Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure

Brief Title

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

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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

 Change from baseline in 6-minute walking distance

Condition

Pulmonary Hypertension

Intervention

Mirabegron

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

80

Start Date

June 2016

Completion Date

June 2019

Primary Completion Date

January 2017

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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, 003491 4531200, [email protected]



Administrative Informations


NCT ID

NCT02775539

Organization ID

SPHERE-HF


Responsible Party

Sponsor

Study Sponsor

Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III

Collaborators

 Hospital Clinic of Barcelona

Study Sponsor

, , 


Verification Date

May 2016