Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure

Phase 2

• Conditions: Pulmonary Hypertension; Mirabegron; Heart Failure; Pulmonary Vascular Resistance Abnormality
• Interventions: Drug: Mirabegron; Drug: Placebo

• Registration Number: NCT02775539
• Lead Sponsor: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Status Verified: 2016-05
• Study First Submitted: 2016-05-14
• Study First Submitted QC: 2016-05-16
• Last Update Submitted: 2016-05-16
• Study First Posted: 2016-05-17
• Last Update Posted: 2016-05-17
• Study Start: 2016-06
• Primary Completion: 2017-01
• Study Completion: 2019-06

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

• 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≥12.

• 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.

Exclusion Criteria

• 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mirabegron	Mirabegron	Oral mirabegron, starting with 50 mg once a day and titrated till a maximum of 200 mg once a day.
Placebo	Placebo	Oral placebo, similarly titrated to ensure blindness.

Primary Outcome Measures

Name	Time	Method
Change in pulmonary vascular resistance (PVR) from baseline to week 16 assessed by right heart catheterization (RHC).	16 weeks

Secondary Outcome Measures

Name	Time	Method
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 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 BNP/NT-proBNP	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