Use of determination of drug levels to optimize pharmacotherapy of heart failure

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fakultni Nemocnice Ostrava

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

9 Apr 2024 → ongoing

Decision date (initial)

2023-11-28

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Fakultní nemocnice Ostrava

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective of the CT is to determine whether and how the serum concentrations of the listed medicinal products, including their metabolites, correlate with selected clinical indicators of heart failure.

Secondary objectives 5

1. To determine serum concentrations of drugs used in patients with HFrEF: - beta-blockers: bisoprolol, carvedilol, metoprolol succinate or nebivolol; when taking metoprolol succinate, determine the serum concentration of the metabolite α-hydroxymetoprolol to determine the metabolic ratio metoprolol/α-hydroxymetoprolol to evaluate the CYP2D6 phenotype - spironolactone (or active metabolite canrenone) - sacubitril including the active metabolite sacubitrilate - valsartan
2. To determine whether the dose of drugs used, or their serum concentration is better correlated with the development of clinical parameters or the prognosis of patients with HFrEF
3. To analyse the correlation of possible adverse effects with the measured drug concentration
4. To evaluate patients' adherence to treatment in a longer-term follow-up
5. On the basis of the obtained data, possibly introduce TDM of the mentioned drugs into routine clinical practice in patients with HFrEF and thus expand the multidisciplinary approach to patients with this diagnosis

Conditions and MedDRA coding

Chronic heart failure with reduced ejection fraction

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. HFrEF with already established or newly started treatment with the listed medicinal products
2. Male and female patients over 18 years of age
3. Signed Informed Consent with participation in the study
4. Women of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) result at the initial visit and use an acceptable method of contraception with a home control urine pregnancy test every 3 months throughout the duration of the study

Exclusion criteria 29

1. Hypersensitivity to the medicinal substance or to any auxiliary substance
2. Pregnant and breastfeeding women
3. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - Unstable or decompensated heart failure belonging to the NYHA IV group according to the New York Heart Association classification, requiring intravenous inotropic support
4. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - Clinically manifest liver dysfunction
5. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - History of bronchospasm or asthma
6. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - Severe obstructive airways disease
7. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - 2nd and 3rd degree A-V block (unless a permanent pacemaker is implanted)
8. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - severe bradycardia (heart rate <50)
9. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - cardiogenic shock
10. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - sinus node dysfunction syndrome (including sinoatrial block)
11. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - severe hypotension (systolic blood pressure <85 mmHg)
12. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - Prinzmetal angina
13. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - untreated pheochromocytoma
14. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - metabolic acidosis
15. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - severe peripheral arterial circulation disorders
16. Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol - concurrent intravenous treatment with verapamil or diltiazem
17. Additional exclusion criteria for patients using Spironolactone - anuria
18. Additional exclusion criteria for patients using Spironolactone - acute renal failure
19. Additional exclusion criteria for patients using Spironolactone - severe renal impairment (estimated glomerular filtration rate <10 ml/min)
20. Additional exclusion criteria for patients using Spironolactone - hyperkalemia >5.5 mmol/l
21. Additional exclusion criteria for patients using Spironolactone - hyponatremia <125 mmol/l
22. Additional exclusion criteria for patients using Spironolactone - Addison's disease
23. Additional exclusion criteria for patients using Spironolactone - concurrent use of eplerenone or other potassium-sparing diuretics
24. Additional exclusion criteria for patients using Spironolactone - porphyria
25. Additional exclusion criteria for patients using Sacubitril/Valsartan - concomitant use with ACE inhibitors
26. Additional exclusion criteria for patients using Sacubitril/Valsartan - angioedema related to previous ACE inhibitor treatment or a history of ARB treatment
27. Additional exclusion criteria for patients using Sacubitril/Valsartan - hereditary or idiopathic angioedema
28. Additional exclusion criteria for patients using Sacubitril/Valsartan - concomitant use with medicinal products containing Aliskiren in patients with diabetes mellitus or in patients with impaired renal function (eGFR <60 ml/min/1.73 m2)
29. Additional exclusion criteria for patients using Sacubitril/Valsartan - severe liver dysfunction, biliary cirrhosis and cholestasis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To determine whether in patients with chronic heart failure with reduced ejection fraction (HFrEF) the serum concentration of the drugs used is more important than the dose of these drugs (beta-blockers bisoprolol, carvedilol, metoprolol succinate or nebivolol; spironolactone, sacubitril, valsartan) for compensating the health status)

Secondary endpoints 3

1. To determine the number of patients in whom a significant dependence between the serum concentration of the mentioned drugs and the values of selected clinical indicators (NT-proBNP concentration, 6-minute walk test, quality of life questionnaire, echocardiographic parameters, hospitalization for HFrEF, length of survival) is demonstrated.
2. To determine the number of patients in whom a significant dependence between the serum concentration of the mentioned drugs and the adverse effects of these drugs is demonstrated
3. To determine the number of patients in whom non-adherence to treatment will be demonstrated

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fakultni Nemocnice Ostrava

Sponsor organisation

Fakultni Nemocnice Ostrava

Address

17. Listopadu 1790/5

City

Poruba

Postcode

708 00

Country

Czechia

Scientific contact point

Organisation

Fakultni Nemocnice Ostrava

Contact name

Marie Lazárová, MD, Ph.D.

Public contact point

Organisation

Fakultni Nemocnice Ostrava

Contact name

Jiří Hynčica

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

3 submissions — initial application plus substantial / non-substantial modifications