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A multi-center 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

Periodic Reporting for period 3 - BETA3_LVH (A multi-center 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)

Reporting period: 2018-05-01 to 2019-10-31

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 discomfort of repeated hospitalisations. Therefore, HFpEF is a chronic, costly, debilitating disease.
A major contributor to HFpEF is myocardial remodeling, 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.


The proposed clinical trial will support proof of concept in humans to assess 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). As many of the elderly patients are also susceptible to suffer from overactive bladder disease, the trial will contribute valuable information on additional benefit for those suffering from cardiovascular diseases.
Using pre-clinical models, we 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 remodeling in patients at high risk of developing HFpEF.
This third period was dedicated to the recruitment and enrollment of patients in the European sites. Protocol and amendments as well as administrative documents were submitted to CTFG, national competent authorities and ethic committees prior to the official launch of the trial on site. Initiation visits were performed on sites and the local databases were screened for finding the profiles matching our inclusion/exclusion criteria. Patients were then contacted and enrolled in the study. For monitoring the recruitment rate of each site, monthly meetings were organised by the coordinator and general assemblies were carried out. As the recruitment rate was sub-optimal related to our target of 297 patients, we setup corrective and preventive actions to increase this rate and so mitigate the risk on the final results. So far, 252 patients are enrolled in the study (220 at the time of reporting).

Core labs reports regularly to the sites and participate to the monthly meetings to provide updates and feedback.

The ESC organizes regular DSMB meetings to ensure the safety of the trial.

The rationale and the design of the study was described in a paper submitted and accepted to ESC Heart failure on 23 April 2018. A flyer was designed and distributed to the site to inform the patients about the study and recruit voluntaries.

The website http://www.beta3lvh.eu/ was fed and updated with the enrolled patients per site and the information for the partners was communicated in the secured tab. A video broadcast on Youtube is available: https://www.youtube.com/watch?v=s1HfOlc_QhY&t=306s and a Facebook page: https://www.facebook.com/profile.php?id=100010325709489.
As the prevalence of HFpEF increases with the ageing population, especially in elderly women this project fully addresses the need for “New treatments for chronic, non-communicable diseases”, while taking the gender aspect into account. HFpEF differently affects men and women, and is typically associated with comorbidity. Sex also affected the outcomes, since women had a better overall prognosis. Our trial will enroll carefully phenotyped patients with significant co- morbidity and test a drug with potential pleiotropic effects likely to significantly affect this comorbidity. Indeed, in addition to LV remodelling and diastolic function, in 2 sub-studies, we will evaluate the effect of mirabegron on endothelial function and NO bioavailability, as well as metabolism, thereby trying to correlate effects on remodelling with β3-mediated modulation of risk factors.

Altogether, the data generated from our trial should provide new avenues for the treatment of a disease with a steadily increasing burden on the health care system and society. Contrary to heart failure with reduced ejection fraction (HFrEF), outcomes have not improved over the last decades, highlighting the need for new, effective therapies for this important syndrome.

If the benefit of mirabegron on top of standard of care is established in our study, this could be easily replicated in additional confirmatory studies and lead to an extension of indication and so would lead to a quick impact for patients, since the drug is already marketed. Original data from the trial may also lead to inventive material that could generate new intellectual property and additional economic growth in Europe.