Clinical trial NCT02599480: Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertrophy, Left Ventricular
Keywords: HFpEF
left ventricular hypertrophy
cardiac remodeling,
Lead sponsor: Université Catholique de Louvain
Sponsor class: OTHER
Collaborators: name: Zentrum für Klinische Studien Leipzig
name: European Clinical Research Infrastructure Network
name: European Society of Cardiology
name: European Commission
name: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
name: Northern Lisbon Hospital Center
name: University of Athens
name: Center for Cardiovascular Research Berlin
name: Wroclaw Medical University
name: Papa Giovanni XXIII Hospital
name: Nantes University Hospital
name: University Medical Center Goettingen
name: University of Oxford
First posted: 2015-11-06
Enrollment: 296
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 \> 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

Primary outcomes:
measure: Change in left ventricular mass index (LVMI)
timeFrame: 12 months
measure: Change in diastolic function
timeFrame: 12 months
Secondary outcomes:
measure: Cardiac fibrosis
timeFrame: 12 months
measure: Left atrial volume index
timeFrame: 12 months
measure: LV mass index (by cardiac MRI)
timeFrame: 6 months
measure: Diastolic function (E/e')
timeFrame: 6 months
measure: serum biomarkers
timeFrame: 3, 6, 12 months
measure: metabolic parameters
timeFrame: 3, 6, 12 months
measure: Maximal exercise capacity
timeFrame: 12 months
measure: Emergence of treatment-related adverse events
timeFrame: 12 months
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc
city: Nantes
country: France
facility: Nantes university hospital (CHU Nantes)
city: Berlin
country: Germany
facility: Center for Cardiovascular Research Berlin (CCR/Charité)
city: Göttingen
country: Germany
facility: University Medical Center Göttingen (UMG-GOE)
city: Leipzig
country: Germany
facility: University of Leipzig
city: Athens
country: Greece
facility: Athens University Medical School (NKUA)
city: Bergamo
country: Italy
facility: Hospital "Papa Giovanni XXIII" (HPG23)
city: Wroclaw
country: Poland
facility: Department of Heart Diseases at Wroclaw Medical University (UMW)
city: Lisbon
country: Portugal
facility: Association for Research and Development of the Faculty of Medicine (AIDFM)
city: Oxford
country: United Kingdom
facility: University of Oxford - Division of Cardiovascular Medicine (UOXF)
Study officials:
affiliation: Université Catholique de Louvain
name: Jean-Luc Balligand, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.