Clinical trial NCT01876433: Beta 3 Agonist Treatment in Heart Failure
Official title: Beta 3 Agonist Treatment in Heart Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2013-06-12
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 chronic heart failure.

Design: The investigators are planning a study aiming at establishing proof of concept that treatment of patients with HF with Mirabegron has significant positive effects, as assessed by clinical and biochemistry measurements, but not by hard endpoints. The investigators are performing a combined dose-finding - chronic efficacy study.

The study is a randomized, placebo-controlled, double-blinded trial. The follow-up period is 6 months. 70 patients with chronic heart failure will be included.

Specific aims

1. Determine safety of administration of Mirabegron to patients with heart failure.
2. Determine if treatment with Mirabegron for 6 months induces beneficial cardiac structural remodelling in patients with heart failure.
3. Determine if Mirabegron improves symptoms and exercise capacity as indicated by questionnaires and 6 min walk test in patients with heart failure.
4. Determine effects of Mirabegron on cardiac conduction, repolarisation and rhythms and arrhythmias in patients with heart failure.
5. Determine effects of Mirabegron on circulating biomarkers in patients with heart failure.


Eligibility criteria: Inclusion Criteria:

1. Stable heart failure NYHA class II-III on ischemic or non-ischemic basis
2. Left ventricular ejection fraction (LVEF) \< 40%
3. Stable sinus rhythm (SR)
4. On optimised evidence-based pharmacological HF treatment stable \> 4 weeks with no current plan for changing HF therapy. The therapy must include a beta-blocker.
5. No change in diuretics \< 4 weeks
6. \>18 years

Exclusion Criteria:

1. Unstable cardiac condition
2. Acute myocardial infarction (AMI) or revascularisation \< 3 month ago
3. Atrial fibrillation (for technical reasons in relation to imaging and HR reporting)
4. Uncorrected significant primary obstructive valve disease
5. Planned major surgery including cardiac revascularisation
6. Hemodynamically significant obstructive cardiomyopathy
7. Stroke with significant neurological deficit
8. Acute myocarditis or constrictive pericarditis
9. Symptomatic bradycardia or \> 1. degree AV-block unless the patient has a pacemaker
10. Clinically significant hepatic (transaminases or bilirubin x 3 above upper reference level) or renal (GFR\< 50 ml/min/1,73 m2) diseases
11. Heart failure due to uncorrected thyroid disease
12. Cardiac mechanical support
13. \< 6 months after CRT
14. Uncontrolled hypotension (defined as symptomatic systolic blood pressure \< 90 mmHg) - or hypertension (defined as systolic at 180 mmHg or above and/or diastolic blood pressure at 110 mmHg or below)
15. Body mass index (BMI) \> 35
16. Unable to give informed consent
17. Reduced compliance
18. All women of child bearing potential will be required to use adequate contraception
19. Pregnant or lactating women
20. Treatment with a tricyclic antidepressant or CYP2D6 substrates other than beta-blockers or treatment with digoxin.

Primary outcomes:
measure: Increase in LVEF (measured by MRI or CT)
timeFrame: 6 months
Secondary outcomes:
measure: A reduction in NT proBNP
timeFrame: 6 months
measure: An increase in 6 min walking distance
timeFrame: 6 months
measure: An increase in CO/SV
timeFrame: 6 months
measure: A reduction in LVIDd
timeFrame: 6 months
measure: An improvement in diastolic function
timeFrame: 6 months
measure: A reduction in LA volume
timeFrame: 6 months
measure: A reduction in LV diameters
timeFrame: 6 months
measure: A shortening of the QT interval
timeFrame: 6 months
measure: Improvement in quality of life
timeFrame: 6 monhs
measure: Improvement in functional class
timeFrame: 6 months
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Monash Center of Cardiovascular Research.
city: Sydney
country: Australia
facility: Department of Cardiology, Royal North Shore Hospital.
city: Copenhagen Ø
country: Denmark
facility: Department of Cardiology, The Heart Centre, Rigshospitalet Copenhagen University Hospital.
Study officials:
affiliation: Rigshospitalet Copenhagen University Hospital, Department of Cardiology
name: Henning Bundgaard, MD, PhD, DMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bundgaard H, Axelsson A, Hartvig Thomsen J, Sorgaard M, Kofoed KF, Hasselbalch R, Fry NA, Valeur N, Boesgaard S, Gustafsson F, Kober L, Iversen K, Rasmussen HH. The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT-HF trial. Eur J Heart Fail. 2017 Apr;19(4):566-575. doi: 10.1002/ejhf.714. Epub 2016 Dec 18.