Periodic Reporting for period 5 - 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)
Okres sprawozdawczy: 2021-09-01 do 2022-08-31
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.
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.
The work 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. In the end, we reached our target of 296 patients randomized, despite the COVID pandemic in 2020-2022.
Core labs reported regularly to the sites and participated to the monthly meetings to provide updates and feedback.
The ESC organized regular DSMB meetings to ensure the safety of the trial. Recommendations to complete the trial to the end were issued.
The rationale and the design of the study were 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 help recruit volunteers.
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.
Last patient out was on February 2022. Then, all data were collected in the central database. A Statistical Analysis Plan was drawn and approved by the partners and the DSMB. A Statistical Analysis Report was then produced with the final results on unblinded data.
The trial results were presented at a Featured Science Section on New Treatments for Heart Failure at the American Heart Association congress 2022 in Chicago. The results show a neutral effect of mirabegron (at 50 mg/d) on co-primary endpoints (left ventricular mass index, by cardiac MRI and E/e', an index of ventricular relaxation, by Doppler echocardiography).
However, an important finding is that the use of mirabegron is safe in a patient population specifically selected for their high cardiovascular risk; indeed, such patients had always been excluded from clinical trials of mirabegron for its primary urological indication; as these are mostly elderly patients with CV risk factors, concerns had always remained as to the safety of the drug; this concern can now reasonably be aleviated.
Core labs reported regularly to the sites and participated to the monthly meetings to provide updates and feedback.
The ESC organized regular DSMB meetings to ensure the safety of the trial. Recommendations to complete the trial to the end were issued.
The rationale and the design of the study were 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 help recruit volunteers.
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.
Last patient out was on February 2022. Then, all data were collected in the central database. A Statistical Analysis Plan was drawn and approved by the partners and the DSMB. A Statistical Analysis Report was then produced with the final results on unblinded data.
The trial results were presented at a Featured Science Section on New Treatments for Heart Failure at the American Heart Association congress 2022 in Chicago. The results show a neutral effect of mirabegron (at 50 mg/d) on co-primary endpoints (left ventricular mass index, by cardiac MRI and E/e', an index of ventricular relaxation, by Doppler echocardiography).
However, an important finding is that the use of mirabegron is safe in a patient population specifically selected for their high cardiovascular risk; indeed, such patients had always been excluded from clinical trials of mirabegron for its primary urological indication; as these are mostly elderly patients with CV risk factors, concerns had always remained as to the safety of the drug; this concern can now reasonably be aleviated.
As the prevalence of HFpEF increases with the ageing population, especially in elderly women this project fully addressed 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 enrolled 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 evaluated 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.
While the results are neutral in the conditions of our trial, this does not invalidate our original hypotheses; indeed, these deserve to be examined in subsequent trials with higher doses of mirabegron in patients with more severe phenotypes and for longer periods of treatment. Indeed, the abundance of the target, cardiac beta3 adrenergic receptors, is known to be higher in more advanced diseases than in patients selected in our trial. Also, more efficacy may be expected from newer, more potent beta3 agonists in development.
Altogether, our and future trials 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.
Given the reassuring data on safety from our BETA3LVH trial, similar protocols with new agonists could be easily replicated in additional studies and lead to an extension of indication of "repurposed" urological drugs and so would lead to a quick impact for patients.
While the results are neutral in the conditions of our trial, this does not invalidate our original hypotheses; indeed, these deserve to be examined in subsequent trials with higher doses of mirabegron in patients with more severe phenotypes and for longer periods of treatment. Indeed, the abundance of the target, cardiac beta3 adrenergic receptors, is known to be higher in more advanced diseases than in patients selected in our trial. Also, more efficacy may be expected from newer, more potent beta3 agonists in development.
Altogether, our and future trials 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.
Given the reassuring data on safety from our BETA3LVH trial, similar protocols with new agonists could be easily replicated in additional studies and lead to an extension of indication of "repurposed" urological drugs and so would lead to a quick impact for patients.