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    Summary
    EudraCT Number:2018-004445-17
    Sponsor's Protocol Code Number:AP30663-2001
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-06-03
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2018-004445-17
    A.3Full title of the trial
    A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group Study
    of AP30663 Given Intravenously for Cardioversion in Patients with
    Atrial Fibrillation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group Study
    of AP30663 Given Intravenously for Cardioversion in Patients with
    Atrial Fibrillation
    A.4.1Sponsor's protocol code numberAP30663-2001
    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 SponsorAcesion Pharma ApS
    B.1.3.4CountryDenmark
    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 supportAcesion Pharma ApS
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcesion Pharma ApS
    B.5.2Functional name of contact pointChristina Sylvest
    B.5.3 Address:
    B.5.3.1Street AddressOle Maaløes Vej 3
    B.5.3.2Town/ cityCopenhagen N
    B.5.3.3Post codeDK-2200
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4520553877
    B.5.5Fax number----
    B.5.6E-mailcsy@acesionpharma.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.3.2Product code AP30663
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNAP30663
    D.3.9.2Current sponsor codeAP30663
    D.3.9.3Other descriptive nameAPUS0894
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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 placeboSolution for 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
    Atrial Fibrillation
    E.1.1.1Medical condition in easily understood language
    atrial fibrillation (abnormal heart rhythm that can increase risk of stroke, heart failure, and other heart-related complications)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10003658
    E.1.2Term Atrial fibrillation
    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 the study is to demonstrate efficacy of AP30663 on the basis of the ability to convert AF following intravenous administration.
    E.2.2Secondary objectives of the trial
    • To study the stability of rhythm control (immediate relapse of AF [IRAF], i.e. within 5 min after conversion from AF).
    • To study the importance of AF duration with respect to the efficacy and safety of AP30663.
    • To evaluate the safety and tolerability of one or more dose levels of AP30663.
    • To study the relationship between systemic exposure and response, with special regard to the conversion from AF and the effect on QRS and QTcF.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for study entry, patients must satisfy all of the following criteria:
    1. Provision of written informed consent.
    2. Clinical indication for cardioversion of Atrial Fibrillation (AF).
    3. Current episode of symptomatic AF lasting between 3 h and 7 days inclusive at randomisation.
    4. Adequate anticoagulation according to international and/or national guidelines.
    5. Body weight 50 to 110 kg inclusive (with clothes, without shoes).
    6. Male patients and postmenopausal women aged 18 to 80 years inclusive.
    - Male patients who are sexually active must agree to abstain from sexual activity or be willing to use a double-barrier method of birth control (i.e., any double combination of male or female condom with spermicidal gel, diaphragm, sponge or cervical cap with spermicidal gel) if they become sexually active from the time of consent and for 90 days after the infusion day.
    - Post-menopausal women are defined as being >12 months after last menstrual period.
    - Women can also be included if permanently sterilised since ≥6 weeks (i.e. documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy). Breastfeeding women are excluded.
    E.4Principal exclusion criteria
    1. Significant clinical illness or surgical procedure within 4 weeks preceding the screening visit.
    2. Present renal dysfunction (estimated glomerular filtration rate [eGFR]< 30 mL/min), hepatic dysfunction (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 3 × upper limit of normal), or uncontrolled hyperthyroidism or hypothyroidism.
    3. History of significant mental, renal or hepatic disorder, chronic obstructive pulmonary disease or other significant disease, as judged by the investigator.
    4. Any cardioversion attempt of AF or atrial flutter (AFl) within 4 weeks preceding randomisation.
    5. Prior failed attempt (no conversion) of pharmacological or DC cardioversion of previous or current AF episode.
    6. Failure to find a large antecubital (or equivalent) vein for the infusion.
    7. Any of the following events, or any other significant cardiovascular event as judged by the investigator, during the last 6 weeks before randomisation: myocardial infarction, unstable angina pectoris or other signs of myocardial ischaemia, stroke or transient ischaemic attack (TIA), myocardial revascularisation (percutaneous coronary intervention [PCI], coronary artery bypass graft [CABG]), or other revascularisation procedure.
    8. Haemodynamically unstable condition as judged by the investigator; systolic BP <90 mmHg or >180 mmHg, or diastolic BP >105 mmHg at randomisation.
    9. Blood haemoglobin <100 g/L at screening.
    10. Congestive heart failure New York Heart Association class III or IV. Left ventricular ejection fraction <40% on echocardiography, or other clinically significant abnormality on the echocardiogram (not older than 6 months) as judged by the investigator.
    11. Known hypertrophic cardiomyopathy or significant left ventricular hypertrophy (free wall or septal thickness >13 mm).
    12. Any clinically significant valvular heart disease.
    13. History or previous signs of sinus nodal disease, including sinus bradycardia <50 beats per minute (bpm).
    14. Pacemaker or implantable cardioverter defibrillator (ICD) therapy.
    15. Personal or family history of Torsades de Pointes, any other polymorphic ventricular tachycardia, sustained ventricular tachycardia, long QT syndrome, and/or Brugada syndrome.
    16. QTc (Fridericia, QTcF) interval >450 ms at randomisation. (When measured during AF, the mean heart rate should be 50 to 100 bpm. The QTcF should be calculated at AF as the mean of at least 5 consecutive RR intervals with consecutive QT intervals).
    17. QRS duration >120 ms at randomisation.
    18. Known atrioventricular (AV)-block I (prolonged PQ [PR] interval >220 ms), AV-block II, AV-block III, or complete bundle branch block (BBB), or a ventricular rate <60 bpm during AF.
    19. Potassium in serum or plasma below 3.5 or above 5.3 mmol/L at randomisation.
    20. Need for the use of loop diuretic from screening to the end of infusion.
    21. Previous or current use of any anti-arrhythmic drug class I and/or III for maintenance of SR.
    22. Use of digitalis glycoside, QT-prolonging drug, and/or drug that inhibits cytochrome P450 (CYP)3A4, as well as St John's Wort within 10 days before randomisation .
    23. Administration of an investigational drug within the preceding 3 months before randomisation.
    24. Administration of AP30663 at any time before randomisation.
    25. History of drug addiction and/or alcohol abuse within the last 12 months at the discretion of the investigator.
    26. Blood or plasma donation within the preceding 12 weeks before randomisation.
    27. Any suspected or manifested clinically significant infection as judged by the investigator.
    28. Involvement in the planning and conduct of the study (applies to Acesion Pharma staff, Syneos Health staff, and staff at the investigational site).
    29. Clinical judgement by the investigator that the patient should not participate in the study.
    30. Any malignant cancer within 5 years (except for successfully treated in-situ nonmelanoma skin cancer and in-situ cervical cancer) of signing the informed consent form (ICF).
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients who have converted from AF within 90 min from the start of infusion, and subsequently have no AF recurrence within 1 min of conversion from AF.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1
    E.5.2Secondary end point(s)
    Efficacy Endpoints:
    • The time to conversion from AF from start of infusion.
    • The proportion of patients with relapse of AF within 5 min (IRAF) following pharmacological or DC cardioversion.
    • The proportion of patients in SR at 3 h ± 1 h after start of infusion.
    • The proportion of patients in SR at 24 h after start of infusion.
    • The proportion of patients in SR at 30 days ± 5 days after start of infusion.
    Safety Endpoints
    • Adverse events (AEs), electrocardiogram (ECG) variables including significant arrhythmia, physical examination, vital signs, and laboratory evaluations.
    • Changes in QTcF interval data over time.
    PK Endpoints
    • Systemic exposure derived from the population PK model.
    • Population PK model parameter estimates derived from plasma concentrations of AP30663.
    Exploratory Endpoints
    • Correlation of drug exposure (plasma Cmax and area under the concentration time curve [AUC]) and the time of conversion.
    • Correlation of atrial size and conversion rate.
    • Correlation of atrial size to relapse or failure.
    • Correlation of gender and age and conversion rate.
    • Correlation of duration of current AF, conversion rate and duration of SR after conversion.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy Variables: timepoints are defined within the endpoint.
    Safety assessments: timepoints as outlined in the Schedule of Assessments in Section 8.1.2 of the protocol.
    Pharmacokinetic Variables: PK sampling will be taken at baseline (pre-infusion) and at the following time points after start of infusion: 5 min ± 1 min, 15 min ± 1 min, 25 min ± 1 min, 30 min - 1 min (the infusion will not be stopped before the 30-min plasma sample has been collected), 45 min ± 5 min, 1 h ± 5 min, 2 h ± 5 min, 4 h ± 5 min, 8 h ± 5 min, and 24 h ± 15 min. In the case of conversion from atrial fibrillation during infusion, an additional sample will be taken immediately after conversion.
    Exploratory Endpoints: timepoints are defined within the endpoint.
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 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 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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 No
    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 - "After completion of the study (end of study defined as the date of the last visit of the last patient)"
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days26
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days26
    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: 43
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 65
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state44
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 108
    F.4.2.2In the whole clinical trial 108
    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)
    None
    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 Decision2019-05-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-02
    P. End of Trial
    P.End of Trial StatusOngoing
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