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    Summary
    EudraCT Number:2007-004953-27
    Sponsor's Protocol Code Number:CV185-057
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-06-27
    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 ConcernedUK - MHRA
    A.2EudraCT number2007-004953-27
    A.3Full title of the trial
    A SAFETY AND EFFICACY TRIAL EVALUATING THE USE OF APIXABAN FOR THE EXTENDED TREATMENT OF DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
    (Apixaban after the initial Management of PuLmonary embolIsm and deep vein thrombosis with First-line therapY- EXTended treatment. The AMPLIFY-EXT study)
    Revised Protocol 03 (version 5.0 dated 18-Apr-2011) incorporating
    Amendment 05 (version 1.0 dated 18-Apr-2011)
    + Protocol Amendment 01 (version 1.0 dated 21-Apr-08) Site-specific - Molecular Profiling Supplement Samples For Pfizer’s Exploratory Research Biobank
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and Safety Study of Apixaban for Extended Treatment of Deep
    Vein Thrombosis or Pulmonary Embolism
    A.4.1Sponsor's protocol code numberCV185-057
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00633893
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBristol-Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    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 supportBristol-Myers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol-Myers Squibb International Corporation
    B.5.2Functional name of contact pointEU Start Up Unit/Attn: Dept Manager
    B.5.3 Address:
    B.5.3.1Street Addressavenue de Finlande, 8 - Parc de l'Alliance
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailclinical.trials@bms.com
    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 nameApixaban
    D.3.2Product code BMS-562247-01
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 503612-47-3
    D.3.9.2Current sponsor codeBMS-562247-01
    D.3.9.3Other descriptive nameApixaban
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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.IMP: 2
    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 nameApixaban
    D.3.2Product code BMS-562247-01
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 503612-47-3
    D.3.9.2Current sponsor codeBMS-562247-01
    D.3.9.3Other descriptive nameApixaban
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Venous Thromboembolism (VTE)
    E.1.1.1Medical condition in easily understood language
    Venous Thrombosis
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10037377
    E.1.2Term Pulmonary embolism
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10051055
    E.1.2Term Deep vein thrombosis
    E.1.2System Organ Class 10047065 - Vascular disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if at least one of the apixaban dose regimens is superior to placebo in the combined endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death in subjects who have an objectively documented index event of symptomatic proximal DVT or symptomatic PE, have completed approximately 6 to 12 months of anticoagulant therapy for the treatment of the index event, and have no objectively documented symptomatic recurrence of VTE after the index event.
    E.2.2Secondary objectives of the trial
    To characterize treatment effects of the two apixaban doses relative to placebo for the following:
    • adjudicated composite of recurrent symptomatic VTE or VTE-related death
    • adjudicated composite of recurrent symptomatic VTE or CV-related death
    • adjudicated symptomatic nonfatal DVT
    • adjudicated symptomatic nonfatal PE
    • adjudicated VTE-related death
    • adjudicated CV-related death
    • all-cause death
    • adjudicated major bleeding
    • the adjudicated composite of major bleeding and clinically relevant non-major bleeding

    To characterize the primary efficacy outcome in the subset of subjects with index events of DVT only and in the subset of subjects with index events of PE with or without DVT.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Signed Written Informed Consent

    2) Target Population
    a) Subjects who have:
    • an unprovoked index event OR a provoked index event with a risk for
    recurrence as described in the eligibility checklist.
    • an objectively documented index event of symptomatic proximal DVT or symptomatic PE;
    (1) Symptomatic proximal DVT is defined as symptomatic DVT with evidence of proximal thrombosis that involves at least the popliteal vein or a more proximal vein, demonstrated by imaging with compression ultrasound (CUS), including grey-scale or color-coded Doppler, or ascending contrast venography.
    (2) Symptomatic PE with evidence of thrombosis demonstrated by imaging as follows:
    - an intraluminal filling defect in segmental or more proximal branches on spiral CT scan; or
    - an intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram; or
    - a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS)
    completed approximately 6 to 12 months of standard anticoagulant therapy, or completed assigned CV185056 (AMPLIFY) study treatment, for the treatment of the index event; and
    • no objectively documented symptomatic recurrence of VTE after the index event.
    b) Subjects should be randomized within approximately 7 days of the last dose of their initial 6-to 12-month treatment. If a VKA was used as standard anticoagulant therapy, then an INR must be documented as 2 or less before randomization. If the subject received CV185056 (AMPLIFY) study treatment, then a blinded INR must be documented as 2 or less before randomization.
    Every attempt should be made to randomize subjects as soon as possible after discontinuation of their initial treatment.
    The index DVT and/or PE will be adjudicated by the ICAC according to the adjudication manual. Investigators are encouraged to assemble and to submit imaging dossiers to the ICAC as soon as possible during the period that extends from the beginning of the screening period up to 2 weeks after randomization.

    3) Age and Sex
    a) Men and women, ages 18 years or greater.
    Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized.
    E.4Principal exclusion criteria
    1) Sex and Reproductive Status
    a) WOCBP who are unwilling or unable to use an acceptable method of birth
    control to avoid pregnancy for the entire study
    b) Women who are pregnant or breastfeeding
    c) Women with a positive pregnancy test on enrollment or prior to investigational product administration

    2) Medical History and Concurrent Diseases
    a) Subjects with a provoked index event without the existence of a persistent risk factor for recurrence as described in the eligibility checklist.
    b) More than 12 months of anticoagulation planned for the most recent DVT or PE (index event).
    c) Subjects with indications for long-term treatment with a VKA, such as:
    • Mechanical valve
    • Atrial fibrillation or atrial flutter with moderate to high risk of systemic thromboembolism
    • Multiple episodes of unprovoked DVT or PE
    • Documented anti-phospholipid antibodies, anti-thrombin III deficiency, protein C deficiency, protein S deficiency, homozygous factor V Leiden, or homozygous prothrombin gene mutation.
    d) Subjects with cancer who will be treated indefinitely with anticoagulation therapy;
    e) Serious bleeding prior to randomization (see table under Protocol section 4.2.2 for exact timing of occurence resulting in subject exclusion from the study);
    f) Active and clinically significant liver disease (eg, hepatorenal syndrome);
    g) Life expectancy < 12 months;
    h) Bacterial endocarditis;
    i) Uncontrolled hypertension: systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg.

    3) Physical and Laboratory Test Findings
    a) Platelet count <100,000/mm3
    b) Hemoglobin <9 g/dL
    c) Serum creatinine >2.5 mg/dL [221 umol/L]
    d) Calculated creatinine clearance <25 ml/min (see Section 6.3.2.2.)
    e) ALT or AST >2 times upper limit of normal
    f) Total bilirubin >1.5 times upper limit of normal (unless an alternative causative factor is identified [eg, Gilbert’s syndrome]).

    4) Prohibited Treatments and/or Therapies
    a) Subjects requiring ASA >165 mg/day at randomization.
    b) Subjects requiring dual anti-platelet therapy (such as ASA plus clopidogrel or ASA plus ticlopidine) at randomization. Subjects who transition from dual anti-platelet therapy to monotherapy prior to randomization will be eligible for the trial
    c) Subjects who have used any oral direct factor Xa inhibitor, any oral direct thrombin inhibitor, or any investigational antithrombotic agent during the period between the onset of the index event to randomization. Subjects who participated in the CV185056 (AMPLIFY) study may participate in this study and are exempt from this exclusion (see Section 5.7)

    5) Other Exclusion Criteria
    a) Prisoners or subjects who are involuntarily incarcerated
    b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    c) Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of study treatment (with the exception of approved medications being used for an approved indication, eg, investigating a new dosing regimen for an approved indication).
    Subjects who participated in the CV185056 (AMPLIFY) study may participate in this study and are exempt from this exclusion (see Section 5.7)
    d) Any condition, which in the opinion of the investigator, would put the subject at an unacceptable risk from participating in the study; or
    e) Any other medical, social, logistical, or psychological reason, which in the opinion of the investigator, would preclude compliance with, or successful completion of, the study protocol
    E.5 End points
    E.5.1Primary end point(s)
    - The primary efficacy outcome is the incidence of an adjudicated
    composite of recurrent symptomatic VTE (nonfatal DVT and/or nonfatal
    PE) or all-cause death.
    - The primary safety outcome is the incidence of adjudicated major
    bleeding during the treatment period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    upon occurrence during study treatment
    E.5.2Secondary end point(s)
    Bleeding
    E.5.2.1Timepoint(s) of evaluation of this end point
    upon occurrence during study treatment
    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 No
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarker and Post-treatment Thromboembolic Events assessments
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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.8.2.4Number of treatment arms in the trial3
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA95
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Chile
    Hong Kong
    Israel
    Korea, Republic of
    Mexico
    Philippines
    Puerto Rico
    Russian Federation
    Singapore
    United States
    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
    Telephone follow-up call 30 days after final treatment visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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 No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 735
    F.4.2.2In the whole clinical trial 2430
    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 Decision2008-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-12-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-08-24
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