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Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE-HF)

Primary Purpose

Pulmonary Hypertension, Mirabegron, Heart Failure

Status

Unknown status

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Mirabegron

Placebo

About this trial

This is an interventional treatment trial for Pulmonary Hypertension focused on measuring Pulmonary hypertension, Mirabegron, Heart failure, B3 adrenergic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Mirabegron

Placebo

Arm Description

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

Oral placebo, similarly titrated to ensure blindness.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Change from baseline in 6-minute walking distance

Change from baseline in NYHA functional class

Change from baseline in quality of life

Change from baseline in dyspnea Borg score

Change from baseline in mean PAP as assessed by RHC

Change from baseline in cardiac index (CI) as assessed by RHC and cardiac magnetic resonance (CMR)

Change from baseline in RV ejection fraction as assessed by CMR

Change from baseline in BNP/NT-proBNP

Hospital admissions due to worsening cardiopulmonary status

Mortality

Urgent heart transplantation

New onset arrhythmia

Need for initiation of intravenous therapy due to worsening HF

Adverse drug effects

Full Information

NCT ID

NCT02775539

First Posted

May 14, 2016

Last Updated

May 16, 2016

Sponsor

Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III

Collaborators

Hospital Clinic of Barcelona, Hospital Universitario 12 de Octubre, Puerta de Hierro University Hospital, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

1. Study Identification

Unique Protocol Identification Number

NCT02775539

Brief Title

Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure

Acronym

SPHERE-HF

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2016

Overall Recruitment Status

Unknown status

Study Start Date

June 2016 (undefined)

Primary Completion Date

January 2017 (Anticipated)

Study Completion Date

June 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III

Collaborators

Hospital Clinic of Barcelona, Hospital Universitario 12 de Octubre, Puerta de Hierro University Hospital, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Pulmonary hypertension, Mirabegron, Heart failure, B3 adrenergic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Mirabegron

Arm Type

Active Comparator

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Oral placebo, similarly titrated to ensure blindness.

Intervention Type

Drug

Intervention Name(s)

Mirabegron

Intervention Description

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

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

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

Time Frame

16 weeks

Secondary Outcome Measure Information:

Title

Change from baseline in 6-minute walking distance

Time Frame

16 weeks

Title

Change from baseline in NYHA functional class

Time Frame

16 weeks

Title

Change from baseline in quality of life

Time Frame

16 weeks

Title

Change from baseline in dyspnea Borg score

Time Frame

16 weeks

Title

Change from baseline in mean PAP as assessed by RHC

Time Frame

16 weeks

Title

Change from baseline in cardiac index (CI) as assessed by RHC and cardiac magnetic resonance (CMR)

Time Frame

16 weeks

Title

Change from baseline in RV ejection fraction as assessed by CMR

Time Frame

16 weeks

Title

Change from baseline in BNP/NT-proBNP

Time Frame

16 weeks

Title

Hospital admissions due to worsening cardiopulmonary status

Time Frame

16 weeks

Title

Mortality

Time Frame

16 weeks

Title

Urgent heart transplantation

Time Frame

16 weeks

Title

New onset arrhythmia

Time Frame

16 weeks

Title

Need for initiation of intravenous therapy due to worsening HF

Time Frame

16 weeks

Title

Adverse drug effects

Time Frame

16 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Ana García-Álvarez, MD, PhD

Phone

003491 4531200

Ext

1507

anagarci@clinic.ub.es

First Name & Middle Initial & Last Name or Official Title & Degree

Borja Ibañez, MD, PhD

Phone

003491 4531200

Ext

1507

bibanez@cnic.es

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

32368692

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.

Results Reference

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Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure

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