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    Summary
    EudraCT Number:2015-003146-75
    Sponsor's Protocol Code Number:BETA3_LVH
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-03-16
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2015-003146-75
    A.3Full title of the trial
    A multi-centre randomized, placebo-controlled trial of mirabegron, a new beta3-adrenergic receptor agonist on the progression of left ventricular mass and diastolic function in patients with structural heart disease.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multi-centre placebo-controlled clinical trial, to show, if treatment with the drug tested (mirabegron, trade name of the finished medication: Betmiga®)‬‬‬‬‬ prevents/delays myocardial remodeling (thickening of the myocardial wall) in patients at high risk of developing diastolic heart failure (heart failure with preserved ejection fraction/HFpEF) due to their underlying structural heart disease.‬‬‬‬‬‬
    A.3.2Name or abbreviated title of the trial where available
    BETA3_LVH
    A.4.1Sponsor's protocol code numberBETA3_LVH
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN65055502
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02599480
    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 SponsorUniversité catholique de Louvain (UCL)
    B.1.3.4CountryBelgium
    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 supportEuropean Commission
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Leipzig, Clinical Trial Centre Leipzig - KKS
    B.5.2Functional name of contact pointDr. Petra Neuhaus
    B.5.3 Address:
    B.5.3.1Street AddressHaertelstr. 16-18
    B.5.3.2Town/ cityLeipzig
    B.5.3.3Post code04107
    B.5.3.4CountryGermany
    B.5.4Telephone number493419716255
    B.5.5Fax number493419716189
    B.5.6E-mailpetra.neuhaus@zks.uni-leipzig.de
    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.2.1.1.1Trade name Betmiga
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe BV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameMirabegron
    D.3.2Product code YM178
    D.3.4Pharmaceutical form Capsule, hard
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    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
    Structural heart disease at high risk for progressive hypertrophic cardiac remodeling at risk of developing HFpEF (heart failure with preserved ejection fraction).
    E.1.1.1Medical condition in easily understood language
    Structural heart disease: the walls of the heart thicken over time and this leads to a progressive loss of heart function (heart insufficiency).
    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 LLT
    E.1.2Classification code 10019290
    E.1.2Term Heart insufficiency
    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
    The primary objective is to evaluate the effect of mirabegron (a new β3-specific agonist) on change in left ventricular mass and/or changes in diastolic function after 12 months of treatment in patients with cardiac structural remodeling with or without symptoms of heart failure (maximum NYHA II).
    E.2.2Secondary objectives of the trial
    Effect of mirabegron on other indicators for diastolic heart disease, i.e. cardiac fibrosis, left atrial volume index, diastolic function (E/e’), maximal exercise capacity and laboratory markers (analysed after 6 or 12 months of mirabegron treatment).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Endothelial Function/Pulse amplitude tonometry and measurement of HbNO, to evaluate endothelial function and potentially yield a better stratification of patients at risk of endothelial dysfunction and HFpEF, beyond traditional cardiovascular risk factors.

    Abundance/activity of brown/beige fat: Brown fat is activated by and expresses beta3-AR, and mediates thermogenic lipolysis, with bearing on metabolism (fat depots, circulating lipids, glucose tolerance). Changes in brown fat under mirabegron will be correlated with metabolic parameters; improvement in the latter may also influence cardiac remodelling.
    E.3Principal inclusion criteria
    • • Age between 18 and 90 years
    • Morphological signs of structural cardiac remodelling by echocardiography, i.e. increased LV mass index (≥95 g/m2 or higher for female; ≥115 g/m2 or higher for male subjects (Ponikowski et al. 2016)) or end-diastolic wall thickness ≥13 mm in at least one wall segment
    • Written informed consent
    For subjects unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the subject has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the subject.
    E.4Principal exclusion criteria
    • Unstable arterial hypertension with systolic BP≥160 mm Hg and/or diastolic BP≥100 mm Hg (confirmed at three consecutive office measurements in sitting position); if so, the patient may be re-screened after optimization of anti-hypertensive treatment
    • Hypertensive patients not under stable therapy according to current guideline algorithm (Mancia et al. 2013) (including stable medication for at least 4 weeks before inclusion)
    • Documented ischemic cardiac disease:
    o current angina pectoris or
    o ischemia on stress test or
    o untreated coronary stenosis >50% or
    o history of acute myocardial infarction (AMI) or
    o coronary artery bypass graft (CABG, < than 3 months prior to screening) or
    o percutaneous transluminal coronary angioplasty (PTCA) less than 3 months prior to screening.
    • Patients with uncontrolled recurrent persistent and permanent atrial fibrillation (AF) according to AHA/ACC/ESC guidelines (Dixon et al. 2005) (with a heart rate > 100/min, RACE II - (Groenveld et al. 2013, 2013)). If AF with HR>100/min, the patient may be rescreened after treatment for rate control.
    • History of hospitalization for overt heart failure within last 12 months
    • History of high degree impulse conduction blocks (> 2nd degree AV block type 2)
    • Patients after heart transplantation
    • Genetic hypertrophic or dilated cardiomyopathy
    • Dysthyroidism
    • Severe valvulopathy (less than 1 cm2 aortic valve area, mitral insufficiency of severe grade at Doppler echo)
    • Congenital valvulopathies
    • Patients with a known history of QT prolongation (QT> 450 ms) (CHMP/ICH)) or patients with documented QT prolongation (QT> 450 ms)while taking medicinal products known to prolong the QT interval
    • NYHA-class > II
    • BMI > 40 kg/m2
    • EF < 50%, regardless of symptoms
    • Known other cause (i.e. COPD) of respiratory dysfunction; patients under positive pressure (CPAP) treatment for sleep apnea syndrome may be included, provided they have been efficiently controlled by CPAP for at least one year before inclusion in the study
    • Moderate renal impairment defined as eGFR < 30 ml/min
    • Abnormal liver function tests (AST or ALT >2 X upper normal limit or patients with known hepatic impairment defined as Child-Pugh class B or higher)
    • Type I diabetes, complicated type II diabetes (i.e. with documented coronary macroangiopathy , cfr exclusion criterion 1 or documented other vascular complication) (National Diabetes Education Initiative - NDEI).
    • Patients with anaemia (male: Hb <130 g/l, female: Hb <120 g/l)
    • Patients with bladder outlet obstruction
    • Patients using antimuscarinic cholinergic drugs for treatment of OAB
    • Current use of digitalis, bupranolol, propranolol, nebivolol (known to interfere with β3AR signalling)
    Note: patients are allowed to take a β(1-2)-blocker, other than the drugs listed above (for explanation, see chapter 5.4.5).
    • Patients continuously treated with Sildenafil or other PDE5 inhibitors.
    • Current use of antifungal azole derivatives (fluconazole, itraconazole, miconazole, posaconazole, voriconazole) (known inhibitors of CYP3A4, the main metabolizer of mirabegron)
    • Current treatment with mirabegron or indication for future treatment with mirabegron due to other indications
    • Contraindication for MRI (e.g. defibrillator, ferromagnetic devices or severe claustrophobia, pacemaker - the latter only, if MRI is contraindicated)
    • Pregnant or nursing women
    • Women of child bearing potential without highly effective contraceptive measures (Clinical Trial Facilitation Group (CTFG) 9/15/2014):
    o combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
    o progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
    o intrauterine device (IUD)
    o intrauterine hormone-releasing system ( IUS)
    o bilateral tubal occlusion
    o vasectomised partner
    o sexual abstinence (only if in agreement with the preferred and usual lifestyle of the subject)
    while participating in the trial. There are no known interactions of the trial medication and hormone-based methods of contraception. In particular, no clinically relevant interactions have been observed when mirabegron was co-administered with therapeutic doses of a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel.
    • Participation in any other interventional trial
    • Patients unable to give informed consent (people under legal guardianship)
    • Patients placed in an institution by official or court order
    • Contraindication to mirabegron (e.g. hypersensitivity) or any other components of the trial medication
    E.5 End points
    E.5.1Primary end point(s)
    Two equally ranked, primary endpoints:
    • Change in left ventricular mass index (LVMI in g/m2, defined as left ventricular mass divided by body surface) measured at baseline and 12 months after randomisation.
    • Change in diastolic function, assessed as the ratio of peak early transmitral ventricular filling velocity to early diastolic tissue Doppler velocity (E/e’) measured at baseline and 12 months after randomisation.
    E.5.1.1Timepoint(s) of evaluation of this end point
    In each patient, the primary endpoints will be assessed thrice: at the baseline visit, and at the 6 months (without exercise capacity) and 12 months visits. Analyses of both primary endpoints are identically structured
    E.5.2Secondary end point(s)
    Secondary endpoints:
    • Further MRI endpoints (all measured in the central MRI core lab)
    o Cardiac fibrosis at baseline and at 12 months. Fibrosis is a key pathogenic mechanism of diastolic dysfunction, which is at the origin of HFpEF
    o Left atrial volume index at baseline and at 12 months. This parameter determines diastolic filling (and was shown to predict treatment efficacy in HFpEF in the J-DHF trial (Yamamoto et al. 2013))
    o LV mass index (by cardiac MRI) at 6 months,
    o Diastolic function (E/e’) at 6 months;
    • Laboratory parameters at baseline and at 3, 6 and 12 months
    o serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)
    o metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids)
    • Maximal exercise capacity (peak VO2) at baselineand 12 months.
    • Safety endpoints
    o Incidence, severity and frequency of adverse and serious adverse events
    o Mortality
    E.5.2.1Timepoint(s) of evaluation of this end point
    baseline visit and at the 6 months (without exercise capacity) and 12 months visits
    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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    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 months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    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: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 176
    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 state33
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 296
    F.4.2.2In the whole clinical trial 296
    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, treatment ba 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 Decision2016-03-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-02-16
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