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    Summary
    EudraCT Number:2007-005254-24
    Sponsor's Protocol Code Number:HA009
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2008-01-21
    Trial 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 ConcernedAustria - BASG
    A.2EudraCT number2007-005254-24
    A.3Full title of the trial
    PHASE 2, MULTICENTER, OPEN-LABEL, TWO-STAGE STUDY TO EVALUATE THE SAFETY AND EFFICACY OF INTRA-ARTERIAL CATHETER-DIRECTED ALFIMEPRASE FOR RESTORATION OF NEUROLOGIC FUNCTION AND RAPID OPENING OF ARTERIES IN STROKE (CARNEROS-1)
    A.3.2Name or abbreviated title of the trial where available
    CARNEROS-1
    A.4.1Sponsor's protocol code numberHA009
    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 SponsorNuvelo, Inc
    B.1.3.4CountryUnited States
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAlfimeprase
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntraarterial use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAlfimeprase
    D.3.9.1CAS number 259074-76-5
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.5 mg/mL to 7.5 mg/mL
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeRecombinantly produced metalloproteinase
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute Ischemic Stroke (AIS)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10055221
    E.1.2Term Ischemic stroke
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    PRIMARY SAFETY OBJECTIVE:
    To evaluate the safety of intra-arterial catheter-directed bolus alfimeprase as measured by symptomatic intracerebral hemorrhage (ICH) rate up to 24-30 hours after initiation of alfimeprase dosing
    PRIMARY EFFICACY OBJECTIVE:
    To evaluate the technical efficacy of intra-arterial catheter-directed bolus alfimeprase as measured by recanalization of the primary arterial occlusive lesion (AOL) at 120 minutes after initiation of alfimeprase dosing OR recanalization of the primary AOL at 60 minutes after initiation of alfimeprase dosing if TIMI Grade 3 flow is achieved and the underlying cerebral vessel is normal angiographically.
    E.2.2Secondary objectives of the trial
    SECONDARY OBJECTIVES:
    To evaluate safety:
    • Relative hypotension requiring treatment (i.e., volume expanders and/or vasopressors)
    • New cardiac events (e.g., cardiac ischemia, congestive heart failure, and dysrhythmia)
    • Relative hypotension not requiring treatment
    • Asymptomatic ICH up to 24 hours after initiation of alfimeprase dosing
    • New AIS up to 24 hours after initiation of alfimeprase dosing
    • New AIS up to 7 days after initiation of alfimeprase dosing
    • Major bleeding events up to 30 days after alfimeprase dosing
    • Adverse events (AEs) and serious adverse events (SAEs) up to 30 days after alfimeprase dosing
    • Mortality up to 30 and 90 days after alfimeprase dosing

    For the secondary objectives to evaluate Efficacy: Please refer to the HA009 study Protocol p.34
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects who meet all of the following criteria will be eligible for this study:
    a. Clinical diagnosis of AIS defined as the sudden onset of an acute focal neurological deficit presumed to be due to cerebral ischemia
    b. Arterial occlusion of the carotid T or a M1, M2, or M1-M2 branch of the middle cerebral artery (MCA) as documented by CT angiography or magnetic resonance angiography
    c. Arteriographically confirmed occlusion of the carotid T or a M1, M2, or M1-M2 branch of the MCA
    d. The subject (or legally acceptable representative) must give written informed consent
    e. Age 18 years to 85 years
    f. Onset of symptoms of AIS (i.e., last known well time) within 3-9 hours
    g. Baseline NIHSS of 4 to 25
    h. Available for follow-up assessments at 30 and 90 days
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria are not eligible for the study.
    a. Contraindication to systemic anticoagulation, e.g., history of documented hemorrhage requiring treatment within the past 30 days; history of a hereditary bleeding disorder or known bleeding diathesis; major surgery or trauma, open chest massage, ocular surgery or hemorrhagic retinopathy within the past 30 days; puncture at non-compressible site within 48 hours prior to administration of study drug; history of stroke (excluding the index event), unstable central nervous system structural abnormalities (e.g., arteriovenous malformation or brain tumor) within the past 3 months, and any history of prior intracranial hemorrhage
    b. Uncontrolled hypertension at study entry as defined by systolic blood pressure (SBP) greater than 180 mmHg or diastolic blood pressure (DBP) greater than or equal to 100 mmHg on repeated measures prior to study entry despite the use of IV antihypertensive agents
    c. Expectation based on timing of presentation that alfimeprase administration will not be able to be completed by 9 hours after stroke onset
    d. Inability to initiate alfimeprase dosing within 120 minutes of the qualifying imaging scan
    e. Coma
    f. Rapidly improving neurological symptoms at the time of screening
    g. Brain CT or MRI evidence of intracranial bleeding of any age
    h. High clinical suspicion for subarachnoid hemorrhage despite a negative baseline CT or MRI
    i. CT evidence of an acute and/or evolving hypodensity greater than 1/3 of the MCA territory in the vascular territory to be treated or Alberta Stroke Program Early CT Score (ASPECTS) of less than or equal to 5
    j. MRI diffusion weighted imaging lesion greater than 1/3 of the MCA territory in the vascular distribution to be treated
    k. Carotid artery and/or intracranial artery stenosis that precludes safe passage of a microcatheter to treat the primary AOL
    l. Life expectancy of less than 6 months (e.g., terminal cancer)
    m. History of significant acute or chronic kidney disease, including known nephrotic syndrome, that would preclude safe contrast angiography
    n. Known allergy to contrast agents
    o. History of immune deficiency
    p. History of heparin-induced thrombocytopenia (HIT)
    q. Participation in any study of an investigational device, medication, biologic, or other agent within 30 days prior to enrollment (Stage I) / randomization (Stage II)
    r. Any stroke, myocardial infarction, or use of thrombolytic therapy (including investigational thrombolytic therapy) within 3 months prior to enrollment (Stage I) / randomization (Stage II)
    s. Past participation in any alfimeprase clinical trial
    t. Pregnant, lactating, or actively menstruating women and women of child-bearing potential who are not using adequate contraceptive precautions (e.g., intrauterine device, oral contraceptives, barrier methods, or other contraception deemed adequate by the investigator)
    u. Current use of oral anticoagulants or an international normalized ratio (INR) greater than 1.4
    v. Any non-atherosclerotic arteriopathy (e.g., vasculitis)
    w. Any prior neurologic event that would obscure the radiographic or clinical evaluation of the new index neurologic deficits
    x. Subjects with known renal insufficiency defined as a serum creatinine > 2 mg/dL (> 180 μmol/L)
    y. Subjects with known clinically significant hepatic disease defined as transaminase values > 3x ULN
    z. Subjects with any malignant neoplasm diagnosed within five years prior to screening, with the exception of basal cell carcinoma of the skin and fully resected squamous cell carcinoma of the skin
    aa. Subjects with a platelet count less than 100,000/mm3
    bb. Subjects with a baseline serum glucose level less than 50 mg/dL or greater than 300 mg/dL
    cc. Subjects receiving any dose of a heparinoid (e.g., danaparoid and fondaparinux) or a non-prophylactic intensity dose of a low molecular weight heparin (LMWH) within the 24-hour period prior to study drug administration are excluded. Prophylactic doses of LMWH, including enoxaparin 40 mg or less and dalteparin 5000 units or less are acceptable. Unfractionated heparin commenced prior to study enrollment (Stage I) / randomization (Stage II) is allowed as long as upon enrollment/randomization, the infusion is changed to that specified in Section 3.4.2 of the protocol.
    dd. Any other subject feature that in the opinion of the investigator should preclude study participation
    E.5 End points
    E.5.1Primary end point(s)
    PRIMARY SAFETY ENDPOINT:
    • Rate of symptomatic ICH at 24 hours (based on CT performed up to 24-30 hours after initiation of alfimeprase dosing)
    PRIMARY EFFICACY ENDPOINT:
    • Rate of recanalization of the primary AOL at 120 minutes after initiation of alfimeprase dosing OR recanalization of the primary AOL at 60 minutes after initiation of alfimeprase dosing if TIMI Grade 3 flow is achieved and the underlying cerebral vessel is normal angiographically
    SECONDARY SAFETY ENDPOINTS:
    • Rate of relative hypotension requiring treatment (i.e., volume expanders and/or vasopressors)
    • Rate of new cardiac events (e.g., cardiac ischemia, congestive heart failure, and dysrhythmia)
    • Rate of relative hypotension not requiring treatment
    • Rate of asymptomatic ICH up to 24 hours after initiation of alfimeprase dosing
    • Rate of new AIS up to 24 hours after initiation of alfimeprase dosing
    • Rate of new AIS up to 7 days after initiation of alfimeprase dosing
    • Rate of major bleeding events up to 30 days after alfimeprase dosing
    • AE and SAE rates up to 30 days after alfimeprase dosing
    • Mortality rates up to 30 and 90 days after alfimeprase dosing
    SECONDARY EFFICACY ENDPOINTS:
    • Rate of recanalization of the primary AOL at 30 minutes after initiation of alfimeprase dosing and at 60 minutes after initiation of alfimeprase dosing for those subjects who did not achieve TIMI Grade 3 flow with an underlying cerebral vessel that is normal angiographically
    • Rate of global reperfusion of the primary AOL distal vascular bed at 30 and 60 minutes after initiation of alfimeprase dosing
    • Rate of global reperfusion of the primary AOL distal vascular bed at 120 minutes after initiation of alfimeprase dosing for all subjects who undergo a 120-minute cerebral angiogram
    • Rates of improvement in NIHSS of greater than or equal to 8 points at 30 and 90 days after alfimeprase dosing
    • Rate of achievement of mRS of 2 or less at 90 days after alfimeprase dosing
    • Rates of neurological benefit as assessed individually and by combined analysis of NIHSS, mRS, and BI at 30 and 90 days after alfimeprase dosing
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    TWO-STAGE
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    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 Yes
    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
    Legally acceptable representative can give written consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 104
    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 Decision2008-01-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-01-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2008-03-17
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