Beta3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 80
- 主要终点
- Change in pulmonary vascular resistance (PVR) from baseline to week 16 assessed by right heart catheterization (RHC).
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of mirabegron (a B3 adrenergic receptor agonist) in patients with pulmonary hypertension secondary to heart failure by conducting a randomized multicenter phase II placebo-controlled clinical trial.
详细描述
Pulmonary hypertension (PH) affects 60-80% of patients with chronic heart failure (HF) and has a critical impact on prognosis. Currently, there is no specific treatment approved for this indication. Experimental research, performed by members of the consortium, demonstrates that treatment with B3 adrenergic receptor agonists produces a beneficial effect on pulmonary hemodynamics, right ventricular (RV) remodeling and pulmonary vascular proliferation in a translational pig model of postcapillary PH. Mirabegron, an oral B3AR agonist, is currently approved for a different medical condition (overactive bladder syndrome) with a good safety profile. Our main objective is to evaluate the efficacy and safety of mirabegron in patients with PH secondary to HF.
The objective will be evaluated by conducting a phase-2 randomized placebo-controlled clinical trial in patients with PH associated to HF. Patients will be randomized 1:1 to mirabegron or placebo, and dose will be titrated till 200 mg/day. Patients will be evaluated with quality of life questionnaire, blood analysis, ECG, echocardiography, 6-minute walking test, right heart catheterization (RHC) and cardiac magnetic resonance (CMR) at baseline and after 16 weeks of treatment.
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written inform consent;
- •>18 years-old;
- •HF with reduced or preserved ejection fraction, according to the definition of the European Society of Cardiology guidelines.
- •Severe PH and/or combined postcapillary and precapillary PH (also knows as reactive or out-of-proportion PH) determined by RHC showing the following:
- •Pulmonary arterial wedge pressure or end-diastolic left ventricular pressures ≥15 mmHg;
- •Mean PAP≥25, and:
- •PVR≥3 UW and/or diastolic gradient≥7 mmHg or
- •Transpulmonary gradient≥
- •NYHA functional class II-IV;
- •On optimized evidence-based pharmacological treatment;
- •Stable clinical condition defined as no changes in therapeutic regimen or hospitalization in the 30 days preceding recruitment and no current plan for changing therapy.
排除标准
- •Non-coronary cardiac surgery or non-coronary percutaneous procedure within the 12 months preceding recruitment or programmed;
- •Myocardial infarction or coronary revascularization during the last 3 months,
- •Myocardial resynchronization therapy initiated during the last 6 months;
- •Sinus tachycardia or atrial fibrillation with uncontrolled heart rate (>100 bpm);
- •Uncontrolled hypertension (PAS>180 or PAD>110 mmHg) or symptomatic hypotension (PAS<90 mmHg).
- •Infiltrative myocardial disease.
- •Expected survival <1 year due to a disease other than PH;
- •Severe renal failure (GFR <30 mL/min/1.73 m2 or haemodialysis);
- •Severe hepatic impairment (serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3x the upper limit of normality at screening;
- •cQT interval on the ECG >430 ms in male or >450 ms in female;
- •Concomitant use of specific pulmonary vasodilator therapy (i.e. endothelin receptor antagonists, phosphodiesterase -5 inhibitors, guanylate cyclase stimulators).
- •Concomitant use of digoxin, flecainide, propafenone, dabigatran, tricycle antidepressants, or another strong inhibitors of CYP2D6 (with the exception of betablockers).
- •Significant obstructive lung disease (FEV1/FVC<0.7 associated with FEV1<50% of predicted value).
- •Significant restrictive lung disease (TLC<60%).
- •Participation in another clinical trial.
- •Female with childbearing potential.
- •Known hypersensitivity to mirabegron or to any of its excipients.
研究组 & 干预措施
Mirabegron
Oral mirabegron, starting with 50 mg once a day and titrated till a maximum of 200 mg once a day.
干预措施: Mirabegron (Drug)
Placebo
Oral placebo, similarly titrated to ensure blindness.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in pulmonary vascular resistance (PVR) from baseline to week 16 assessed by right heart catheterization (RHC).
时间窗: 16 weeks
次要结局
- Change from baseline in BNP/NT-proBNP(16 weeks)
- Change from baseline in cardiac index (CI) as assessed by RHC and cardiac magnetic resonance (CMR)(16 weeks)
- Change from baseline in RV ejection fraction as assessed by CMR(16 weeks)
- Change from baseline in NYHA functional class(16 weeks)
- Change from baseline in quality of life(16 weeks)
- Change from baseline in dyspnea Borg score(16 weeks)
- Change from baseline in mean PAP as assessed by RHC(16 weeks)
- Change from baseline in 6-minute walking distance(16 weeks)
- Hospital admissions due to worsening cardiopulmonary status(16 weeks)
- Adverse drug effects(16 weeks)
- Mortality(16 weeks)
- Urgent heart transplantation(16 weeks)
- New onset arrhythmia(16 weeks)
- Need for initiation of intravenous therapy due to worsening HF(16 weeks)