A Multi-centre Randomized, Placebo-controlled Trial of Mirabegron, a New beta3-adrenergic Receptor Agonist on Left Ventricular Mass and Diastolic Function in Patients With Structural Heart Disease
Phase: PHASE2
Conditions: Hypertrophy, Left Ventricular
Sponsor: Jean-Luc Balligand

 
The information provided in this document is confidential and is not to be circulated to third parties. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coordinating investigator 
Prof. Jean-Luc Balligand 
Full professor, Head of Department 
Pharmacology and Therapeutics (FATH) 
Avenue Mounier, 52, B1.53.09 
1200 Brussels, Belgium 
Phone: +32-2-7645260/+32-2-7645262 
Fax: +32-2-7645269 
Biometry 
Dr. Oana Brosteanu, Dr. Dirk Hasenclever 
Clinical Trial Centre Leipzig 
Universität Leipzig  
Härtelstraße 16-18,  
04107 Leipzig, Germany 
Phone: +49-341-97 16 250 
Fax: +49-341-97 16 189 
Sponsor 
UNIVERSITÉ CATHOLIQUE DE LOUVAIN 
PLACE DE L UNIVERSITE 1, 1348 LOUVAIN LA NEUVE, Belgium 
 
Date: November 3rd, 2016 
Version: Final 5.0 
EudraCT-Nr.: 2015‐003146‐75 
Clinical Trials.gov identifier: NCT02599480 
                              ISRCTN-Number: ISRCTN65055502 
 
Trial Protocol 
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 
 
BETA3_LVH 

 
 
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 Version 08 valid as of 01 January 2013 
 
Print:  [xxx] 
Written by/authors: 
 
Based on the protocol template from the Zentrum für 
Klinische Studien Leipzig - KKS. 

 
 
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Table of Contents 
 
 
 ........................................................................................................................ PAGE 
GENERAL INFORMATION .................................................................................................... 6 
Responsible Parties ............................................................................................................... 6 
Synopsis .............................................................................................................................. 10 
Schedule of Assessments and Procedures .................................. Erreur ! Signet non défini. 
1 
RATIONALE ......................................................... ERREUR ! SIGNET NON DEFINI. 
1.1 
Medical Background ....................................................... Erreur ! Signet non défini. 
1.2 
Rationale ........................................................................ Erreur ! Signet non défini. 
1.3 
Risk-Benefit Considerations ............................................ Erreur ! Signet non défini. 
2 
OBJECTIVES ....................................................... ERREUR ! SIGNET NON DEFINI. 
2.1 
Primary Objective ........................................................... Erreur ! Signet non défini. 
2.2 
Secondary Objectives ..................................................... Erreur ! Signet non défini. 
3 
TRIAL DESIGN AND DESCRIPTION ................... ERREUR ! SIGNET NON DEFINI. 
3.1 
Trial Design .................................................................... Erreur ! Signet non défini. 
3.2 
Requirements at the Trial Sites regarding Personnel and EquipmentErreur ! Signet 
non défini. 
3.3 
Trial Sites and Number of Trial Subjects ......................... Erreur ! Signet non défini. 
3.4 
Expected Duration of Trial .............................................. Erreur ! Signet non défini. 
3.5 
Premature Termination of the Trial ................................. Erreur ! Signet non défini. 
4 
TRIAL SUBJECTS ............................................... ERREUR ! SIGNET NON DEFINI. 
4.1 
Inclusion Criteria ............................................................. Erreur ! Signet non défini. 
4.2 
Exclusion Criteria ............................................................ Erreur ! Signet non défini. 
4.3 
Justification for the Inclusion of vulnerable Populations .. Erreur ! Signet non défini. 
4.4 
Participation in more than one Clinical Trial .................... Erreur ! Signet non défini. 
4.5 
Statement on the Inclusion of Dependent Individuals ...... Erreur ! Signet non défini. 
4.6 
Rationale for Gender Distribution .................................... Erreur ! Signet non défini. 
5 
INVESTIGATIONAL PRODUCT ........................... ERREUR ! SIGNET NON DEFINI. 
5.1 
Trial Drugs ...................................................................... Erreur ! Signet non défini. 
5.2 
Packaging and Labelling of the Trial Drug ...................... Erreur ! Signet non défini. 
5.3 
Drug Accountability ......................................................... Erreur ! Signet non défini. 
5.4 
Administration of the Study Drug .................................... Erreur ! Signet non défini. 
5.5 
Blinding and Unblinding .................................................. Erreur ! Signet non défini. 
6 
INDIVIDUAL TRIAL PROCEDURES .................... ERREUR ! SIGNET NON DEFINI. 
6.1 
Patient Information and Informed Consent ...................... Erreur ! Signet non défini. 
6.2 
Enrolment in the Trial ...................................................... Erreur ! Signet non défini. 
6.3 
Description of the Treatment Procedures ........................ Erreur ! Signet non défini. 
6.4 
Premature Termination of the Therapy for Individual PatientsErreur ! Signet non 
défini. 
6.5 
Premature study termination for individual patients ......... Erreur ! Signet non défini. 
6.6 
Plan for Further Treatment .............................................. Erreur ! Signet non défini. 
7 
METHODS OF DIAGNOSTICS AND DATA SAMPLINGERREUR ! SIGNET NON 
DEFINI. 
8 
ADVERSE EVENTS (AE/SAE) ............................. ERREUR ! SIGNET NON DEFINI. 
8.1 
Adverse Events (AE) ...................................................... Erreur ! Signet non défini. 

 
 
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8.2 
Safety Analysis ............................................................... Erreur ! Signet non défini. 
8.3 
Concomitant Diseases .................................................... Erreur ! Signet non défini. 
8.4 
Serious Adverse Events (SAE) ....................................... Erreur ! Signet non défini. 
8.5 
Periodic Reports ............................................................. Erreur ! Signet non défini. 
8.6 
Suspected Unexpected Serious Adverse Reactions (SUSAR)Erreur ! Signet non 
défini. 
8.7 
Other Safety Relevant Issues ......................................... Erreur ! Signet non défini. 
8.8 
Therapeutic Procedures.................................................. Erreur ! Signet non défini. 
8.9 
Dealing with Pregnancy .................................................. Erreur ! Signet non défini. 
9 
BIOMETRY........................................................... ERREUR ! SIGNET NON DEFINI. 
9.1 
Biometrical Aspects of the Trial Design ........................... Erreur ! Signet non défini. 
9.2 
End Points ...................................................................... Erreur ! Signet non défini. 
9.3 
Statistical Description of the trial hypothesis ................... Erreur ! Signet non défini. 
9.4 
Sample Size Discussion ................................................. Erreur ! Signet non défini. 
9.5 
Statistical Methods .......................................................... Erreur ! Signet non défini. 
9.6 
Statistical Monitoring ....................................................... Erreur ! Signet non défini. 
9.7 
Interim Analysis .............................................................. Erreur ! Signet non défini. 
9.8 
Final Analysis ................................................................. Erreur ! Signet non défini. 
10 
CONCOMITANT SCIENTIFIC PROJECTS .......... ERREUR ! SIGNET NON DEFINI. 
10.1 
Endothelial Function/Pulse amplitude tonometry and measurement of HbNO Erreur ! 
Signet non défini. 
10.2 
Abundance/activity of brown/beige fat ............................. Erreur ! Signet non défini. 
10.3 
Analysis of blood and urine samples for scientific purposes related to cardiac disease
 ....................................................................................... Erreur ! Signet non défini. 
11 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTSERREUR ! SIGNET NON 
DEFINI. 
11.1 
GCP-Statement .............................................................. Erreur ! Signet non défini. 
11.2 
Initial Submission ............................................................ Erreur ! Signet non défini. 
11.3 
Protocol Amendments .................................................... Erreur ! Signet non défini. 
12 
DOCUMENTATION .............................................. ERREUR ! SIGNET NON DEFINI. 
12.1 
Case Report Forms (CRF) .............................................. Erreur ! Signet non défini. 
12.2 
Data Management .......................................................... Erreur ! Signet non défini. 
12.3 
Archiving ......................................................................... Erreur ! Signet non défini. 
13 
SUPERVISION OF THE CLINICAL TRIAL .......... ERREUR ! SIGNET NON DEFINI. 
13.1 
Access to Source Data ................................................... Erreur ! Signet non défini. 
13.2 
Monitoring ....................................................................... Erreur ! Signet non défini. 
13.3 
Audits ............................................................................. Erreur ! Signet non défini. 
13.4 
Inspections ..................................................................... Erreur ! Signet non défini. 
13.5 
Independent Supervision of the Trial .............................. Erreur ! Signet non défini. 
14 
DATA PROTECTION AND CONFIDENTIALITY .. ERREUR ! SIGNET NON DEFINI. 
14.1 
Declaration regarding Data Protection ............................ Erreur ! Signet non défini. 
14.2 
Declaration regarding the Pseudonymized Transfer of Personal DataErreur ! Signet 
non défini. 
15 
ADMINISTRATIVE AGREEMENTS ..................... ERREUR ! SIGNET NON DEFINI. 
15.1 
Adherence to the Protocol .............................................. Erreur ! Signet non défini. 
15.2 
Funding and Insurance ................................................... Erreur ! Signet non défini. 
15.3 
Notification of the Local Authorities (Germany only) ........ Erreur ! Signet non défini. 
15.4 
Publication Policy and Registration ................................. Erreur ! Signet non défini. 

 
 
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16 
REFERENCES ..................................................... ERREUR ! SIGNET NON DEFINI. 
17 
PROTOCOL SIGNATURES ................................. ERREUR ! SIGNET NON DEFINI. 
18 
PROTOCOL AGREEMENT .................................. ERREUR ! SIGNET NON DEFINI. 
19 
APPENDIX ........................................................... ERREUR ! SIGNET NON DEFINI. 
19.1 
Classification of Adverse Events ..................................... Erreur ! Signet non défini. 
19.2 
Definitions ....................................................................... Erreur ! Signet non défini. 
19.3 
Acronyms ....................................................................... Erreur ! Signet non défini. 
19.4 
Labelling ......................................................................... Erreur ! Signet non défini. 
 
 
List of Tables 
table 1: Schedule of Assessments and Procedures ...................... Erreur ! Signet non défini. 
 
List of Figures 
Figure 1: Flowchart of the trial ...................................................... Erreur ! Signet non défini. 
Figure 2: Sample of blister-label ................................................... Erreur ! Signet non défini. 
Figure 3: Sample of box-label ....................................................... Erreur ! Signet non défini. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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GENERAL INFORMATION 
Responsible Parties 
Sponsor  
(according to Belgian drug law) 
Université catholique de Louvain (UCL)  
Place de l’Université 1 
1348 Louvain la Neuve 
Belgium 
Authorised representative of the sponsor, Promotor: 
Prof. Jean-Luc Balligand 
Coordinating investigator(s) 
Prof. Dr. Jean-Luc Balligand 
Full professor, Head of Department 
Pharmacology and Therapeutics (FATH) 
Avenue Mounier, 52, B1.53.09 
1200 Brussels, Belgium 
Phone: +32-2-7645260/+32-2-7645262 
Fax: +32-2-7645269 
E-Mail: jean-luc.balligand@uclouvain.be 
Deputy of Coordinating 
investigator 
Anne-Catherine Pouleur  
Cliniques universitaires Saint-Luc 
Avenue Hippocrate, 10 
1200 Bruxelles, Belgique 
Phone: +32-2-764 28 12,  
Fax: +32-2-764 89 80  
E-Mail: anne-catherine.pouleur@uclouvain.be 
Project Management 
Dr Ir Nancy van Overstraeten 
UCL-FATH 
Institut de Recherche Expérimentale et Clinique (IREC) 
Building Vésale 5th floor ; 52 Avenue Mounier  
B1.53.09; 1200 Brussels; Belgium 
Phone: +32-2-764 52 88 
Fax: +32-2-764 5269 
E-Mail: nancy.vanoverstraeten@uclouvain.be 
 
Dr. Petra Neuhaus 
Zentrum für Klinische Studien Leipzig – KKS 
Universität Leipzig  
Härtelstraße 16-18, 04107 Leipzig, Germany 
Phone: +49 341 97 16255 
Fax: +49 341 97 16 16189  
E-Mail: petra.neuhaus@zks.uni-leipzig.de 
Pharmacovigilance 
Madlen Dörschmann 
Zentrum für Klinische Studien Leipzig – KKS 
Universität Leipzig  

 
 
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Härtelstraße 16-18, 04107 Leipzig, Germany 
Phone: +49 341 97 16129 
Fax: +49 341 97 16 16278  
E-Mail: madlen.doerschmann@zks.uni-leipzig.de 
Data Management 
Angelika Beyer 
Zentrum für Klinische Studien Leipzig – KKS 
Universität Leipzig  
Härtelstraße 16-18, 04107 Leipzig, Germany 
Phone: +49 341 97 16261 
Fax: +49 341 97 16259  
E-Mail: angelika.beyer@zks.uni-leipzig.de 
Biometry 
Dr. Oana Brosteanu 
Zentrum für Klinische Studien Leipzig – KKS 
Universität Leipzig  
Härtelstraße 16-18, 04107 Leipzig, Germany 
Phone: +49 341 97 16251 
Fax: +49 341 97 16189  
E-Mail: oana.brosteanu@zks.uni-leipzig.de 
 
Dr. Dirk Hasenclever 
Institut für Medizinische Informatik, Statistik und 
Epidemiologie 
Universität Leipzig  
Härtelstraße 16-18, 04107 Leipzig, Germany 
Phone: +49 341 97 16121 
Fax: +49 341 97 16109 
E-Mail: dirk.hasenclever@imise.uni-leipzig.de 
Monitoring 
Nicole Köppe-Bauernfeind 
Zentrum für Klinische Studien Leipzig – KKS 
Universität Leipzig  
Härtelstraße 16-18, 04107 Leipzig, Germany 
Phone: +49 341 97 16266 
Fax: +49 341 97 16259 
E-Mail: nicole.koeppe-bauernfeind@zks.uni-leipzig.de 
Funding 
EU 
Framework 
Programme 
for 
Research 
and 
Innovation, Horizon 2020: 
Mr. Grzegorz OWSIANIK  
 Marie-Christine Groenen 
Medical research and the challenge of ageing  
European Commission 
DIRECTORATE-GENERAL FOR RESEARCH & 
INNOVATION 
Medical research and the challenge of ageing 
Directorate Health 

 
 
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Mirabegron, Université catholique de Louvain 
B-1049 Brussels Belgium 
 
Phone: +32 22951192 
E-Mail: Grzegorz.OWSIANIK@ec.europa.eu  
Marie-Christine.Groenen@ec.europa.eu 
Data Safety and Monitoring Board 
Organisation: 
Prof. Dr. Stefan Anker 
Charité - Universitätsmedizin Berlin 
Campus Virchow-Klinikum 
Augustenburger Platz 1,  
13353 Berlin, Germany  
Phone: +49 (0) 30-450 553463 
Fax: +49 (0) 30-450 553951 
E-Mail: s.anker@cachexia.de 
 
Chair:  
Karl Swedberg, Prof. MD 
Department of Molecular and Clinical Medicine, 
Sahlgrenska Academy, University of Gothenburg, 
Sweden, and National Heart and Lung Institute, Imperial 
College, London, UK 
E-mail: karl.swedberg@gu.se 
 
Members: 
Dan Atar, MD, FESC, FACC, FAHA 
Professor of Cardiology 
Head of Research, Div. of Medicine 
Oslo University Hospital, Ullevål 
Kirkeveien 166, Building 3-A 
N - 0407 Oslo - Norway  
Ph: + 47 22 11 91 00  
Email W: dan.atar@ous-hf.no   
Email H: dan.atar@online.no   
 
Luigi Tavazzi, MD, FESC, FACC 
GVM Care and Research,  
E.S. Health Science Foundation, Maria Cecilia Hospital 
Via Corriera, 1  
48010 Cotignola (RA) - Emilia-Romagna 
Italy 
E-mail: 
'Elisa 
Ghizzardi 
GVM 
Care&Research' 
<direzionescientifica-mch@gvmnet.it> 
 
Hans Wedel 
KB Biostatistics 
Apelsingatan 115 

 
 
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Mirabegron, Université catholique de Louvain 
426 54 Västra Frölunda 
Phone: 070-829 72 88 
E-mail : hans.wedel@biostat.se 
Concomitant scientific projects  
Endothelial Function/Pulse amplitude tonometry and 
measurement of HbNO: 
Dr Ignatios Ikonomidis,MD,PhD,FESC 
Assistant Professor, Member of EACVI 
Nucleus member of ESC WG Peripheral Circulation 
2nd Cardiology Department 
University of Athens 
Attikon Hospital 
Rimini 1, 12462 
Haidari, Greece 
E-mail: ignoik@otenet.gr,ignoik@gmail.com 
tel +30 6944805732 
fax +30 210 5832351 ,210 5832192 
 
Abundance/activity of brown/beige fat: 
Dr Renaud Lhommel (CUSL) 
Cliniques universitaires Saint-Luc 
Avenue Hippocrate, 55 bte B1.55.01 
1200 Bruxelles 
Belgique 
Phone: +32 2 764 25 82 
Fax: +32 2 764 16 02 
E-Mail: renaud.lhommel@uclouvain.be 
 

 
 
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Synopsis 
 
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. 
Acronym 
BETA3_LVH 
Indication 
Structural heart disease at high risk for progressive hypertrophic 
cardiac remodeling at risk of developing HFpEF (heart failure with 
preserved ejection fraction). 
Primary goal of the trial / primary 
end point 
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). 
 
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. 
Secondary goals of the trial / 
secondary end points 
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).  
 
Secondary endpoints: 
• Further MRI endpoints (all measured in the central MRI core lab)  
- 
Cardiac fibrosis at baseline and at 12 months. Fibrosis is a 
key pathogenic mechanism of diastolic dysfunction, which is 
at the origin of HFpEF  
- 
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))  
- 
LV mass index (by cardiac MRI) at 6 months,  
- 
Diastolic function (E/e’) at 6 months;  
• Laboratory parameters at baseline and at 3, 6 and 12 months  
- 
serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)  
- 
metabolic parameters (fasting glucose, modified HOMA 
test, HbA1c, serum lipids)  
• Maximal exercise capacity (peak VO2) at baselineand 12 
months.  

 
 
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• Safety endpoints  
- 
Incidence, severity and frequency of adverse and serious 
adverse events  
- 
Mortality 
Trial design 
Two armed, prospective, randomized, placebo-controlled, multi-
centric international phase IIb trial  
Trial population 
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. 
 
Major 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:  
- current angina pectoris or  
- ischemia on stress test or  
- untreated coronary stenosis >50% or  
- history of acute myocardial infarction (AMI) or  
- coronary artery bypass graft (CABG, < than 3 months prior to 
screening) or  
- 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  

 
 
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• 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>450ms) 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 anemia (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 Erreur ! Source 
du renvoi introuvable.).  
• 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):   
- combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal) 
- progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, implantable)  
- intrauterine device (IUD) 

 
 
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- intrauterine hormone-releasing system ( IUS) 
- bilateral tubal occlusion 
- vasectomised partner 
- 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 
Sample size 
296 patients overall  
(148 patients per treatment arm) will be randomised  
Therapy 
Experimental group: 
Administration of 50 mg mirabegron once daily per os (Betmiga®, 
Astellas Pharma) over a period of 12 months. 
 
Control group: 
Administration of placebo once daily per os over a period of 12 
months.  
 
Verum and placebo will be manufactured by:  
Pharmacy of the University Hospital Leipzig 
Liebigstr. 20 
D-04103 Leipzig 
Biometry 
Primary endpoints: 
Confirmatory analysis follows the intention to treat principle as close 
as possible and will be based on the full analysis set.  
In each patient, the primary endpoints will be assessed thrice: at the 
baseline visit, and at the 6 months and 12 months visits. Analyses 
of both primary endpoints are identically structured: 
 
Mean changes from baseline mean will be analysed using a 
repeated measurement linear mixed model without intercept 
containing the fixed, categorical effects of  
• visit (baseline, 6 months, 12 months),  
• treatment (verum / placebo),  
• treatment by visit interaction 
• Atrial fibrillation (yes / no),  
• Diabetes mellitus (yes / no),  
as well as a patient-specific, visit random effect (3-dimensional 
normal with a general unstructured variance covariance matrix). 
 

 
 
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Secondary endpoints: 
All other MRI and echocardiographic endpoints as well as peak VO2 
will be analysed along the same lines as the primary endpoints. Time 
courses of metabolic parameters and specific biomarkers will be 
described.  
Adverse and serious adverse events will be compared by chi-square 
tests. Odds ratios with 95% confidence intervals will be provided. 
Trial Duration 
Individual treatment period: 
12 months treatment per patient with an additional follow-up-phone 
visit at month 13 
 
Trial:  
 
First patient in: April 2016 
 
Patient-screening and recruitment: 33 months 
 
Last patient out (planned): December 2019 
 
Final analysis (planned) December 2020