Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure

Hypertrophy, Left Ventricular Clinical Trial

— Beta3_LVH  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02599480
• Other study ID #: Beta3_LVH V1.0
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 2016
• Est. completion date: September 2022

Study information

• Verified date: September 2021
• Source: Université Catholique de Louvain
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 296
• Est. completion date: September 2022
• Est. primary completion date: August 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Hypertrophy
• Hypertrophy, Left Ventricular

Intervention

Drug:
• mirabegron
50 mg daily during 12 months

Procedure:
• Echocardiography
Echocardiography
• Cardiac MRI
Cardiac MRI
• Maximal exercise capacity
Maximal exercise capacity
• Blood sampling
Blood sampling for study assessments and future exploratory studies.
• Endothelial function measurement
EndoPAT assessment

Radiation:
• 18FDG-PET
PET scanning for beige/brown fat activation

Locations

Country	Name	City	State
Belgium	Cliniques universitaires Saint-Luc	Brussels
France	Nantes university hospital (CHU Nantes)	Nantes
Germany	Center for Cardiovascular Research Berlin (CCR/Charité)	Berlin
Germany	University Medical Center Göttingen (UMG-GOE)	Göttingen
Greece	Athens University Medical School (NKUA)	Athens
Italy	Hospital "Papa Giovanni XXIII" (HPG23)	Bergamo
Poland	Department of Heart Diseases at Wroclaw Medical University (UMW)	Wroclaw
Portugal	Association for Research and Development of the Faculty of Medicine (AIDFM)	Lisbon
United Kingdom	University of Oxford - Division of Cardiovascular Medicine (UOXF)	Oxford

Sponsors (14)

Lead Sponsor

Collaborator

Jean-Luc Balligand

Center for Cardiovascular Research Berlin, Cliniques universitaires Saint-Luc- Université Catholique de Louvain, European Clinical Research Infrastructure Network, European Commission, European Society of Cardiology, Nantes University Hospital, Northern Lisbon Hospital Center, Papa Giovanni XXIII Hospital, University Medical Center Goettingen, University of Athens, University of Oxford, Wroclaw Medical University, Zentrum für Klinische Studien Leipzig

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Greece,  Italy,  Poland,  Portugal,  United Kingdom, 

References & Publications (3)

Balligand JL. beta(3)-Adrenoceptor stimulation on top of beta(1)-adrenoceptor blockade "Stop or Encore?". J Am Coll Cardiol. 2009 Apr 28;53(17):1539-42. doi: 10.1016/j.jacc.2009.01.048. — View Citation

Belge C, Hammond J, Dubois-Deruy E, Manoury B, Hamelet J, Beauloye C, Markl A, Pouleur AC, Bertrand L, Esfahani H, Jnaoui K, Götz KR, Nikolaev VO, Vanderper A, Herijgers P, Lobysheva I, Iaccarino G, Hilfiker-Kleiner D, Tavernier G, Langin D, Dessy C, Balligand JL. Enhanced expression of ß3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation. 2014 Jan 28;129(4):451-62. doi: 10.1161/CIRCULATIONAHA.113.004940. Epub 2013 Nov 4. — View Citation

Dessy C, Balligand JL. Beta3-adrenergic receptors in cardiac and vascular tissues emerging concepts and therapeutic perspectives. Adv Pharmacol. 2010;59:135-63. doi: 10.1016/S1054-3589(10)59005-7. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in left ventricular mass index (LVMI)	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.	12 months
Primary	Change in diastolic function	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.	12 months
Secondary	Cardiac fibrosis	Cardiac fibrosis at baseline and at 12 months. Fibrosis is a key pathogenic mechanism of diastolic dysfunction, which is at the origin of HFpEF	12 months
Secondary	Left atrial volume index	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))	12 months
Secondary	LV mass index (by cardiac MRI)	LV mass index (by cardiac MRI) at 6 months,	6 months
Secondary	Diastolic function (E/e')	Diastolic function (E/e') at 6 months	6 months
Secondary	serum biomarkers	serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)	3, 6, 12 months
Secondary	metabolic parameters	metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids)	3, 6, 12 months
Secondary	Maximal exercise capacity	Maximal exercise capacity (peak VO2) at baseline and 12 months.	12 months
Secondary	Emergence of treatment-related adverse events	Incidence of Treatment-Emergent Adverse Events	12 months