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  • Periodic Reporting for period 1 - 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)
H2020

BETA3_LVH Report Summary

Project ID: 634559
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - 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: 2015-05-01 to 2016-10-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This first period was dedicated to the organization and setup of the frame that will support the clinical trial.
First of all, we appointed a Risk Manager, set up rules for making decisions and described means for operating the follow up actions aligned with the global strategy.
UCL and UNI-Leipzig consolidated a “task allocation list” distributing the tasks among the partners. Regular meetings of the steering committee were organized to endorse decisions on the inclusion/exclusion criteria and to consolidate the protocol .

A risk analysis plan was set up. The risks on each activity are mitigated and corrective and preventing actions (CAPA) meetings are organized. For instance, we identified a slow recruitment as a major risk. Accordingly, we made a SOP describing the way we will assess the recruitment rate and the follow up actions in case of slow recruitment.

The clinical trial was registered on Clinical NCT02599480 and ISRCTN (ISRCTN65055502). UCL coordinates and implements the administrative organization of the project (insurance, coordination of the consortium agreement, templates and contracts setup, and financial dispatch).

To monitor the safety of the trial, a DSMB was constituted and improved the trial protocol. An Event Adjudication Committee consisting of three external expert cardiologists who will analyze serious and adverse events (SAEs) from the clinical trial was also organized.

The trial protocol was approved by the CTFG-board in the VHP-procedure on february 26th, 2016. Subsequently the relevant documents were submitted to all involved competent authorities.

The informed consent procedures were established in English. This document was used for translation into the national languages by the involved ECRIN-ERIC offices in all concerned participant states. Moreover, country specific information was added / adjusted according to the local requirements.

The study received a favorable opinion of the ethics committee in Belgium on March 14th, 2016. National EC submissions were performed as a follow-up action. So far, all have approved the protocol, except in the UK. Actions are taken by the national ECRIN partner to fulfill the EC demands.

Once the administrative authorizations had been obtained from the Competent Authorities (CA) and Ethic Committees (EC), the initiation visits took place on all other sites.

An inventory of the equipment (model, software, personel in charge) available on each site was performed and each core lab wrote a manual describing the procedure and the expected quality for images. In order to secure this quality and confirm the correct implementation, core labs of Echocardiography, MRI and PET decided to organize a dummy run prior to certification of the respective recruiting centers. T1 mapping in particular requires a high level of expertise to fulfill the criteria of quality required by the core lab. This process delayed the start of the trial, but was deemed essential to ensure quality and reproducibility of major endpoint data.

UCL designed a website describing the project: http://www.beta3lvh.eu/

A video broadcast on Youtube is also available: https://www.youtube.com/watch?v=s1HfOlc_QhY&t=306s and a Facebook page: https://www.facebook.com/profile.php?id=100010325709489

The recruitment of patients started on September 13th, 2016 (first patient in – FPI). UMG-GOE enrolled its first patient in on September 13th 2016 and CUSL on September 26th 2016. So far 5 patients have been enrolled.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.

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