Assessment of efficacy of Mirabegron, a new beta3-adrenergic receptor in the prevention of heart failure

Study Objective

This trial 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).
Mirabegron, is a drug already marketed indicated for the treatment of bladder disorders. In this trial, Mirabegron or placebo will be administered to patients in a new indication on top of a standard treatment.
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.

Participation conditions

Inclusion Criteria:

• 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 >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.

Exclusion Criteria:

• 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
 

Cliniques Universitaires Saint-Luc, Service de Cardiologie, Avenue Hippocrate, 10, 1200 Bruxelles, Belgique