Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure

NCT ID: NCT02775539

Last Updated: 2016-05-17

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2019-06-30

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.

Conditions

Pulmonary Hypertension; Mirabegron; Heart Failure; Pulmonary Vascular Resistance Abnormality

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Mirabegron

Oral mirabegron, starting with 50 mg once a day and titrated till a maximum of 200 mg once a day.

Group Type: ACTIVE_COMPARATOR

Mirabegron

Intervention Type: DRUG

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

Oral placebo, similarly titrated to ensure blindness.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

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.

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospital Clinic of Barcelona

OTHER

Sponsor Role: collaborator

Hospital Universitario 12 de Octubre

OTHER

Sponsor Role: collaborator

Puerta de Hierro University Hospital

OTHER

Sponsor Role: collaborator

Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

OTHER

Sponsor Role: collaborator

Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Ana García-Álvarez, MD, PhD

Role: CONTACT

anagarci@clinic.ub.es

003491 4531200 ext. 1507

Borja Ibañez, MD, PhD

Role: CONTACT

bibanez@cnic.es

003491 4531200 ext. 1507

References

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.

Reference Type: DERIVED

PMID: 32368692 (View on PubMed)

Other Identifiers

SPHERE-HF

Identifier Type: -

Identifier Source: org_study_id