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Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure (Beta3_LVH)

Primary Purpose

Hypertrophy, Left Ventricular

Status

Unknown status

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

mirabegron

Echocardiography

Cardiac MRI

Maximal exercise capacity

Blood sampling

Endothelial function measurement

18FDG-PET

About this trial

This is an interventional treatment trial for Hypertrophy, Left Ventricular focused on measuring HFpEF, left ventricular hypertrophy, cardiac remodeling,

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Cliniques universitaires Saint-Luc
Nantes university hospital (CHU Nantes)
Center for Cardiovascular Research Berlin (CCR/Charité)
University Medical Center Göttingen (UMG-GOE)
Athens University Medical School (NKUA)
Hospital "Papa Giovanni XXIII" (HPG23)
Department of Heart Diseases at Wroclaw Medical University (UMW)
Association for Research and Development of the Faculty of Medicine (AIDFM)
University of Oxford - Division of Cardiovascular Medicine (UOXF)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

mirabegron

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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

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))

LV mass index (by cardiac MRI)

LV mass index (by cardiac MRI) at 6 months,

Diastolic function (E/e')

Diastolic function (E/e') at 6 months

serum biomarkers

serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)

metabolic parameters

metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids)

Maximal exercise capacity

Maximal exercise capacity (peak VO2) at baseline and 12 months.

Emergence of treatment-related adverse events

Incidence of Treatment-Emergent Adverse Events

Full Information

NCT ID

NCT02599480

First Posted

October 30, 2015

Last Updated

September 28, 2021

Sponsor

Jean-Luc Balligand

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT02599480

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2021

Overall Recruitment Status

Unknown status

Study Start Date

April 2016 (Actual)

Primary Completion Date

August 2022 (Anticipated)

Study Completion Date

September 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Jean-Luc Balligand

Collaborators

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertrophy, Left Ventricular

Keywords

HFpEF, left ventricular hypertrophy, cardiac remodeling,

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

296 (Actual)

8. Arms, Groups, and Interventions

Arm Title

mirabegron

Arm Type

Active Comparator

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

mirabegron

Other Intervention Name(s)

Betmiga, Myrbetriq

Intervention Description

50 mg daily during 12 months

Intervention Type

Procedure

Intervention Name(s)

Echocardiography

Intervention Description

Echocardiography

Intervention Type

Procedure

Intervention Name(s)

Cardiac MRI

Intervention Description

Cardiac MRI

Intervention Type

Procedure

Intervention Name(s)

Maximal exercise capacity

Intervention Description

Maximal exercise capacity

Intervention Type

Procedure

Intervention Name(s)

Blood sampling

Intervention Description

Blood sampling for study assessments and future exploratory studies.

Intervention Type

Procedure

Intervention Name(s)

Endothelial function measurement

Intervention Description

EndoPAT assessment

Intervention Type

Radiation

Intervention Name(s)

18FDG-PET

Intervention Description

PET scanning for beige/brown fat activation

Primary Outcome Measure Information:

Title

Change in left ventricular mass index (LVMI)

Description

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.

Time Frame

12 months

Title

Change in diastolic function

Description

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Cardiac fibrosis

Description

Cardiac fibrosis at baseline and at 12 months. Fibrosis is a key pathogenic mechanism of diastolic dysfunction, which is at the origin of HFpEF

Time Frame

12 months

Title

Left atrial volume index

Description

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))

Time Frame

12 months

Title

LV mass index (by cardiac MRI)

Description

LV mass index (by cardiac MRI) at 6 months,

Time Frame

6 months

Title

Diastolic function (E/e')

Description

Diastolic function (E/e') at 6 months

Time Frame

6 months

Title

serum biomarkers

Description

serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)

Time Frame

3, 6, 12 months

Title

metabolic parameters

Description

metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids)

Time Frame

3, 6, 12 months

Title

Maximal exercise capacity

Description

Maximal exercise capacity (peak VO2) at baseline and 12 months.

Time Frame

12 months

Title

Emergence of treatment-related adverse events

Description

Incidence of Treatment-Emergent Adverse Events

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Facility Information:

Facility Name

Cliniques universitaires Saint-Luc

City

Brussels

ZIP/Postal Code

1200

Country

Belgium

Facility Name

Nantes university hospital (CHU Nantes)

City

Nantes

ZIP/Postal Code

44000

Country

France

Facility Name

Center for Cardiovascular Research Berlin (CCR/Charité)

City

Berlin

ZIP/Postal Code

10115

Country

Germany

Facility Name

University Medical Center Göttingen (UMG-GOE)

City

Göttingen

ZIP/Postal Code

37099

Country

Germany

Facility Name

Athens University Medical School (NKUA)

City

Athens

ZIP/Postal Code

115 27

Country

Greece

Facility Name

Hospital "Papa Giovanni XXIII" (HPG23)

City

Bergamo

ZIP/Postal Code

1 - 24127

Country

Italy

Facility Name

Department of Heart Diseases at Wroclaw Medical University (UMW)

City

Wroclaw

ZIP/Postal Code

50-981

Country

Poland

Facility Name

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

City

Lisbon

ZIP/Postal Code

1649-028

Country

Portugal

Facility Name

University of Oxford - Division of Cardiovascular Medicine (UOXF)

City

Oxford

ZIP/Postal Code

OX3 9DU

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

24190960

Citation

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.

Results Reference

background

PubMed Identifier

19389565

Citation

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.

Results Reference

background

PubMed Identifier

20933201

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.

Results Reference

background

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

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