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

NCT ID: NCT02599480

Last Updated: 2025-02-10

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

296 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-09-12

Study Completion Date

2022-02-16

Brief Summary

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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

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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.

Conditions

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Hypertrophy, Left Ventricular

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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mirabegron

Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.

Group Type ACTIVE_COMPARATOR

mirabegron

Intervention Type DRUG

50 mg daily during 12 months

Echocardiography

Intervention Type PROCEDURE

Echocardiography

Cardiac MRI

Intervention Type PROCEDURE

Cardiac MRI

Maximal exercise capacity

Intervention Type PROCEDURE

Maximal exercise capacity

Blood sampling

Intervention Type PROCEDURE

Blood sampling for study assessments and future exploratory studies.

Endothelial function measurement

Intervention Type PROCEDURE

EndoPAT assessment

18FDG-PET

Intervention Type RADIATION

PET scanning for beige/brown fat activation

Placebo

Patients will be orally administererd with a placebo once a day during 12 months.

Group Type PLACEBO_COMPARATOR

Echocardiography

Intervention Type PROCEDURE

Echocardiography

Cardiac MRI

Intervention Type PROCEDURE

Cardiac MRI

Maximal exercise capacity

Intervention Type PROCEDURE

Maximal exercise capacity

Blood sampling

Intervention Type PROCEDURE

Blood sampling for study assessments and future exploratory studies.

Endothelial function measurement

Intervention Type PROCEDURE

EndoPAT assessment

18FDG-PET

Intervention Type RADIATION

PET scanning for beige/brown fat activation

Interventions

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mirabegron

50 mg daily during 12 months

Intervention Type DRUG

Echocardiography

Echocardiography

Intervention Type PROCEDURE

Cardiac MRI

Cardiac MRI

Intervention Type PROCEDURE

Maximal exercise capacity

Maximal exercise capacity

Intervention Type PROCEDURE

Blood sampling

Blood sampling for study assessments and future exploratory studies.

Intervention Type PROCEDURE

Endothelial function measurement

EndoPAT assessment

Intervention Type PROCEDURE

18FDG-PET

PET scanning for beige/brown fat activation

Intervention Type RADIATION

Other Intervention Names

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Betmiga, Myrbetriq

Eligibility Criteria

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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 \> 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.

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
Minimum Eligible Age

18 Years

Maximum Eligible Age

90 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Zentrum für Klinische Studien Leipzig

OTHER

Sponsor Role collaborator

European Clinical Research Infrastructure Network

OTHER

Sponsor Role collaborator

European Society of Cardiology

NETWORK

Sponsor Role collaborator

European Commission

OTHER

Sponsor Role collaborator

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

OTHER

Sponsor Role collaborator

Northern Lisbon Hospital Center

OTHER

Sponsor Role collaborator

University of Athens

OTHER

Sponsor Role collaborator

Center for Cardiovascular Research Berlin

OTHER

Sponsor Role collaborator

Wroclaw Medical University

OTHER

Sponsor Role collaborator

Papa Giovanni XXIII Hospital

OTHER

Sponsor Role collaborator

Nantes University Hospital

OTHER

Sponsor Role collaborator

University Medical Center Goettingen

OTHER

Sponsor Role collaborator

University of Oxford

OTHER

Sponsor Role collaborator

Jean-Luc Balligand

OTHER

Sponsor Role lead

Responsible Party

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Jean-Luc Balligand

Professor

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Jean-Luc Balligand, Prof. MD

Role: PRINCIPAL_INVESTIGATOR

Université Catholique de Louvain

Locations

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Cliniques universitaires Saint-Luc

Brussels, , Belgium

Site Status

Nantes university hospital (CHU Nantes)

Nantes, , France

Site Status

Center for Cardiovascular Research Berlin (CCR/Charité)

Berlin, , Germany

Site Status

University Medical Center Göttingen (UMG-GOE)

Göttingen, , Germany

Site Status

University of Leipzig

Leipzig, , Germany

Site Status

Athens University Medical School (NKUA)

Athens, , Greece

Site Status

Hospital "Papa Giovanni XXIII" (HPG23)

Bergamo, , Italy

Site Status

Department of Heart Diseases at Wroclaw Medical University (UMW)

Wroclaw, , Poland

Site Status

Association for Research and Development of the Faculty of Medicine (AIDFM)

Lisbon, , Portugal

Site Status

University of Oxford - Division of Cardiovascular Medicine (UOXF)

Oxford, , United Kingdom

Site Status

Countries

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Belgium France Germany Greece Italy Poland Portugal United Kingdom

References

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Belge C, Hammond J, Dubois-Deruy E, Manoury B, Hamelet J, Beauloye C, Markl A, Pouleur AC, Bertrand L, Esfahani H, Jnaoui K, Gotz 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 beta3-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.

Reference Type BACKGROUND
PMID: 24190960 (View on PubMed)

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. No abstract available.

Reference Type BACKGROUND
PMID: 19389565 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20933201 (View on PubMed)

Menghoum N, Badii MC, Leroy M, Parra M, Roy C, Lejeune S, Vancraeynest D, Pasquet A, Brito D, Casadei B, Depoix C, Filippatos G, Gruson D, Edelmann F, Ferreira VM, Lhommel R, Mahmod M, Neubauer S, Persu A, Piechnik S, Hellenkamp K, Ikonomidis I, Krakowiak B, Pieske B, Pieske-Kraigher E, Pinto F, Ponikowski P, Senni M, Trochu JN, Van Overstraeten N, Wachter R, Gerber BL, Balligand JL, Beauloye C, Pouleur AC. Exploring the impact of metabolic comorbidities on epicardial adipose tissue in heart failure with preserved ejection fraction. Cardiovasc Diabetol. 2025 Mar 22;24(1):134. doi: 10.1186/s12933-025-02688-7.

Reference Type DERIVED
PMID: 40121452 (View on PubMed)

Balligand JL, Brito D, Brosteanu O, Casadei B, Depoix C, Edelmann F, Ferreira V, Filippatos G, Gerber B, Gruson D, Hasenclever D, Hellenkamp K, Ikonomidis I, Krakowiak B, Lhommel R, Mahmod M, Neubauer S, Persu A, Piechnik S, Pieske B, Pieske-Kraigher E, Pinto F, Ponikowski P, Senni M, Trochu JN, Van Overstraeten N, Wachter R, Pouleur AC. Repurposing the beta3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial. JAMA Cardiol. 2023 Nov 1;8(11):1031-1040. doi: 10.1001/jamacardio.2023.3003.

Reference Type DERIVED
PMID: 37728907 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan: Planned analyses

View Document

Document Type: Statistical Analysis Plan: Trial results according to ICH E3

View Document

Other Identifiers

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Beta3_LVH V1.0

Identifier Type: -

Identifier Source: org_study_id

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