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The European Union Clinical Trials Register   allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   43614   clinical trials with a EudraCT protocol, of which   7207   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2013-000797-30
    Sponsor's Protocol Code Number:SPI-IIT-002
    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:2013-10-08
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2013-000797-30
    A.3Full title of the trial
    Inhibition of aldosterone to diminish diffuse myocardial fibrosis in atrial fibrillation
    Hæmning af aldosteron for reduktion af diffus fibrose i myokardiet hos patienter med aftrieflimren
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Suppression of the hormone aldosterone to diminish scar tissue in heart in patients with atrial fibrillation
    Hæmning af hormonet aldosteron til reduktion af arvævsdannelse i hjertemuskulaturen hos patienter med forkammerflimren
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberSPI-IIT-002
    A.5.4Other Identifiers
    Name:Amendment 3, protocol 3.0Number:SPI-IIT-002
    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 SponsorDepartment of Medical Research, Odense University Hospital, Svendborg Hospital
    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 supportDepartment of Medical Research, Odense University Hospital, Svendborg Hospital
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDepartment of Medical Research, Odense University Hospital, Svendborg Hospital
    B.5.2Functional name of contact pointDragana Rujic
    B.5.3 Address:
    B.5.3.1Street AddressValdemarsgade 53
    B.5.3.2Town/ citySvendborg
    B.5.3.3Post code5700
    B.5.4Telephone number+4563202402
    B.5.5Fax number+4563202407
    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 Yes
    D. name Spirix
    D. of the Marketing Authorisation holderTakeda Pharma A/S
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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.3.4Pharmaceutical 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 INNspironolactone
    D.3.9.3Other descriptive nameSPIRONOLACTONE
    D.3.9.4EV Substance CodeSUB10631MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Paroxysmal and persistent atrial fibrillation
    Paroksystisk og persisterende atrieflimren
    E.1.1.1Medical condition in easily understood language
    Intermittent atrial fibrillation
    Anfaldsvis forkammerflimren
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10071667
    E.1.2Term Persistent atrial fibrillation
    E.1.2System Organ Class 100000004849
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10066664
    E.1.2Term Recurrent symptomatic atrial fibrillation
    E.1.2System Organ Class 100000004849
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10003661
    E.1.2Term Atrial fibrillation paroxysmal
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate whether or not therapy with a mineralocorticoid receptor antagonist (MRA), in this case spironolactone, added to optimal medical treatment in normotensive or hypertensive patients with paroxysmal or persistent atrial fibrillation diminishes diffuse myocardial fibrosis in left atria and ventricle, atrial remodeling and thus improve left atrial function as compared with conventional treatment.
    At efterprøve hypotesen, at tillægsbehandling med et mineralocorticoid receptor antagonist, i dette tilfælde spironolacton, hos normotensive eller hypertensive patienter med paroksystisk eller persisterende atrieflimren vil reducere diffus myokardiefibrose i venstre atrium og ventrikel og forbedre venstre atriums funktion sammenlignet med konventionel behandling.
    E.2.2Secondary objectives of the trial
    To investigate whether or not add-on therapy with spironolactone reduces recurrent episodes of atrial fibrillation, health economics thus improves quality of life and decreses inflammatory and neurohumoral marksers in blood in patients with paroxysmal or persistent atrial fibrillation compared to usual care.
    At undersøge, hvorvidt tillægsbehandling med spironolacton hos patienter med paroksystisk eller persisterende atrieflimren reducerer antal tilbagevendende anfald af atrieflimren, sundhedsmæssige omkostninger følgelig forbedrer livskvalitet og reducerer biomarkører for inflammation og neurohumoral aktivitet sammenlignet med konventionel behandling.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Late gadolinium enhancement and modified look locker sequences for quantification of the effect of spironolactone on diffuse atrial and ventricular fibrosis in patients with atrial fibrillation. The CMR sub-study, version 2.0.
    The primary study objectives of this sub-study are:
    1. To detect and quantify the myocardial ECV as a surrogate for DMF in the left atrium and ventricle by T1 mapping using modified look locker sequences and late gadolinium enhancement technique.
    2. To measure volume and volume dynamics of the left atrium.
    T1 mapping på venstre atrium og ventrikel for at kvantificere myokardiets ekstracellulære matrix volumen (ECV) som surrogatmarkør for diffus myokardiefibrose ved hjælp af LGE og MOLLI sekvenser, bedømt ud fra CMR skanning.
    De primære endepunkter for dette sub-studie er:
    1. T1 mapping på venstre atrium og ventrikel ved hjælp af LGE teknik og MOLLI sekvenser.
    2. Volumen og ændringer i volumen svarende til venstre forkammer.
    E.3Principal inclusion criteria
    Patients ≥ 18 years of age, male or female.
    Signed written informed consent.
    Paroxysmal atrial fibrillation on one or more occasions, detected on 12-lead ECG or Holter monitoring with each AF-episode lasting ≥ 30 seconds, within the last 12 months prior to the screening visit, or persistent AF on one or more occasions that has been direct current (DC) cardioverted within the last 12 months prior to the screening visit.
    Patients with CHA2DS2-VASc score ≥ 1 will be encouraged to start anticoagulant treatment, but will not be excluded if there are reasonable reasons not to, i.e. risk of bleeding. Patients can choose between standard anticoagulation therapies, i.e. warfarin or non vitamin-K oral anticoagulants (NOAC) such as dabigatran, apixaban and rivaroxaban.
    Women with childbearing potency must use effective contraception (e.g. implants, hormonal depot injections, combined oral contraceptives, intra-uterine devices or vasectomized partner). Men enrolled in this study must agree to use adequate barrier birth control measures during the treatment period of the study. Reliable contraception should be maintained throughout the study and for 30 days after study drug discontinuation.
    Alder > 18 år.
    Underskrevet samtykkeerklæring.
    Mindst en episodermed EKG- eller Holterdokumenteret paroksystisk atrieflimren af mindst 30 sekunders varighed inden for de sidste 12 måneder eller mindst en episode med EKG- eller Holterdokumenteret persisterende atrieflimren inden for sidste 12 måneder.
    Fertile mænd og kvinder i den fødedygtige alder (< 2 år efter sidste menstruation for kvinder) skal anvende sikker antikonception i form af spiral, hormonel antikonception (p-piller, implantat, transdermal depotplaster, vaginalring eller depotinjektion), barrieremetode i kombination med sæddræbende creme eller kirurgisk sterilisation. Kvinder i den fødedygtige alder skal have negativ graviditetstest forud for indgåelse i forsøget.
    E.4Principal exclusion criteria
    Chronic atrial fibrillation.
    Previous radiofrequency ablation for atrial fibrillation or previous surgical treatment of atrial fibrillation, i.e. MAZE or His-ablation.
    Heart failure (New York Heart Association (NYHA) class ≥ II and/or LVEF less than 40%).
    Severe coronary artery disease (acute myocardial infarction within 6 months prior to the screening visit, previous coronary artery bypass graft (CABG) or stabile angina pectoris (Canadian Cardiovascular Society (CCS) class ≥II).
    Stroke or transient ischemic cerebral attack within 6 months prior to the screening visit.
    Pregnant women or women of childbearing potential not on adequate birth control. Only women with a highly effective method of contraception (oral contraception, intra-uterine device or sterile women) can be randomized.
    Presence of severe and hemodynamically significant valvular heart disease.
    Any disease that limits life expectancy to less than 1 year.
    Hepatic insufficiens classified as Child-Pugh B or C.
    Participation in another clinical trial, either within the last 30 days or ongoing.
    Breastfeeding women.
    Ongoing therapy with class IC antiarrhythmics (flecainide, propafenone), amiodarone, dronedarone or sotalol.
    Chronic or acute kidney disease (estimated glomerular filtration rate (eGFR) ≤ 45 ml/min/1,73m2 (4-variable MDRD equation)).
    Baseline serum potassium > 5,0 mmol/l.
    Intolerance or contradictions to spironolactone, i.e. latest product information on Spirix®.
    Intolerance or contradictions to dabigatran (Pradaxa®) i.e. latest product information.
    Patients who are noncompliant to the medical treatment.
    Atrial fibrillation that is associated with an acute reversible condition, i.e. heart surgery, untreated hyperthyroidism etc.
    Permanent (kronisk) atrieflimren.
    Patienter med hjerteinsufficiens i NYHA funktionsklasse II-IV og / eller venstre ventrikels uddrivningsfraktion (EF) mindre eller lig med 40 %.
    Patienter med atrieflimren, som må betragtes som værende sekundær og dermed reversibel, specielt thyreotoksikose, infektion, kirurgi, akut myokardieinfarkt, alkoholmisbrug, hjerte- eller lungekirurgi.
    Aktuel behandling med klasse IC- (flekainid, propafenon) eller klasse III antiarytmika (amiodaron og sotalol) inden for sidste 3 måneder.
    Kendte strukturelle hjerteanomalier, herunder hæmodynamisk betydende klapfejl.
    Angina pectoris vurderet ved CCS ≥ III.
    Ukontrolleret hypertension grad ≥ III til trods for adækvat antihypertensiv behandling.
    Patienter, som har fået foretaget radiofrekvensablation for atrieflimren.
    Tidligere MAZE-operation eller His-ablation grundet supraventrikulær arytmi.
    Patienter, som allerede er i behandling med en aldosteronantagonist, eller som har kontraindikationer mod denne behandling, herunder tendens til hyperkaliæmi (P-Kalium > 5,0 mmol/l).
    Nedsat nyrefunktion, herunder akutnyreinsufficiens, anuri, bilateral renal arteriel stenose og nefrotisk syndrom. Kronisk nyreinsufficiens ved eGFR ≤ 45ml/min/1,73 m2 eller P-kreatinin > 220 mikromol/l (beregnet vha. MDRD-formlen).
    Baseline P-kalium > 5,0 mmol/l eller P-natrium < 135 mmol/l.
    Uacceptable bivirkninger ved behandling med aldosteronantagonist, herunder hyperkaliæmi, gener fra gastrointestinalkanalen og gynækomasti.
    Deltagelse i et andet forsøg inden for 30 dage inden inklusion.
    E.5 End points
    E.5.1Primary end point(s)
    1. Myocardial extracellular volume (ECV) will be quantified as a surrogate for diffuse myocardial fibrosis in left atrium and ventricle by T1 mapping using modified look locker sequences (Siemens) and late gadolinium enhancement technique asserssed by cardiac magnetic resonanse (CMR).
    2. Function and volume dynamics of left atrium and ventricle will be assessed with CMR and speckle tracking, strain and strain rate on 2-dimensional (2D) and 3-dimensional (3D) transthoracic echocardiography.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. CMR will be assessed at the time of randomization and at 12 months.
    2. Transthoracic echocardiography: both two (2D) and three dimensional (3D) images will be assessed at the time of randomization and at 6 and 12 months.
    E.5.2Secondary end point(s)
    1. The burden of atrial fibrillation will be assessed as cumulative burden of atrial fibrillation, registered on 12-lead ECG recordings and serial longterm Holter monitoring, where a recurrent episode of atrial fibrillation is defined as atrial fibrillation ≥ 30 seconds of duration. Burden of atrial fibrillation will also include the total duration of atrial fibrillation, recorded on Holter monitoring.
    2. Health economics, including total number of hospitalizations, hospitalizations related to atrial fibrillation and the total duration of hospitalizations in days.
    3. Quality of life assessed with Short Form-12 (SF-12) questionnaire.
    4. Inflammatory, neurohumoral and potential markers of atrial fibrosis measured in blood. The following efficacy biomarkers will be measured: high-sensitivity C-reactive protein (hs-CRP), Thyroid Stimulation Hormone (TSH), Interleukin-6 (IL6), N-terminal pro-brain natriuretic peptide (NT-proBNP), Atrial (A-type) natriuretic peptide (pro-ANP), renin, Procollagen III N-terminal propeptide and fibulin-1. Blood samples measurements for safety will include measurement of potassium, sodium, creatinine and BUN.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. 7 days Holter monitoring will be performed at the time of randomization and at 6 and 12 months. 12-lead ECG will be performed at the time of randomization, at 1 week and subsequently at 1, 2,3,6,9 and 12 months. The study subjects patents will be encouraged to seek a doctor of choice in case of symptoms that might indicate recurrence of atrial fibrillation to assess a 12-lead ECG.
    2. Data will be collected thorughtout 12 months of follow-up period.
    3. SF-12 will be performed at baseline and at 12 months.
    4. Blood samples: blood samples measurements for biomarkers will be collected at the time of randomization and at 6 and 12 months. Blood samples measurements for safety will be collected at baseline, 1 week and 1, 2,3,6,9 and 12 months.
    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 Yes
    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. 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 trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    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 months5
    E.8.9.1In the Member State concerned 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: 40
    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 Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state150
    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)
    The subject will be informed whether or not he or shecould benefit from spironolactone supplementation in treatment of atrial fibrillation.
    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 Decision2013-10-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-03-26
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