Heart Failure With Reduced Ejection Fraction NYHA Class III-IV
Conditions
Brief summary
Objective: The objective of the study is to assess the structural and functional cardiac effects of treatment with the beta 3 AR agonist Mirabegron in patients with moderate to severe chronic heart failure (LVEF\<35%, NYHA III-IV). The study is a randomized, placebo-controlled, double-blinded trial in two phases with two hypotheses: Chronic study - study A: Long-term treatment (3 months) with the β3 adrenergic receptor agonist Mirabegron is beneficial in patients with moderate to severe human heart failure Invasive study - Study B: Administration of Mirabegron in patients with heart failure leads to an immediate increase in cardiac output at a constant or reduced left ventricular filling pressure during submaximal exercise Specific aims 1. Determine safety of administration of Mirabegron to patients with moderate to severe heart failure. 2. Determine if treatment with Mirabegron for 3 months induces beneficial cardiac structural remodelling in patients with moderate to severe heart failure. In an open-label follow-up to determine the effects of Mirabegron after an extended duration (a total of 12 months). 3. Determine if Mirabegron improves symptoms and exercise capacity as indicated by questionnaires and 6 min walk test in patients with moderate to severe heart failure. 4. Determine effects of Mirabegron on cardiac conduction, repolarisation and rhythms and arrhythmias in patients with moderate to severe heart failure. 5. Determine effects of Mirabegron on circulating biomarkers in patients with moderate to severe heart failure. 6. Determine the immediate and short term haemodynamic effects of Mirabron as measured by CT and invasively.
Interventions
DRUGMirabegron
Study A The maximum tolerated dose up to a maximum of 300 mg per day for 26 weeks. Study B One single dose of 300 mg at day one followed by 150 mg x 2 for 1 week (8-11 days).
Sponsors
Bispebjerg-Frederiksberg Hospital, Denmark
Hillerød hospital, Denmark
Herlev Hospital
Hvidovre University Hospital
Bornholm Hospital, Denmark
Royal North Shore Hospital
Henning Bundgaard
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Stable heart failure NYHA class III-IV on ischemic or non-ischemic basis 2. Left ventricular ejection fraction (LVEF) \< 35% as assessed by cardiac CT 3. NT proBNP \> 1000 pg/ml 4. On optimised evidence-based pharmacological HF treatment stable ≥2 weeks with no current plan for changing HF therapy. The therapy must include a beta-blocker. 5. No change in diuretics ≤1 week 6. No admittances to hospital for treatment with intravenously administered positive inotropic agents ≤ 4 weeks. 7. \>18 years
Exclusion criteria
1. Acute myocardial infarction (AMI) or revascularisation \< 3 month ago 2. Uncorrected significant primary obstructive valve disease 3. Planned major surgery including cardiac revascularisation 4. Hemodynamically significant obstructive cardiomyopathy 5. Acute myocarditis or constrictive pericarditis 6. Clinically significant hepatic (transaminases or bilirubin x 3 above upper reference level) or renal (GFR\< 30 ml/min/1,73 m2) diseases 7. Heart failure due to uncorrected thyroid disease 8. Cardiac mechanical support 9. \< 6 months after CRT 10. Uncontrolled hypotension (defined as symptomatic systolic blood pressure \< 80 mmHg) - or hypertension (defined as systolic at 180 mmHg or above and/or diastolic blood pressure at 110 mmHg or below) 11. Unable to give informed consent 12. Reduced compliance 13. All women of child bearing potential will be required to use adequate contraception 14. Pregnant or lactating women 15. Treatment with a tricyclic antidepressant or CYP2D6 substrates other than beta-blockers or treatment with digoxin. 16. Known allergy to iodine containing contrast 17. Estimated GFR \< 30 ml/min/1.73 m2 18. Congenital or drug induced QT prolongation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in invasive hemodynamics assesses by right heart catherization | At 3 hours and at 1 week | Study B is explorative assessing the effect on invasive parameters including cardiac output, pulmonary wedge pressure and pulmonary and systemic vascular resistance. |
| Increase in left ventricular ejection fraction as measured by computed tomography | 3 months | Study A |
Countries
Denmark
Outcome results
None listed