Clinical trial NCT02775539: Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure
Official title: Beta3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Pulmonary Hypertension
Mirabegron
Heart Failure
Pulmonary Vascular Resistance Abnormality
Keywords: Pulmonary hypertension
Mirabegron
Heart failure
B3 adrenergic
Lead sponsor: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III
Sponsor class: OTHER
Collaborators: name: Hospital Clinic of Barcelona
name: Hospital Universitario 12 de Octubre
name: Puerta de Hierro University Hospital
name: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
First posted: 2016-05-17
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in pulmonary vascular resistance (PVR) from baseline to week 16 assessed by right heart catheterization (RHC).
timeFrame: 16 weeks
Secondary outcomes:
measure: Change from baseline in 6-minute walking distance
timeFrame: 16 weeks
measure: Change from baseline in NYHA functional class
timeFrame: 16 weeks
measure: Change from baseline in quality of life
timeFrame: 16 weeks
measure: Change from baseline in dyspnea Borg score
timeFrame: 16 weeks
measure: Change from baseline in mean PAP as assessed by RHC
timeFrame: 16 weeks
measure: Change from baseline in cardiac index (CI) as assessed by RHC and cardiac magnetic resonance (CMR)
timeFrame: 16 weeks
measure: Change from baseline in RV ejection fraction as assessed by CMR
timeFrame: 16 weeks
measure: Change from baseline in BNP/NT-proBNP
timeFrame: 16 weeks
measure: Hospital admissions due to worsening cardiopulmonary status
timeFrame: 16 weeks
measure: Mortality
timeFrame: 16 weeks
measure: Urgent heart transplantation
timeFrame: 16 weeks
measure: New onset arrhythmia
timeFrame: 16 weeks
measure: Need for initiation of intravenous therapy due to worsening HF
timeFrame: 16 weeks
measure: Adverse drug effects
timeFrame: 16 weeks
Other outcomes:
Locations:
Study officials:
References:
citation: Garcia-Lunar I, Blanco I, Fernandez-Friera L, Prat-Gonzalez S, Jorda P, Sanchez J, Pereda D, Pujadas S, Rivas M, Sole-Gonzalez E, Vazquez J, Blazquez Z, Garcia-Picart J, Caravaca P, Escalera N, Garcia-Pavia P, Delgado J, Segovia-Cubero J, Fuster V, Roig E, Barbera JA, Ibanez B, Garcia-Alvarez A. Design of the beta3-Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure Trial. JACC Basic Transl Sci. 2020 Mar 11;5(4):317-327. doi: 10.1016/j.jacbts.2020.01.009. eCollection 2020 Apr.