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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 296
- 试验地点
- 10
- 主要终点
- Change in left ventricular mass index (LVMI)
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
mirabegron
Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
干预措施: mirabegron (Drug)
mirabegron
Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
干预措施: Echocardiography (Procedure)
mirabegron
Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
干预措施: Cardiac MRI (Procedure)
mirabegron
Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
干预措施: Maximal exercise capacity (Procedure)
mirabegron
Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
干预措施: Blood sampling (Procedure)
mirabegron
Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
干预措施: Endothelial function measurement (Procedure)
mirabegron
Patients will be orally administererd with 50 mg of mirabegron once a day during 12 months.
干预措施: 18FDG-PET (Radiation)
Placebo
Patients will be orally administererd with a placebo once a day during 12 months.
干预措施: Echocardiography (Procedure)
Placebo
Patients will be orally administererd with a placebo once a day during 12 months.
干预措施: Cardiac MRI (Procedure)
Placebo
Patients will be orally administererd with a placebo once a day during 12 months.
干预措施: Maximal exercise capacity (Procedure)
Placebo
Patients will be orally administererd with a placebo once a day during 12 months.
干预措施: Blood sampling (Procedure)
Placebo
Patients will be orally administererd with a placebo once a day during 12 months.
干预措施: Endothelial function measurement (Procedure)
Placebo
Patients will be orally administererd with a placebo once a day during 12 months.
干预措施: 18FDG-PET (Radiation)
结局指标
主要结局
Change in left ventricular mass index (LVMI)
时间窗: 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
时间窗: 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.
次要结局
- Left atrial volume index(12 months)
- LV mass index (by cardiac MRI)(6 months)
- Diastolic function (E/e')(6 months)
- metabolic parameters(3, 6, 12 months)
- Maximal exercise capacity(12 months)
- Cardiac fibrosis(12 months)
- serum biomarkers(3, 6, 12 months)
- Emergence of treatment-related adverse events(12 months)
研究者
Jean-Luc Balligand
Professor
Université Catholique de Louvain