judgement of the Critical Events Committee.
    A valid rescue therapy is defined as the initiation or increase in dose of one of the following therapies:
    •Intravenous vasopressor (e.g., dopamine, dobutamine, phenylephrine, epinephrine, norepinephrine) with or without fluid therapy
    •Intra-arterial vasodilator (e.g., nicardipine, nimodipine, verapamil, papaverine)
    •Balloon angioplasty
    Administration of intravenous vasodilators, intravenous magnesium, statins, and fluid therapy alone to correct hypovolemia or bleeding, are not considered as valid rescue therapy.
    In order to qualify for the rescue therapy component of the primary endpoint, a patient treated with vasopressors and fluids must have a central line and a urine catheter. If vasopressors are initiated or increased, then a sustained increase in blood pressure should occur (details in Patient Management Guidelines, Appendix 3).
    Conscious patients must show clinical symptoms suggestive of cerebral vasospasm (e.g., drowsiness, fever, confusion, decrease of at least two points on mGCS or increase of at least two points on abbreviated NIHSS).
    Unconscious or sedated patients can qualify for this component of the primary endpoint, in the absence of clinical symptoms suggestive of vasospasm, provided they have a cerebral angiogram positive for vasospasm.
    A patient cannot qualify for this component of the primary endpoint based on a positive Doppler or abnormal CT perfusion scan alone.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Information not present in EudraCT
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients who are unconscious or otherwise unable to give their own informed consent may participate, providing a surrogate informed consent has been obtained, as allowed by local legislation.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 620
    F.4.2.2In the whole clinical trial 1146
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-11-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-11-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2010-07-13
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