Assessment of efficacy of mirabegron, a new beta3-adrenergic receptor in the prevention of heart failure
| ISRCTN | ISRCTN65055502 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN65055502 |
| EudraCT/CTIS number | 2015-003146-75 |
| ClinicalTrials.gov number | NCT02599480 |
| Secondary identifying numbers | Beta3_LVH V1.0 |
- Submission date
- 28/10/2015
- Registration date
- 30/10/2015
- Last edited
- 11/10/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English Summary
Background and study aims
Heart failure (HF) is a medical condition caused by the heart not being able to pump enough blood around the body at the right pressure. Symptoms include breathlessness, feeling very tired and ankle swelling. Patients can be split into one of two groups, depending on the type of heart failure that they have. HF caused by the part of the heart that pumps blood around the body (left ventricle) becoming weak is called heart failure with left ventricular systolic dysfunction or heart failure with reduced ejection fraction (HFREF). Heart failure caused by the left ventricle becoming stiff, making it more difficult for the heart chamber to fill with blood is called heart failure with preserved ejection fraction (HFPEF). As HF is a progressive disorder increasing with age, the proportion of these patients is rising due to the aging of the population. Beside costs, HFPEF also puts a heavy burden on the quality of life of (mostly elderly) patients, with a loss of independence and repeated hospitalisations. Therefore, HFPEF is a chronic, costly, debilitating disease. A major contributor to HFPEF is myocardial (heart) remodelling, e.g. hypertrophy (abnormal growth of heart muscle) and fibrosis, as well as cellular functional/structural modifications leading to changes in how the heart contracts (contractile properties) and ventricular distensibility (distending of the left ventricle). Unfortunately, there are currently no evidence-based treatment strategies for this. This study will look at a novel therapeutic concept: β3AR activation to reduce/prevent cardiac remodeling. Recently, a new drug, called mirabegron has been developed and marketed for clinical use in overactive bladder disease. This study will test if the drug can also be used for the prevention of cardiac remodeling leading to HFPEF. Previous studies have shown that activation of β3AR reduces myocardial hypertrophy and fibrosis without affecting the function of the left ventricle. Therefore, the recent availability of this new drug offers the possibility to test the potential benefit of mirabegron as a therapy in addition to standard care (add-on therapy) to prevent/delay myocardial remodelling in patients at high risk of developing HFPEF.
Who can participate?
Patients with structural cardiac disease with or without HF symptoms.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in group 1 are given mirabegron. Those in group 2 are given a placebo. They are then all monitored for change in left ventricular mass (i.e. change in the size of the left ventricle) (assessed by MRI) and/or changes in diastolic function (loss of ventricle function) (assessed by echocardiography) over the next 12 months.
What are the possible benefits and risks of participating?
Benefits of taking part for participants include close monitoring and treatment of high blood pressure, according to most recent guidelines, as well as protection from the development of heart failure with preserved ejection fraction, a frequent form of heart failure in the targeted patient population. Possible risks are side effects of the test drug, mirabegron but previous studies have suggested that this risk is small.
Where is the study run from?
A total of 11 medical centres and university hospitals in Belgium, France, Germany, Greece, Portugal, Italy, Poland and the UK.
When is the study starting and how long is it expected to run for?
March 2016 to September 2022
Who is funding the study?
European Commission (Horizon 202 grant)
Who is the main contact?
1. Professor Jean-Luc Balligand (scientific)
2. Dr Christophe L. Depoix (public), christophe.depoix@uclouvain.be
Contact information
Scientific
UCL-FATH Tour Vésale 5th floor
52 Avenue Mounier B1.53.09
Brussels
1200
Belgium
Public
UCL-FATH Tour Vésale 5th floor
52 Avenue Mounier B1.53.09
Brussels
1200
Belgium
| Phone | +32 (0)2 764 5288 |
|---|---|
| christophe.depoix@uclouvain.be |
Study information
| Study design | Interventional prospective multi-centre randomized placebo-controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | 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 |
| Study acronym | Beta3_LVH |
| Study hypothesis | The primary objective is to evaluate the effect of mirabegron (a new β3-specific agonist) on top of standard treatment 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). |
| Ethics approval(s) |
Approved 16/03/2016, Le Comité d'Ethique Hospitalo-Facultaire Saint-Luc - UCL (Promenade de l’ Alma 51 bte B1.43.03, Brussels, 1200, Belgium; +32 2 764 55 14; comission.ethique-saintluc@uclouvain.be), ref: 2015/01DEC/655 |
| Condition | Structural heart disease (hypertrophic cardiac remodeling, stage B AHA) at high risk for developing HFpEF (heart failure with preserved ejection fraction). |
| Intervention | This is a two armed, prospective, randomized, placebo-controlled, multi-centric international phase IIb trial with placebo and mirabegron distributed in a 1:1 fashion. The patients enrolled will have cardiac structural remodeling with or without symptoms of heart failure (maximum NYHA II). Patients will be monitored for change in left ventricular mass (assessed by RMI) and/or changes in diastolic function (assessed by echocardiography) after 12 months of treatment. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Dose response |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Mirabegron |
| Primary outcome measure | 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: 1. 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 2. 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 outcome measures | Effect of mirabegron on other parameters of diastolic heart disease, i.e. cardiac fibrosis, left atrial volume index, diastolic function (E/e’), maximal exercise capacity and laboratory markers (analysed after 6 and 12 months of mirabegron treatment). 1. Further MRI endpoints (all measured in the central MRI core lab): 1.1. Cardiac fibrosis at baseline and at 12 months. Fibrosis is a key pathogenic mechanism of diastolic dysfunction, which is at the origin of HFpEF 1.2. 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)) 1.3. LV mass index (by cardiac MRI) at 6 months 1.4. Diastolic function (E/e’) at 6 months 2. Laboratory parameters at baseline and at 3, 6 and 12 months: 2.1. Serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT) 2.2. Metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids) 3. Maximal exercise capacity (peak VO2) at baseline, 6 and 12 months 4. Safety endpoints: 4.1. Incidence, severity and frequency of adverse and serious adverse events 4.2. Mortality |
| Overall study start date | 01/03/2016 |
| Overall study end date | 01/09/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 297 |
| Total final enrolment | 296 |
| Participant inclusion criteria | 1. Age between 18 and 90 years 2. Arterial hypertension on stable therapy according to current guideline algorithms (including stable medication for at least four weeks before inclusion) 3. Morphological signs of structural cardiac remodelling by echocardiography, i.e. increased LV mass index (110 g/m2 or higher for female; 134 g/m2 or higher for male subjects (Devereux, Reichek 1977)) or end-diastolic wall thickness >13 mm in at least one wall segment 4. Patients may have atrial fibrillation (AF), but with well-regulated ventricular response, i.e. heart rate<100/min at inclusion (RACE II - (Groenveld et al. 2013, 2013)) 5. Written informed consent 6. 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 |
| Participant exclusion criteria | 1. Unstable 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, which should be stabilized for at least four weeks before inclusion. 2. Documented ischemic cardiac disease: 2.1. current angina pectoris or 2.2. ischemia on stress test or 2.3. untreated coronary stenosis >50% or 2.4. history of acute myocardial infarction (AMI) or 2.5. coronary artery bypass graft (CABG, < than 3 months prior to screening) or 2.6. percutaneous transluminal coronary angioplasty (PTCA) less than 3 months prior to screening. 3. History of hospitalization for overt heart failure within last 12 months 4. Patients after heart transplantation 5. Genetic hypertrophic or dilated cardiomyopathy 6. Dysthyroidism. 7. Severe valvulopathy (less than 1 cm2 aortic valve area or major mitral valve insufficiency at Doppler echocardiography) 8. NYHA-class > II 9. BMI > 40 kg/m2 10. EF < 50%, regardless of symptoms 11. 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 under regular treatment for at least one year before inclusion in the study 12. eGFR < 30 ml/min 13. Abnormal liver function tests (AST or ALT >2 X upper normal limit or GGT>3x upper normal limit) 14. Type I diabetes, complicated type II diabetes (i.e. with documented coronary macroangiopathy , cfr exclusion criterion 1 or documented other vascular complication) 15. Patients with anemia (male: Hb <130 g/l, female: Hb <120 g/l) 16. Patients with bladder outlet obstruction 17. Patients using antimuscarinic cholinergic drugs for treatment of OAB 18. Current use of digitalis, bupranolol, propranolol, nebivolol (known to interfere with β3AR signalling)* 19. Patients continuously treated with Sildenafil or other PDE5 inhibitors 20. Current use of antifungal azole derivatives (fluconazole, itraconazole, miconazole, posaconazole, voriconazole) (known inhibitors of CYP3A4, the main metabolizer of mirabegron) 21. Current treatment with mirabegron or indication for future treatment with mirabegron due to other indications 22. Contraindication for MRI (e.g. pacemaker, defibrillator, ferromagnetic devices or severe claustrophobia) 23. Pregnant or nursing women 24. Participation in any other interventional trial 25. Fertile women (within two years of their last menstruation) without appropriate contraceptive measures (hormonal implant, injections, oral contraceptives, intrauterine devices, partner with vasectomy) while participating in the trial (participants using a hormone-based method have to be informed of possible effects from the trial medication on contraception) 26. Contraindication to mirabegron (e.g. hypersensitivity) or any other components of the trial medication * Note: patients are allowed to take a β(1-2)-blocker, other than the drugs listed above |
| Recruitment start date | 01/03/2016 |
| Recruitment end date | 26/02/2021 |
Locations
Countries of recruitment
- Belgium
- England
- France
- Germany
- Greece
- Italy
- Poland
- Portugal
- United Kingdom
Study participating centres
Avenue Hippocrate, 10
Brussels
1200
Belgium
Lisbon
1649-028
Portugal
Athens
115 27
Greece
Berlin
10115
Germany
Wroclaw
50-981
Poland
Cologne
50937
Germany
Bergamo
24127
Italy
Nantes
44000
France
Robert-Koch-Straße 40
Göttingen
37099
Germany
Oxford
OX3 9DU
United Kingdom
Leipzig
04107
Germany
Sponsor information
University/education
Tour Vésale 5th floor
52 Avenue Mounier B1.53.09
Brussels
1200
Belgium
| Phone | +32 (0)2 764 5260 |
|---|---|
| jean-luc.balligand@uclouvain.be | |
"ROR" |
https://ror.org/02495e989 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- European Union, Comisión Europea, Europäische Kommission, EU-Kommissionen, Euroopa Komisjoni, Ευρωπαϊκής Επιτροπής, Европейската комисия, Evropské komise, Commission européenne, Choimisiúin Eorpaigh, Europskoj komisiji, Commissione europea, La Commissione europea, Eiropas Komisiju, Europos Komisijos, Európai Bizottságról, Europese Commissie, Komisja Europejska, Comissão Europeia, Comisia Europeană, Európskej komisii, Evropski komisiji, Euroopan komission, Europeiska kommissionen, EC, EU
Results and Publications
| Intention to publish date | 01/01/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Published as a supplement to the results publication |
| Publication and dissemination plan | We intend to publish a paper on the rationale and design of the study in the next few months, then at least 2-3 additional papers on the results at the end of the study In the meantime, we may communicate about the study at European Society of Cardiology meetings on the design and preliminary results. |
| IPD sharing plan | All data generated or analysed during this study will be included in the subsequent results publication |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 01/10/2018 | 05/06/2020 | Yes | No |
| Results article | 20/09/2023 | 06/10/2023 | Yes | No | |
| Protocol file | version 7.0 | 21/10/2019 | 11/10/2023 | No | No |
| Statistical Analysis Plan | version 7.0 | 21/10/2019 | 11/10/2023 | No | No |
Additional files
Editorial Notes
11/10/2023: The following changes were made:
1. Study protocol and SAP (not peer-reviewed) were added.
2. Dose response was added as a pharmaceutical study type(s)
06/10/2023: The following changes were made to the trial record:
1. The participant level data sharing statement was added.
2. Publication reference added.
08/09/2022: Intention to publish date added, contact details updated.
08/11/2021: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/10/2020 to 26/02/2021.
2. The overall trial end date was changed from 01/11/2021 to 01/09/2022.
3. Total final enrolment added.
10/08/2020: The recruitment end date was changed from 01/08/2020 to 01/10/2020.
05/06/2020: The following changes have been made:
1. The recruitment end date has been changed from 01/01/2019 to 01/08/2020.
2. The overall trial end date has been changed from 01/05/2020 to 01/11/2021.
3. University Hospital Leipzig has been added to the trial participating centres.
4. Publication reference added.
17/07/2019: ClinicalTrials.gov number added.
24/03/2016: Ethics approval information added.
