Assessment of efficacy of mirabegron, a new beta3-adrenergic receptor in the prevention of heart failure

• Register: ISRCTN
• Last refreshed on: 23 October 2023
• Main ID: ISRCTN65055502
• Date of registration: 30/10/2015
• Prospective Registration: Yes
• Primary sponsor: Université catholique de Louvain (Belgium)
• Public title: Assessment of efficacy of mirabegron, a new beta3-adrenergic receptor in the prevention of heart failure
• Scientific title: A multi-centre randomized, placebo-controlled trial of mirabegron, a new beta3-adrenergic receptor agonist on the progression of left ventricular mass and diastolic function in patients with structural heart disease
• Date of first enrolment: 01/03/2016
• Target sample size: 297
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN65055502
• Study type: Interventional
• Study design: Interventional prospective multi-centre randomized placebo-controlled trial (Treatment)
• Phase: Phase II

Countries of recruitment

Belgium, England, France, Germany, Greece, Italy, Poland, Portugal, United Kingdom

Contacts

• Name: Christophe L. Depoix

• Name: Jean-Luc Balligand

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age between 18 and 90 years
2. Arterial hypertension on stable therapy according to current guideline algorithms (including stable medication for at least four weeks before inclusion)
3. Morphological signs of structural cardiac remodelling by echocardiography, i.e. increased LV mass index (110 g/m2 or higher for female; 134 g/m2 or higher for male subjects (Devereux, Reichek 1977)) or end-diastolic wall thickness >13 mm in at least one wall segment
4. Patients may have atrial fibrillation (AF), but with well-regulated ventricular response, i.e. heart rate<100/min at inclusion (RACE II - (Groenveld et al. 2013, 2013))
5. Written informed consent
6. For subjects unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the subject has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the subject

Exclusion criteria:
1. Unstable hypertension with systolic BP=160 mm Hg and/or diastolic BP=100 mm Hg (confirmed at three consecutive office measurements in sitting position); if so, the patient may be re-screened after optimization of anti-hypertensive treatment, which should be stabilized for at least four weeks before inclusion.
2. Documented ischemic cardiac disease:
2.1. current angina pectoris or
2.2. ischemia on stress test or
2.3. untreated coronary stenosis >50% or
2.4. history of acute myocardial infarction (AMI) or
2.5. coronary artery bypass graft (CABG, < than 3 months prior to screening) or
2.6. percutaneous transluminal coronary angioplasty (PTCA) less than 3 months prior to screening.
3. History of hospitalization for overt heart failure within last 12 months
4. Patients after heart transplantation
5. Genetic hypertrophic or dilated cardiomyopathy
6. Dysthyroidism.
7. Severe valvulopathy (less than 1 cm2 aortic valve area or major mitral valve insufficiency at Doppler echocardiography)
8. NYHA-class > II
9. BMI > 40 kg/m2
10. EF < 50%, regardless of symptoms
11. Known other cause (i.e. COPD) of respiratory dysfunction; patients under positive pressure (CPAP) treatment for sleep apnea syndrome may be included, provided they have been under regular treatment for at least one year before inclusion in the study
12. eGFR < 30 ml/min
13. Abnormal liver function tests (AST or ALT >2 X upper normal limit or GGT>3x upper normal limit)
14. Type I diabetes, complicated type II diabetes (i.e. with documented coronary macroangiopathy , cfr exclusion criterion 1 or documented other vascular complication)
15. Patients with anemia (male: Hb <130 g/l, female: Hb <120 g/l)
16. Patients with bladder outlet obstruction
17. Patients using antimuscarinic cholinergic drugs for treatment of OAB
18. Current use of digitalis, bupranolol, propranolol, nebivolol (known to interfere with ß3AR signalling)*
19. Patients continuously treated with Sildenafil or other PDE5 inhibitors
20. Current use of antifungal azole derivatives (fluconazole, itraconazole, miconazole, posaconazole, voriconazole) (known inhibitors of CYP3A4, the main metabolizer of mirabegron)
21. Current treatment with mirabegron or indication for future treatment with mirabegron due to other indications
22. Contraindication for MRI (e.g. pacemaker, defibrillator, ferromagnetic devices or severe claustrophobia)
23. Pregnant or nursing women
24. Participation in any other interventional trial
25. Fertile women (within two years of their last menstruation) without appropriate contraceptive measures (hormonal implant, injections, oral contraceptives, intrauterine devices, partner with vasectomy) while participating in the trial (participants using a hormone-based method have to be informed of possible effects from the trial medication on contraception)
26. Contraindication to mirabegron (e.g. hypersensitivity) or any other components of the trial medication

* Note: patients are allowed

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Structural heart disease (hypertrophic cardiac remodeling, stage B AHA) at high risk for developing HFpEF (heart failure with preserved ejection fraction).
Circulatory System

Intervention(s)

This is a two armed, prospective, randomized, placebo-controlled, multi-centric international phase IIb trial with placebo and mirabegron distributed in a 1:1 fashion. The patients enrolled will have cardiac structural remodeling with or without symptoms of heart failure (maximum NYHA II).

Patients will be monitored for change in left ventricular mass (assessed by RMI) and/or changes in diastolic function (assessed by echocardiography) after 12 months of treatment.

Primary Outcome(s)

The primary objective is to evaluate the effect of mirabegron (a new ß3-specific agonist) on change in left ventricular mass and/or changes in diastolic function after 12 months of treatment in patients with cardiac structural remodeling with or without symptoms of heart failure (maximum NYHA II).

Two equally ranked, primary endpoints:
1. Change in left ventricular mass index (LVMI in g/m2, defined as left ventricular mass divided by body surface) measured at baseline and 12 months after randomisation
2. Change in diastolic function, assessed as the ratio of peak early transmitral ventricular filling velocity to early diastolic tissue Doppler velocity (E/e’) measured at baseline and 12 months after randomisation

Secondary Outcome(s)

Effect of mirabegron on other parameters of diastolic heart disease, i.e. cardiac fibrosis, left atrial volume index, diastolic function (E/e’), maximal exercise capacity and laboratory markers (analysed after 6 and 12 months of mirabegron treatment).

1. Further MRI endpoints (all measured in the central MRI core lab):
1.1. Cardiac fibrosis at baseline and at 12 months. Fibrosis is a key pathogenic mechanism of diastolic dysfunction, which is at the origin of HFpEF
1.2. Left atrial volume index at baseline and at 12 months. This parameter determines diastolic filling (and was shown to predict treatment efficacy in HFpEF in the J-DHF trial (Yamamoto et al. 2013))
1.3. LV mass index (by cardiac MRI) at 6 months
1.4. Diastolic function (E/e’) at 6 months
2. Laboratory parameters at baseline and at 3, 6 and 12 months:
2.1. Serum biomarkers (Galectin3, GDF15, NT-proBNP, hsTnT)
2.2. Metabolic parameters (fasting glucose, modified HOMA test, HbA1c, serum lipids)
3. Maximal exercise capacity (peak VO2) at baseline, 6 and 12 months
4. Safety endpoints:
4.1. Incidence, severity and frequency of adverse and serious adverse events
4.2. Mortality

Secondary ID(s)

Beta3_LVH V1.0

NCT02599480

2015-003146-75

Source(s) of Monetary Support

European Commission (Horizon 2020 grant)

Ethics review

Status: Approved
Approval date: 16/03/2016
Contact:

[e-mail]

Le Comité d'Ethique Hospitalo-Facultaire Saint-Luc - UCL; ref: 2015/01DEC/655

[phone]

[e-mail]

Results

• Results available: Yes
• Date Completed: 01/09/2022