Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure

Heart Failure Clinical Trial

— SPHERE-HF  

Official title:

Beta3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02775539
• Other study ID #: SPHERE-HF
• Status: Not yet recruiting
• Phase: Phase 2
• First received: May 14, 2016
• Last updated: May 16, 2016
• Start date: June 2016
• Est. completion date: June 2019

Study information

• Verified date: May 2016
• Source: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III
• Contact: Ana García-Álvarez, MD, PhD
• Phone: 003491 4531200
• Email: anagarci[@]clinic.ub.es
• Is FDA regulated: No
• Health authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 80
• Est. completion date: June 2019
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure
• Hypertension
• Hypertension, Pulmonary
• Mirabegron
• Pulmonary Hypertension
• Pulmonary Vascular Resistance Abnormality

Intervention

Drug:
• Mirabegron
Patients will receive 50 to 200 mg of mirabegron once a day during 16 weeks. Dose will be titrated during the first 8 weeks.
• Placebo

Locations

Country	Name	City	State
n/a

Sponsors (5)

Lead Sponsor	Collaborator
Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III	Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Hospital Clinic of Barcelona, Hospital Universitario 12 de Octubre, Puerta de Hierro University Hospital

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in pulmonary vascular resistance (PVR) from baseline to week 16 assessed by right heart catheterization (RHC).		16 weeks	No
Secondary	Change from baseline in 6-minute walking distance		16 weeks	No
Secondary	Change from baseline in NYHA functional class		16 weeks	No
Secondary	Change from baseline in quality of life		16 weeks	No
Secondary	Change from baseline in dyspnea Borg score		16 weeks	No
Secondary	Change from baseline in mean PAP as assessed by RHC		16 weeks	No
Secondary	Change from baseline in cardiac index (CI) as assessed by RHC and cardiac magnetic resonance (CMR)		16 weeks	No
Secondary	Change from baseline in RV ejection fraction as assessed by CMR		16 weeks	No
Secondary	Change from baseline in BNP/NT-proBNP		16 weeks	No
Secondary	Hospital admissions due to worsening cardiopulmonary status		16 weeks	Yes
Secondary	Mortality		16 weeks	Yes
Secondary	Urgent heart transplantation		16 weeks	Yes
Secondary	New onset arrhythmia		16 weeks	Yes
Secondary	Need for initiation of intravenous therapy due to worsening HF		16 weeks	Yes
Secondary	Adverse drug effects		16 weeks	Yes