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

Study Status: Enrolling by invitation
Recruit Status: Enrolling by invitation
Study Type: Interventional

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

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 Summary:

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 th
Sponsor: Jean-Luc Balligand

Current Primary Outcome:

  • 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.
  • 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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
  • 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))
  • LV mass index (by cardiac MRI) [ Time Frame: 6 months ]
    LV mass index (by cardiac MRI) at 6 months,
  • Diastolic function (E/e') [ Time Frame: 6 months ]
    Diastolic function (E/e') at 6 months
  • serum biomarkers [ Time Frame: 3, 6, 12 months ]
    serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)
  • metabolic parameters [ Time Frame: 3, 6, 12 months ]
    metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids)
  • Maximal exercise capacity [ Time Frame: 12 months ]
    Maximal exercise capacity (peak VO2) at baseline and 12 months.
  • Emergence of treatment-related adverse events [ Time Frame: 12 months ]
    Incidence of Treatment-Emergent Adverse Events


Original Secondary Outcome: Same as current

Information By: Université Catholique de Louvain

Dates:
Date Received: October 30, 2015
Date Started: April 2016
Date Completion: January 2020
Last Updated: December 12, 2016
Last Verified: December 2016