Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure
- Conditions
- Hypertrophy, Left Ventricular
- Interventions
- Procedure: EchocardiographyProcedure: Cardiac MRIProcedure: Maximal exercise capacityProcedure: Blood samplingProcedure: Endothelial function measurementRadiation: 18FDG-PET
- Registration Number
- NCT02599480
- Lead Sponsor
- Jean-Luc Balligand
- Brief Summary
This study will assess the efficacy of mirabegron, a new beta3-adrenergic receptor in the prevention of heart failure. This is a two armed, prospective, randomized, placebo-controlled, multi-centric european 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 cardiac MRI) and/or changes in diastolic function (assessed by echocardiography) after 12 months of treatment.
- Detailed Description
Background Heart failure (HF) represents a major and growing public health burden. Patients with HF are classically divided into two groups: those with HF with preserved ejection fraction (HFpEF), and those with HF and reduced ejection fraction (HFrEF). 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 autonomy and the dyscomfort of repeated hospitalisations. Therefore, HFpEF is a chronic, costly, debilitating disease.
A major contributor to HFpEF is myocardial remodelling, e.g. hypertrophy and fibrosis, as well as cellular functional/structural modifications leading to alteration in contractile properties and ventricular distensibility. Unfortunately, there are currently no evidence-based treatment strategies.
Study claim The proposed clinical trial will provide a proof of concept in humans for the clinical efficacy of a novel therapeutic concept: β3AR activation to attenuate/prevent cardiac remodeling. Recently, a new, specific agonist at human β3-AR (mirabegron) with higher benefit/risk balance was developed and marketed for clinical use in a non-cardiovascular disease (overactive bladder disease). The trial will test the drug repurposing of mirabegron for the prevention of cardiac remodeling leading to HFpEF.
Using pre-clinical models, the investigators demonstrated that activation of β3AR attenuates myocardial hypertrophy and fibrosis in response to neurohormonal or hemodynamic stresses, without compromising LV function. Therefore, the recent availability of this new drug offers the possibility to test the potential benefit of mirabegron (vs placebo) as add-on therapy (on top of standard care) 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 (max. NYHA 2).
What does the study involve? Patients will be requested to go 5 times to the hospital to perform cardiac MRI (3X), echocardiography (3X), exercise tolerance test (2X), Pet scanning (2X) and blood sampling (4X).
Who is the sponsor? The Université catholique de Louvain (UCL) is the academic sponsor and Prof. Jean-Luc Balligand is the principal coordinator of the study.
Who is funding the study? Beta3_LVH is an investigator-initiated project funded by a Horizon 2020 grant from the European Commission.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 296
- Age between 18 and 90 years
- Arterial hypertension on stable therapy according to current guideline algorithms (including stable medication for at least four weeks before inclusion),
- 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 > or equal to 13 mm in at least one wall segment
- Patients may have atrial fibrillation (AF), but with well-regulated ventricular response, i.e. heart rate<100/min (RACE II - (Groenveld et al. 2013, 2013)),
- 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.
- Unstable hypertension with systolic BP≥160 mm Hg and/or diastolic BP≥100 mm Hg (based on office measurement, not ambulatory measurement)
- Documented ischemic cardiac disease
- History of hospitalization for overt heart failure within last 12 months
- Patients after heart transplantation
- Genetic hypertrophic or dilated cardiomyopathy
- Dysthyroidism.
- Severe valvulopathy
- 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 under regular treatment for at least one year before inclusion in the study
- eGFR < 30 ml/min (by MDRD formula)
- Abnormal liver function tests
- Type I diabetes, complicated type II diabetes
- Patients with anemia
- Patients with bladder outlet obstruction
- Patients using antimuscarinic cholinergic drugs for treatment of OAB
- Current use of digitalis, bupranolol, propranolol, nebivolol
- Patients continuously treated with Sildenafil or other PDE5 inhibitors.
- Current use of antifungal azole derivatives (fluconazole, itraconazole, miconazole, posaconazole, voriconazole)
- Current treatment with mirabegron or indication for future treatment with mirabegron due to other indications
- Contraindication for MRI
- Pregnant or nursing women
- Participation in any other interventional trial
- 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)
- Contraindication to mirabegron (e.g. hypersensitivity) or any other components of the trial medication
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description mirabegron Echocardiography Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months. mirabegron Cardiac MRI Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months. mirabegron Maximal exercise capacity Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months. mirabegron Blood sampling Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months. mirabegron Endothelial function measurement Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months. mirabegron 18FDG-PET Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months. Placebo Echocardiography Patients will be orally administererd with a placebo once a day during 12 months. Placebo Cardiac MRI Patients will be orally administererd with a placebo once a day during 12 months. Placebo Maximal exercise capacity Patients will be orally administererd with a placebo once a day during 12 months. Placebo Blood sampling Patients will be orally administererd with a placebo once a day during 12 months. Placebo Endothelial function measurement Patients will be orally administererd with a placebo once a day during 12 months. Placebo 18FDG-PET Patients will be orally administererd with a placebo once a day during 12 months. mirabegron mirabegron Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
- Primary Outcome Measures
Name Time Method Change in left ventricular mass index (LVMI) 12 months 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 12 months 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
Name Time Method Left atrial volume index 12 months 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) 6 months LV mass index (by cardiac MRI) at 6 months,
Diastolic function (E/e') 6 months Diastolic function (E/e') at 6 months
metabolic parameters 3, 6, 12 months metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids)
Maximal exercise capacity 12 months Maximal exercise capacity (peak VO2) at baseline and 12 months.
Cardiac fibrosis 12 months Cardiac fibrosis at baseline and at 12 months. Fibrosis is a key pathogenic mechanism of diastolic dysfunction, which is at the origin of HFpEF
serum biomarkers 3, 6, 12 months serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)
Emergence of treatment-related adverse events 12 months Incidence of Treatment-Emergent Adverse Events
Trial Locations
- Locations (10)
Athens University Medical School (NKUA)
🇬🇷Athens, Greece
Department of Heart Diseases at Wroclaw Medical University (UMW)
🇵🇱Wroclaw, Poland
Nantes university hospital (CHU Nantes)
🇫🇷Nantes, France
University Medical Center Göttingen (UMG-GOE)
🇩🇪Göttingen, Germany
University of Leipzig
🇩🇪Leipzig, Germany
Hospital "Papa Giovanni XXIII" (HPG23)
🇮🇹Bergamo, Italy
Cliniques universitaires Saint-Luc
🇧🇪Brussels, Belgium
Center for Cardiovascular Research Berlin (CCR/Charité)
🇩🇪Berlin, Germany
Association for Research and Development of the Faculty of Medicine (AIDFM)
🇵🇹Lisbon, Portugal
University of Oxford - Division of Cardiovascular Medicine (UOXF)
🇬🇧Oxford, United Kingdom