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    Summary
    EudraCT Number:2018-001518-13
    Sponsor's Protocol Code Number:10407
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-08-01
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-001518-13
    A.3Full title of the trial
    Comparison between treatment with catheter ablation or anti-arrhythmic drugs (sotalol or combination of verapamil and flecainide) of patients with benign ventricular premature beats and ventricular tachycardia; a prospective, randomized, multicenter trial
    Vergelijking tussen behandeling met katheter ablatie of anti-arritmica (sotalol of combinatie verapamil met flecainide) van patienten met idiopathische premature ventriculaire complexen en ventriculaire tachycardieen, een prospectieve gerandomiseerde multicenter studie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Elimination of ventricular premature beats and ventricular tachycardia with catheter ablation versus optimal anti-arrhythmic drug treatment
    Eliminatie van premature ventriculaire complexen met catheter ablatie versus optimale medicamenteuze behandeling met anti-arritmica.
    A.3.2Name or abbreviated title of the trial where available
    ECTOPIA
    A.4.1Sponsor's protocol code number10407
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03845010
    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 SponsorMaatschap Cardiologie Zwolle
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIsala Zwolle
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIsala Zwolle
    B.5.2Functional name of contact pointD.M.Haanschoten
    B.5.3 Address:
    B.5.3.1Street AddressDokter van Heesweg 2
    B.5.3.2Town/ cityZwolle
    B.5.3.3Post code8025AB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031384243234
    B.5.6E-maild.m.haanschoten@isala.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    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 nameSotalol
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 RoleComparator
    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 Yes
    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 nameVerapamil
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    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 nameFlecainide
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Premature ventricular beats, ventricular ectopy, ventricle tachycardia
    Premature ventriculaire complexen, ventriculaire extrasystolen, ventriculaire tachycardie
    E.1.1.1Medical condition in easily understood language
    Premature cardiac beat
    Ventriculaire extrasystole (VES)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this study is to compare efficacy of antiarrhythmic drugs (sotalol or combination of flecainide and verapamil) and catheter ablation in reducing ventricular premature beats (VPB) burden in patients with symptomatic idiopathic VPB.
    Het doel van dit onderzoek is om twee verschillende antiarritmica soorten (sotalol en combinatie van flecainide/verapamil) en katheter ablatie te vergelijken in de effectiviteit om premature ventriculaire complexen (PVC's) te reduceren bij patienten met symptomatische ‘idiopathische ‘ PVC's.
    E.2.2Secondary objectives of the trial
    1. To explore the influence of different modulating factors on VPB/VT burden and response to treatment measured with change in absolute and relative VPB/VT burden and change in QoL and QALYs
    -Sympathetic drive, assessed by correlation between hourly VPB density and hourly HR during 24 hours ambulatory Holter monitoring
    -Gender differences in VPB/VT burden and response to different treatments
    -Effect of hormonal changes in women, by comparing VPB/VT burden and response to treatment in pre- and postmenopausal women.
    2.To evaluate safety of investigational treatments.
    -The rate of adverse events related to catheter ablation
    -The rate of pro-arrhythmic effects of treatment with sotalol or combination of flecainide/verapamil.
    -The rate of VPB/VT-induced CMP in our study population by early detection of subtle changes in left ventricular function with the use of global longitudinal strain (GLS)
    1. Het exploreren van de invloed van verschillende modulerende factoren in de PVC/VT burden en effectiviteit van de behandeling gemeten met verandering in absolute en relatieve VPB/VT-belasting en verandering in QoL en KWALY's
    - Sympathetische drive, door bepaling van de correlatie tussen aantal PVC/VTs per uur en hartfrequentie in 24 uur.
    -Verschillen tussen mannen en vrouwen wat betreft PVC/VT burden en effectiviteit van behandeling.
    -Invloed van oestrogeen door burden PVC/VTs te vergeleken tussen pre- en post menopausale vrouwen.
    2. Het evalueren van veiligheid van de behandelingen:
    -Percentage ‘adverse events’ die gerelateerd zijn aan catheter ablatie
    -Percentage arritmogene effecten van antiarritmica
    -Percentage PVC/VT-geinduceerde cardiomyopathieen door vroege detectie van subtiele veranderingen in de linkerventrikelfunctie (met behulp van onder andere global longituninal strain (GLS) bij echocardiografie).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Not yet defined
    Nog niet gedefinieerd
    E.3Principal inclusion criteria
    -Patients willing and capable to provide written informed consent
    -Patients with frequent symptomatic VPB/VT and/or nonsustained VTs with a burden of ≥ 5% on 24 hour Holter monitor AND
    -Absence of structural heart disease AND
    -Absence of underlying cardiac ischemia AND
    -Patient is considered an acceptable candidate for catheter ablation treatment with a
    dominant morphology of VPB/VT origin judged by the treating physician.
    -For those already undergoing treatment, all antiarrhythmic drugs including digitalis must be discontinued during a 2-
    week washout period before entry to the study
    - Patienten die informed consent willle en kunnen geven
    - Patienten met frequente symptomatische ventriculaire extrasystolen en/of non-sustained VTs met een minimale burden van 5% (op een 24-uur holter) EN
    -afwezigheid van structurele hartziekten EN
    -afwezigheid van onderliggende cardiale ischemie EN
    -De patient is een geschikte kandidaat voor katheter ablatie therapie met een dominante oorsprong van de ventriculaire extrasystolen, volgens de behandelend cardioloog
    -De patienten die al antiarritmica kregen (inclusief digitalis) moeten hiermee minstens 2 weken zijn gestopt vóór zij in de studie mogen.
    E.4Principal exclusion criteria
    -Age >75 years
    - Previous catheter ablation therapy for VPB/VT
    -Patients with sustained ventricular tachycardia or cardiac channelopathies (e.g. CPVT, long- or short QT syndrome, Brugada syndrome)
    -WPW syndrome
    - Use of medication with risk of QTc prolongation (e.g. antidepressant, antiemetic), except for study medication sotalol.
    - Left ventricular dysfunction (LV ejection fraction <55%)
    -Estimated glomerular filtration rate < 50 ml/min/1.73 m2
    -Hepatic impairment defined by a total bilirubin ≥ 2 times the upper limit (ULN) of normal ALAT or ASAT ≥ 3 times ULN at screening.
    -Untreated hypo- or hyperthyroidism or electrolyte imbalance
    - Untreated obstructive sleep apnea
    -Patients with history of myocardial infarction or bypass surgery
    - More than grade 1/3 valvular regurgitation and/or significant valve stenosis (moderate or severe)
    - ontraindication for any of the antiarrhythmic drugs used in this study
    - Enrolment in another clinical study
    - Woman currently pregnant or breastfeeding or not using reliable contraceptive measures during fertile age
    - Mental or physical inability to participate in the study
    -Life expectancy ≤ 12 months
    - Leeftijd <75 jaar
    - Eerdere catheter ablatie voor ventriculaire extrasystolen.
    - Patienten met sustained VT of aangeboren hartritmestoornissen (e.g. Catecholaminerge polymorfe VTs, long- or short QT syndroom, Brugada syndroom)
    - Wolf-parkinson-white syndrome
    - Gebruik van medicatie die de QTc tijd kan verlenen (vb. antidepressiva, anti-emeticum), met uitzondering van studiemedicatie sotalol
    - Linker ventrikel dysfunctie (ejectie fractie <55%)
    - eGFR (nierfunctie) < 50 ml/min/1.73 m2
    - Leverfunctiestoornissen, gedefinieerd als totale bilirubine ≥ 2 keer zo hoog als bovenste grenswaarde of ALAT of ASAT ≥ 3 keer de bovenste grenswaarde
    - Onbehandelde hypo- of hyperthyreoidie of elektrolyt stoornissen
    - Onbehandeld obstructief slaapapneu
    - Patienten die eerder een myocardinfarct of bypass chirurgie hebben ondergaan.
    - Matig of ernstig kleplijden.
    - Contraindicaties voor een van de antiarritmica in deze studie
    - Deelname in een ander medisch wetenschappelijk onderzoek
    - Een zwangere vrouw of een vrouw die borstvoeding geeft of geen betrouwbare anticonceptie gebruikt.
    - Mentaal/psychisch niet in staat deel te nemen aan een studie
    - Levensverwachting korter dan 12 maanden
    E.5 End points
    E.5.1Primary end point(s)
    Successful therapy, defined as >80 % reduction of VPB/VT burden and expressed in % of 24-hours ambulatory Holter monitoring period, after 3 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 months after start of treatment
    E.5.2Secondary end point(s)
    -QOL ranking using self-administered questionnaires in all patients, before (baseline) and after treatment (3 months, 6 months and 12 months)
    -Difference in VPB/VT burden at baseline between males and females and in females between pre- and postmenopausal women, expressed in % of 24 hour ambulatory Holter monitoring
    -Association between hourly VPB/VT density and hourly HR during 24-hours Holter- monitoring (VPB/VT frequency dependent on fast or slow HR or independent of HR) in all patients
    -Difference in VPB/VT burden reduction, expressed in % of 24-hours ambulatory Holter monitoring, after 3 months compared to 6 months in AAD arms.
    -Increase in VPB/VT burden with isoprenaline infusion during catheter ablation
    - Pro-arrhythmic effects, (non)-sustained VT or atrial flutter, in group A+ B with frequent visits and use of 24-hour Holter monitoring at 3 months, 6 months and 1 year
    -QTc prolongation (sotalol) and QRS broadening (flecainide) with requiring frequent checks with standard ECG and/or treadmill test 4-6 weeks after first administration of AAD.
    - Complication rate of catheter ablation in all patients with special interest to the subgroup of patients with anatomically challenging origin of (non-RVOT) VPB/VTs
    -Extended evaluation of left ventricular function with TTE (including global longitudinal strain rate measurement during sinus beats and during VPB/VT) at baseline and 12 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    Different time points, comparing baseline, 4-6 weeks, 3 months, 6 months and 1 year (*see E.5.2)
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Catheter Ablation
    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 concerned6
    E.8.5The trial involves multiple Member States No
    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 No
    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
    The last follow-up visit of the last patient
    De laatste follow-up visite van de laatste patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    E.8.9.2In all countries concerned by the trial months0
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state180
    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
    Nee
    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 Decision2018-08-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-12
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-01-17
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