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    Summary
    EudraCT Number:2007-001723-36
    Sponsor's Protocol Code Number:D1250C0051
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-07-02
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2007-001723-36
    A.3Full title of the trial
    A controlled, randomized, parallel, multi-centre, feasibility study of the oral direct thrombin inhibitor AZD0837, given as extended-release formulation, in the prevention of stroke and systemic embolic events in patients with atrial fibrillation, who are appropriate for but unable or unwilling to take Vitamin-K antagonist therapy
    A.4.1Sponsor's protocol code numberD1250C0051
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 nameAZD0837
    D.3.4Pharmaceutical form Prolonged-release tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 631916-97-7
    D.3.9.2Current sponsor codeAZD0837 besylate
    D.3.9.3Other descriptive nameAR-H067639TM
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number198
    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 Information not present in EudraCT
    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 placeboProlonged-release 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
    This is a phase II study to evaluate the feasibility of conducting a study in patients with AF who are appropriate for, but unable or unwilling to take VKA therapy.


    The intended indication for the product under development is the prevention of stroke and other thromboembolic complicationds associated with atrial fibrillation (AF)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10003658
    E.1.2Term Atrial fibrillation
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to assess feasibility of conducting a study in patients with atrial fibrillation (AF), who are appropriate for but unable or unwilling to take Vitamin-K antagonist (VKA) therapy, by evaluation of drop-out rate and compliance with treatment and study procedures.
    E.2.2Secondary objectives of the trial
    To provide information on recruitment rate, expressed as number of randomised patients, in this patient population, with focus on the participating countries
    To provide dose-guiding information through evaluation of safety and tolerability of 2 dosing regimens of AZD0837 in relation to “standard therapy” according to local clinical practice (acetylsalicylic acid (ASA), clopidogrel or no therapy) in patients with AF, who are appropriate for but unable or unwilling to take VKA therapy
    To evaluate the pharmacokinetics of AZD0837, the intermediary metabolite (AR H069927XX) and the active form (AR H067637XX) with special regard to the variability in this patient population and the relationship between systemic plasma exposure of AR H067637XX and bleeding events by evaluation of pharmacokinetic variables of AZD0837, AR-H069927XX and AR H067637XX
    To evaluate the pharmacodynamic properties of AZD0837 in patients with AF who are appropriate for but unable or unwilling to take VKA therapy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Signed informed consent given by the patient before any study-specific procedures are initiated

    Paroxysmal, persistent or permanent NVAF verified by at least 2 ECGsa in the last year separated by at least one weekb; for:
    - Newly diagnosed patients: the second ECG should be carried out within the 2 weeks prior to randomization
    - Other patients: the second ECG should be carried out within the 12 weeks prior to randomization
    a Clarification:
    ECG verification can be done by 12 lead ECG, 24 hour Holter monitoring or event recording of good quality, but not via pacemaker. Thus, paroxysmal AF can be defined by 2 or more episodes of AF (lasting >30 seconds) on a single 24 hour Holter performed within 3 months of randomisation.
    b Clarification:
    In 'high risk' AF patients not on VKA treatment, the one week gap between the 1st and 2nd ECGs [which should still be on separate days] is not mandatory, if local clinical practice requires initiation of antithrombotic therapy as soon as possible. The second ECG should still be carried out within the 2 weeks prior to randomisation.

    In addition to AF the patient must have the following risk factors
    Either one of the following risk factors is sufficient for inclusion (high risk patient):
    - Previous cerebral ischaemic attack (stroke or transient ischaemic attack (TIA), >30 days prior to randomization)
    - Previous systemic embolism
    or at least one of the following risk factors are needed for inclusion (1 risk factor = moderate risk patient, 2 or more risk factors = high risk patient):
    - Age ≥75 years
    - Symptomatic congestive heart failure
    - Impaired left ventricular systolic function
    - Diabetes mellitus
    - Hypertension requiring anti-hypertensive treatmentc
    c Hypertensive patients who are enrolled and randomized into the study should be well controlled and have antihypertensive treatment aiming for a blood pressure <160/100 mmHg.

    In addition to AF the patient must be appropriate for but unable or unwilling to take VKA therapy by fulfilling at least one of the following criteria
    - In hospital records, documented inability to keep International normalized ration (INR) levels within 2.0 to 3.0 during a continuous and recent period of at least 3 months, leading to the conclusion that VKA therapy does not offer an adequate level of benefit vs. risk, in the specific patientd, e.
    - Permanent cessation or refusalf by the patient to take VKA therapy due to reasons specified in hospital records present, recorded no later than one month before start of the study.
    - Refusal to participate in study D1250C00008 due to the possibility of being randomized to VKA treatmentd. For VKA naïve patients this must have been stated in the hospital records at least 1 week in advance of enrolment in the study.
    - Treating physician’s assessment that VKA is inappropriate for this patient recorded no later than one month before start of this studyd.
    - Allergic reactions to VKA as documented in hospital recordsf.
    d Reason must be stated in the hospital records and in the pCRF.
    e INR must be <2 at randomization.
    f Reason must be stated in the pCRF.
    E.4Principal exclusion criteria
    Aged <18 years at randomization

    Weight <50 kg at enrolment

    Lactation; child-bearing potential, ie, women must be either post-menopausal, permanently sterilised or, if of child-bearing potential, must have a negative pregnancy test prior to initiation of study drug and use a reliable form of contraception before and during participation in the study.
    - Post menopausal patients are defined as patients with: natural or induced menopause with last menstruation >1 year ago or bilateral oophorectomy.
    - Reliable form of contraception is defined as: oral contraceptive, implant, long term injectable contraceptive, intrauterine device or tubal ligation. However, female patients using hormonal anti conception method (oral, transdermal, vaginal ring or combination injectables) must agree to use an additional barrier method for contraception (condom or diaphragm).

    Atrial fibrillation secondary to reversible disorders, eg, hyperthyroidism, drugs and pulmonary embolism

    Presence of a clinically significant valvular heart disease, as well as mechanical heart valves, active endocarditis, left ventricular aneurysm or thrombus, atrial myxoma or any condition other than AF requiring chronic anticoagulation treatment

    Myocardial infarction, heart surgery (eg, coronary artery bypass graft) or percutaneous transluminal coronary angioplasty within the previous 3 months prior to randomization

    Stroke or TIA and/or systemic embolism within the previous 30 days prior to randomization

    Conditions associated with increased risk of major bleeding for example:
    - High risk of falling accident
    - High bleeding risk, exceeding possible benefit of the antithrombotic treatment
    - History of intracranial bleeding
    - History of bleeding gastrointestinal disorder and/or endoscopically verified ulcer disease within the last year prior to randomization
    - Major surgical procedure or trauma 2 weeks prior to randomization

    Diastolic blood pressure >100 mmHg or systolic blood pressure >180 mmHg with or without antihypertensive treatment

    Renal impairment (calculated creatinine clearance <30 ml/min)

    Known hepatic disease and/or ALAT >3 x ULN

    History or presence of infectious hepatitis (including known HbSAg positive or antibodies against Hepatitis C) or human immunodeficiency virus (HIV)

    Known Gilbert’s syndrome

    Anemia (Hb<100g/L = 6.2 mmol/L)

    Platelet count <100 x109/L

    Treatment with antiplatelet other than ASA or fibrinolytic agents within 10 days before randomization

    Planned cardioversion or surgery during the study

    Other serious disease that gives a calculated survival less than 12 months or any condition making a patient too frail to participate in the study

    Known drug addiction or alcohol abuse

    Inability to complete the study according to the protocol

    Previous enrolment or randomization of treatment in the present study. Participating in any other clinical study within 4 weeks (in UK within 12 weeks) prior to enrolment

    Treatment with AZD0837 in previous or ongoing AZD0837 study(ies)

    Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site)
    E.5 End points
    E.5.1Primary end point(s)
    Not applicable

    The primary variables in this study are:
    Drop Out,
    - defined as premature discontinuation of study drug, due to any reason
    - defined as premature discontinuation of study, due to any reason

    Compliance,
    - for AZD0837 patients: with regards to study drug, defined as how large percentage of the amount of study drug specified by the protocol that a patient has actually taken
    - for all patients: with regards to study visits, defined as how large fraction of the visits stipulated by the study protocol that the patient attended
    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 No
    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 Information not present in EudraCT
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Assess feasibility of conducting a trial in 'VKA non-taker' AF patients
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Patients will be blinded to doses of AZD0837
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    End of study is defined as date of database lock, after this time no patient will be exposed to study-related activities.
    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 months6
    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 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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 150
    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 Decision2007-07-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-08-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2008-11-27
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