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    Summary
    EudraCT Number:2011-004376-11
    Sponsor's Protocol Code Number:AZM-MD-302
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-05-16
    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 number2011-004376-11
    A.3Full title of the trial
    A Phase 3 Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Effects of Once-Daily Oral Doses of 75 mg Azimilide Dihydrochloride on the Incidence of Cardiovascular Hospitalizations/Emergency Department Visits or Cardiovascular Death in Patients with an Implantable Cardioverter Defibrillator
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of Azimilide Dihydrochloride given orally in patients with implantable defibrillators on the incidence of cardiovascular hospitializations/emergency room visit or cardiovascular death
    A.4.1Sponsor's protocol code numberAZM-MD-302
    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 SponsorForest Research Institute, 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 supportForest Research Institutue
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace Inc.
    B.5.2Functional name of contact pointMedpace Regulatory Submissions
    B.5.3 Address:
    B.5.3.1Street AddressGmunder Strasse 53
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code81379
    B.5.3.4CountryGermany
    B.5.4Telephone number4989895 57 180
    B.5.5Fax number4989895 571 81 00
    B.5.6E-mailregsubmissions@medpace.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 nameAzimilide Dihydrochloride
    D.3.4Pharmaceutical form 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.3.8INN - Proposed INNAZIMILIDE
    D.3.9.1CAS number 149908-53-2
    D.3.9.3Other descriptive nameAzimilide dihydrochloride
    D.3.9.4EV Substance CodeSUB05657MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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 placeboTablet
    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
    Ventricular arrhythmia in patients with implantable cardioverter-defibrillator (ICD)
    E.1.1.1Medical condition in easily understood language
    abnormal heartbeat in patients with defibrillator
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10047281
    E.1.2Term Ventricular arrhythmia
    E.1.2System Organ Class 10007541 - Cardiac disorders
    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 the impact of 75 mg azimilide versus placebo on the occurrence of unplanned (non-elective) cardiovascular hospitalizations, unplanned cardiovascular emergency department visits, or cardiovascular death in patients with an ICD. Analysis of efficacy will be done by comparing the effect of azimilide versus placebo on the time-to-first-occurrence of a qualifying event.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to determine whether treatment with 75 mg azimilide versus placebo in patients with an ICD:
    • Reduces the occurrence of all-cause shocks, as assessed by prolonging time-to-first event; and
    • Reduces unplanned physician-office visits that resulted in a change in therapy (reprogramming ICD or change in medication as it relates to ICD findings), as assessed by prolonging time-to-first event.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men or women at least 18 years of age with a left ventricular ejection fraction (LVEF) ≤ 40% as determined by echocardiography (ECHO), nuclear scan, left ventriculography, or cardiac magnetic resonance (CMR) imaging within 120 days
    prior to randomization;
    2. Have an ICD implanted that meets the following criteria:
    a. generates a biphasic waveform discharge;
    b. stores intracardiac electrograms;
    c. has both anti-tachycardia pacing and anti-bradycardia pacing capabilities;
    d. has a minimum of 2 anti-tachycardia detecting zones and a ventricular fibrillation zone; and
    e. has arrhythmia-discriminating algorithms (eg, high rate or sudden onset or rate stability).
    3. Patients who had their qualifying event before their first ICD implantation (“New ICD Patient”): must have had a documented episode of spontaneous sustained VT or VF (ventricular arrhythmia ≥ 150 bpm lasting at least 30 seconds or
    requiring intervention during the sustained VT), or cardiac arrest, or VF during the 42 days preceding their first ICD implantation and be randomized during the 60 days immediately following their OR
    4. Patients who had their qualifying event after their first ICD implantation or any subsequent re-implantation (“Existing ICD Patient”): must have had an ICD shock triggered by a spontaneous VT or VF after implantation and be randomized
    during the 180 days following this shock
    5. Must have their ICD programmed in the following manner:
    a. Antitachycardia pacing must be programmed “on” for all patients at the time of randomization (see exception in 4[b]).
    b. The device will be set for a minimum of 2 attempts of ATP in the lowest detection zone. Every attempt should be made to leave the ATP programmed “on” during the study unless, in the Investigator’s judgment, it is medically necessary to turn
    ATP “off.” If ATP is turned “off,” the reason must be recorded on the eCRF.
    c. The first shock will be delivered no lower than the lowest successful defibrillation energy at implantation or immediately before randomization.
    d. Programming of the ventricular tachycardia detection rate (the detection zone in which ATP will be given) should follow the parameters shown below, with adaptation dictated by the patient’s clinical condition and the Investigator’s judgment (VT = ventricular tachycardia):
    *If the slowest VT rate is ≤ 150 bpm, then the floor should be 10 bpm less than the VT rate and the ceiling should be 200 bpm
    *If the slowest VT rate is 151 to 194 bpm, then the floor should be 20 bpm less than the VT rate and the ceiling should be 200 bpm
    *If the slowest VT rate is ≥ 195 bpm or cardiac arrest with no documented VT rate, then the floor should be Ventricular rate: 175 bpm and the ceiling should be 200 bpm
    e. For dual chamber devices, at least 1 VT discriminator should be enabled (eg, for
    dual chamber devices, AV dissociation detection).
    5. Women who meet one of the following:
    a. Women of childbearing potential with a negative serum pregnancy test at
    screening who are not breast feeding, do not plan to become pregnant during the
    study, and agree to use one or more approved methods of birth control during the
    study as judged to be appropriate by the Investigator. Approved methods of birth
    control are: oral, patch, injectable, or implantable hormonal contraception;
    intrauterine device; diaphragm plus spermicide; or female condom plus
    spermicide. Abstinence, partner’s use of condoms, and partner’s vasectomy are
    not acceptable methods of contraception.
    b. Women who have been postmenopausal for at least 1 year (with amenorrhea for
    at least 1 year) or have had a hysterectomy, bilateral salpingo-oophorectomy, or
    tubal ligation at least 6 months prior to signing the informed consent.
    E.4Principal exclusion criteria
    1. Have New York Heart Association (NYHA) Class IV CHF or have decompensated CHF at the time of randomization;
    2. Have unstable angina pectoris or a myocardial infarction within 30 days of randomization;
    3. Have a history of Torsade de Pointes or heart transplantation;
    4. Have chronic atrial fibrillation or atrial fibrillation/flutter, that is not adequately rate-controlled in the judgment of the Investigator, at screening;
    5. Have an electrocardiogram (ECG) with a QTc value > 460 msec (with a QRS ≤ 120 msec), or a JTc value > 340 msec (with a QRS > 120 msec) (QT and JT intervals corrected by Bazett’s formula for heart rate) recorded during screening;
    6. Have abnormalities (at screening) in the following clinical laboratory parameters: creatinine > 2.5 mg/dL (221 μmol/L); serum alanine aminotransferase, aspartate aminotransferase, or gamma-glutamyltransferase ≥ 3 · upper limit of normal (ULN),
    or bilirubin ≥ 2 · ULN; potassium < 4.0 mEq or > 5.5 mEq, or magnesium below the lower limit of normal (potassium and magnesium levels can be adjusted back to normal range if judged by the Investigator, in consultation with the Study Medical Monitor, to be stabilized before randomization);
    7. Have an absolute neutrophil count (ANC) < 1000/μL prior to randomization;
    8. Are currently taking systemic Class I or other Class III antiarrhythmic drugs (must be off for ≥ 5 dosing-intervals prior to randomization), including but not limited to quinidine, procainamide, disopyramide, systemic lidocaine, phenytoin, mexiletine, dofetilide, ibutilide, dronedarone, propafenone, moricizine, ranolazine, and sotalol; see exclusion criterion 11 regarding amiodarone;
    9. Are currently taking systemic drugs that prolong the QT interval (must be off for 5 half-lives before dosing), including but not limited to clarithromycin, azithromycin, erythromycin, hydroxyzine, phenothiazines, and probucol;
    10. Are currently taking or have taken immune-modulating drugs (eg, azathioprine, methotrexate, tumor necrosis factor alpha modifying drugs, or similar drugs which could affect the immune system or white blood cells) within 90 days before randomization;
    11. Have taken oral amiodarone within 60 days before randomization or intravenous amiodarone within 14 days before randomization; or if amiodarone treatment (oral or IV) was ≤ 24 hours, have taken it within 5 days before randomization;
    12. Use ticlopidine 30 days before randomization;
    13. Have uncontrolled or untreated hypertension (systolic > 170 mm Hg, diastolic > 100 mm Hg). If a patient is receiving medical therapy for hypertension, his or her blood pressure should be stable for at least 1 week before randomization;
    14. If female, are currently pregnant or breast feeding, or plan to become pregnant during the course of the study;
    15. Have neoplasia, immune, infectious, or degenerative diseases that are likely to cause death or significant morbidity during the clinical study;
    16. Have a systemic disease that, in the opinion of the Investigator, could impact compliance or study results;
    17. Have qualifying ventricular fibrillation (episode that justified ICD implantation) during the acute phase (within 48 hours) of a myocardial infarction;
    18. Are taking an investigational new drug, or have participated in any investigational study (with an approved or non-approved drug) within 30 days of randomization;
    19. Have a non-approved ICD system (lead or generator);
    a. Have an ICD system (lead or generator) under current “recall” by the manufacturer; if a component of the ICD system is under “intensive monitoring”
    status by the manufacturer, the case should be discussed with the study’s medical monitor prior to randomization.
    b. Have an ICD pulse generator with a battery level of ERI (elective replacement indicator), EOL (end-of-life), or other indication of replacement need likely to occur in the 12 months following randomization.
    20. Have a current diagnosis of psychosis;
    21. Have known drug-induced organ toxicity;
    22. Evidence of active hepatic disease, or any of the following: positive human immunodeficiency virus antibodies, positive hepatitis C antibody, positive hepatitis B surface antigen;
    23. Use illicit drugs, or abuse alcohol (per Investigator’s judgment); or
    24. Are unwilling or unable to give or understand informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the time-to-first-event of unplanned cardiovascular hospitalizations, unplanned cardiovascular emergency department visits, or cardiovascular death.
    E.5.1.1Timepoint(s) of evaluation of this end point
    For the purposes of this study, cardiovascular events which trigger unplanned cardiovascular hospitalizations, unplanned cardiovascular emergency department visits are:
    • arrhythmias,
    • heart failure,
    • non-fatal cardiac arrest,
    • acute coronary syndrome,
    • cerebrovascular accident (except intracranial hemorrhage),
    • transient ischemic attack,
    • cardiovascular lightheadedness,
    • cardiovascular dizziness,
    • cardiovascular syncope, and
    • cardiovascular near-syncope.
    As part of the adjudication process, the CEC will classify cardiovascular events as arrhythmic or non-arrhythmic.
    E.5.2Secondary end point(s)
    Time-to-first all-cause shock; and

    Time-to-first unplanned physician-office visits that resulted in a change in therapy
    (reprogramming ICD or change in medication as it relates to ICD findings).
    E.5.2.1Timepoint(s) of evaluation of this end point
    unplanned cardiovascular hospitalization, unplanned cardiovascular emergency room department visit, or cardiovascular death, unscheduled ICD-related physician office visit, or end of study, or withdrawal
    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) 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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    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
    Australia
    Austria
    Belgium
    Canada
    Chile
    Czech Republic
    Denmark
    France
    Germany
    Hungary
    Israel
    Italy
    Netherlands
    New Zealand
    Poland
    Spain
    Sweden
    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
    LVLS
    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 months0
    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 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.1.2.1Number of subjects for this age range: 790
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 445
    F.4.2.2In the whole clinical trial 890
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will receive standard of care.
    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 Decision2012-05-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2013-06-14
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