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

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ClinicalTrials.gov Identifier: NCT02599480
Recruitment Status : Enrolling by invitation
First Posted : November 6, 2015
Last Update Posted : May 8, 2018
Sponsor:
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
Information provided by (Responsible Party):
Jean-Luc Balligand, Université Catholique de Louvain

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.


Condition or disease Intervention/treatment Phase
Hypertrophy, Left Ventricular Drug: mirabegron Procedure: Echocardiography Procedure: Cardiac MRI Procedure: Maximal exercise capacity Procedure: Blood sampling Procedure: Endothelial function measurement Radiation: 18FDG-PET Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 297 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : April 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Mirabegron

Arm Intervention/treatment
Active Comparator: mirabegron
Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
Drug: mirabegron
50 mg daily during 12 months
Other Name: Betmiga, Myrbetriq

Procedure: Echocardiography
Echocardiography

Procedure: Cardiac MRI
Cardiac MRI

Procedure: Maximal exercise capacity
Maximal exercise capacity

Procedure: Blood sampling
Blood sampling for study assessments and future exploratory studies.

Procedure: Endothelial function measurement
EndoPAT assessment

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

Placebo Comparator: Placebo
Patients will be orally administererd with a placebo once a day during 12 months.
Procedure: Echocardiography
Echocardiography

Procedure: Cardiac MRI
Cardiac MRI

Procedure: Maximal exercise capacity
Maximal exercise capacity

Procedure: Blood sampling
Blood sampling for study assessments and future exploratory studies.

Procedure: Endothelial function measurement
EndoPAT assessment

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




Primary Outcome Measures :
  1. Change in left ventricular mass index (LVMI) [ Time Frame: 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.

  2. Change in diastolic function [ Time Frame: 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 :
  1. Cardiac fibrosis [ Time Frame: 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

  2. Left atrial volume index [ Time Frame: 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))

  3. LV mass index (by cardiac MRI) [ Time Frame: 6 months ]
    LV mass index (by cardiac MRI) at 6 months,

  4. Diastolic function (E/e') [ Time Frame: 6 months ]
    Diastolic function (E/e') at 6 months

  5. serum biomarkers [ Time Frame: 3, 6, 12 months ]
    serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)

  6. metabolic parameters [ Time Frame: 3, 6, 12 months ]
    metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids)

  7. Maximal exercise capacity [ Time Frame: 12 months ]
    Maximal exercise capacity (peak VO2) at baseline and 12 months.

  8. Emergence of treatment-related adverse events [ Time Frame: 12 months ]
    Incidence of Treatment-Emergent Adverse Events



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02599480


Locations
Belgium
Cliniques universitaires Saint-Luc
Brussels, Belgium, 1200
France
Nantes university hospital (CHU Nantes)
Nantes, France, 44000
Germany
Center for Cardiovascular Research Berlin (CCR/Charité)
Berlin, Germany, 10115
University Medical Center Göttingen (UMG-GOE)
Göttingen, Germany, 37099
Greece
Athens University Medical School (NKUA)
Athens, Greece, 115 27
Italy
Hospital "Papa Giovanni XXIII" (HPG23)
Bergamo, Italy, 1 - 24127
Poland
Department of Heart Diseases at Wroclaw Medical University (UMW)
Wroclaw, Poland, 50-981
Portugal
Association for Research and Development of the Faculty of Medicine (AIDFM)
Lisbon, Portugal, 1649-028
United Kingdom
University of Oxford - Division of Cardiovascular Medicine (UOXF)
Oxford, United Kingdom, OX3 9DU
Sponsors and Collaborators
Jean-Luc Balligand
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
  Study Documents (Full-Text)

Documents provided by Jean-Luc Balligand, Université Catholique de Louvain:
Study Protocol  [PDF] November 3, 2016


Publications:
Responsible Party: Jean-Luc Balligand, Professor, Université Catholique de Louvain
ClinicalTrials.gov Identifier: NCT02599480     History of Changes
Other Study ID Numbers: Beta3_LVH V1.0
First Posted: November 6, 2015    Key Record Dates
Last Update Posted: May 8, 2018
Last Verified: May 2018

Keywords provided by Jean-Luc Balligand, Université Catholique de Louvain:
HFpEF
left ventricular hypertrophy
cardiac remodeling,

Additional relevant MeSH terms:
Hypertrophy
Hypertrophy, Left Ventricular
Pathological Conditions, Anatomical
Cardiomegaly
Heart Diseases
Cardiovascular Diseases
Mirabegron
Adrenergic Agents
Adrenergic beta-3 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Urological Agents