Acute Heart Failure, Dilated Cardiomyopathy
Conditions
Keywords
Ivabradine, Heart Failure, Pediatric, Cardiomyopathy
Brief summary
This is a monocentric, prospective, single arm, not for profit study. It is designed to study the early use of ivabradine in patients with dilated cardiomyopathy and Ejection Fraction (EF) \< 45%.
Detailed description
The study is divided into a screening and enrollment visit (V1) where eligibility for treatment will be confirmed. Ivabradine will be administered to eligible patients with increasing dosage during the titration period (TP) which will last from a minimum of 3 days to a maximum of 15 days. This will be followed by a maintenance period (MP) of the drug for a further 14 days. The follow-up period (FU) will last 4 months. The dose of ACE inhibitors will be introduced after 72 hours of clinical stability after the introduction of titrated ivabradine at maximum dose according to protocol. The anti-aldosterone will be introduced 24 hours after the introduction of ivabradine. The diuretic will not be modified during the titration phase of the drug, unless there is clinical necessity. During the FU ivabradine will be continued at stable dosage, in order to maintain the target heart rate (HR) reached during the maintenance phase (HR \> 80 bpm, in the group of patients older than 6-12 months, or HR \> 70 bpm in patients aged 1-3 years or HR \> 50 bpm between 3-18 years). In all patients, the drug dose will be decreased or discontinued in case of bradycardia (HR\< 80 bpm in patients 6-12 months, HR\< 70 bpm in patients 1-3 years of age or HR\< 60 bpm in patients 3-18 years of age) and/or symptoms related to bradycardia or for other safety reasons.
Interventions
Initial dose of ivabradine will be: 0.02 mg/kg/dose twice daily in patients between 6-12 months 0.05 mg/kg/dose twice daily in patients between 1-3 years and 3-18 years with a weight \< 40 kg 2.5 mg/day in patients between 3-18 years with weight \> 40 kg During titration phase, the dose may be increased, maintained, reduced or discontinued in accordance with titration rules. The titration rules will be adjusted on the basis of age subset and of each patient's evaluation during the titration phase, whether or not the target heart rate is reached (HR ≥ 20% compared to baseline HR) and whether or not are present bradycardia (HR should be greater than predefined by a HR threshold per age subset) and/or bradycardia-related symptoms. Maximum dose to be reached will be: 0.2 mg/kg/dose twice daily in patients between 6-12 months 0.3 mg/kg/dose twice daily in patients between 1-3 years and 3-18 years with a weight \< 40 kg 15 mg/day in patients between 3-18 years, weight \> 40 kg
Sponsors
Ministero della Salute, Italy
Bambino Gesù Hospital and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Simon's two-stage design
Eligibility
Sex/Gender
ALL
Age
6 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
* Dilated cardiomyopathy defined according to the indications of the Cardiomyopathy Task Force (dilation \> 2 Standard Deviations (SD) and hypokinesia); * Class NYHA/Ross ≥ II; * Ejection fraction \< 40%; * Patients with acute heart failure episodes (both new episode and relapse) in the last three months; * Systolic blood pressure \> 50° age and height; * Heart rate: 6-12 months: ≥105 bpm, \>1 year \<3 years: ≥95 bpm, 3-5 years: ≥75 bpm, 5-18 years: \>70 bpm.
Exclusion criteria
* Cardiogenic shock in the three months; * Hypertrophic, restrictive or mixed cardiomyopathy; * Acute lymphocytic myocarditis diagnosed with endomyocardial biopsy; * Significant Valvular Pathology; * Sinus block and congenital long QT syndrome; * Atrial Fibrillation; * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels \> 2.5 times normal, bilirubin \> 3 and creatinine \> 2.5 mg/dL; * Pregnancy and/or positive pregnancy test patients; * Hypersensitivity to the active substance or any of the excipients; * Participation in a clinical trial in which an experimental drug was administered within 30 days or 5 half-lives of the investigational drug; * Chronic lung disease or other clinical condition that the investigating physician believes is incompatible with the study; * eGFR \<15 mL/min/1.73 m2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Heart rate in b.p.m. (mean (±SD) difference from baseline) at the end of maintenance | At the end of the two weeks maintenance period (17-29 days from enrollment) | To assess the response to ivabradine on heart rate after 14 days of stable therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heart rate in b.p.m. (mean (±SD) difference from baseline) at the end of follow-up | At the end of the 16 weeks follow-up period (129-141 days from enrollment) | To assess the response to ivabradine on heart rate after 16 weeks of follow-up |
| Serum NT-proBNP in pg/mL (mean (±SD) difference from baseline) at the end of maintenance | At the end of the two weeks maintenance period (17-29 days from enrollment) | To assess the response to ivabradine on serum NT-proBNP levels after 14 days of stable therapy |
| Serum NT-proBNP in pg/mL (mean (±SD) difference from baseline) at the end of follow-up | At the end of the 16 weeks follow-up period (129-141 days from enrollment) | To assess the response to ivabradine on serum NT-proBNP levels after 16 weeks of follow-up |
| Correlation between heart rate and NT-proBNP value (Pearson correlation) at the end of maintenance | At the end of the two weeks maintenance period (17-29 days from enrollment) | To assess the correlation between heart rate and serum NT-proBNP levels after 14 days of stable therapy |
| Correlation between heart rate and NT-proBNP value (Pearson correlation) at the end of follow-up | At the end of the 16 weeks follow-up period (129-141 days from enrollment) | To assess the correlation between heart rate and serum NT-proBNP levels after 16 weeks of follow-up |
| Left ventricular function, calculated by 2D echocardiographic technique (calculation of left ventricular volume and ejection fraction - mean (±SD) difference from baseline) at the end of maintenance | At the end of the two weeks maintenance period (17-29 days from enrollment) | To assess EF, Left Ventricular End Diastolic Volume (LVEDV), Left Ventricular End Systolic Volume (LVESV) after 14 days of stable therapy |
| Left ventricular function, calculated by 2D echocardiographic technique (calculation of left ventricular volume and ejection fraction - mean (±SD) difference from baseline) at the end of follow-up | At the end of the 16 weeks follow-up period (129-141 days from enrollment) | To assess EF, LVSV, LVDV after 16 weeks of follow-up |
| Systolic blood pressure in mmHg (mean (±SD) difference from baseline) at the end of maintenance | At the end of the two weeks maintenance period (17-29 days from enrollment) | To assess the response to ivabradine on systolic blood pressure after 14 days of stable therapy |
| Systolic blood pressure in mmHg (mean (±SD) difference from baseline) at the end of follow-up | At the end of the 16 weeks follow-up period (129-141 days from enrollment) | To assess the response to ivabradine on systolic blood pressure after 16 weeks of follow-up |
| Use of inotropic drugs (number and % of patients who had to use inotropes at the end of maintenance) | At the end of the two weeks maintenance period (17-29 days from enrollment) | To assess the need to resort to inotropic drugs within 14 days of stable ivabradine therapy |
| Use of inotropic drugs (number and % of patients who had to use inotropes at the end of follow-up) | At the end of the 16 weeks follow-up period (129-141 days from enrollment) | To assess the need to resort to inotropic drugs within 16 weeks of follow-up |
| Number and % of dropouts at the end of maintenance | At the end of the two weeks maintenance period (17-29 days from enrollment) | To assess the frequency of patients who exit from the study within 14 days of stable ivabradine therapy |
| Number and % of dropouts at the end of follow-up | At the end of the 16 weeks follow-up period (129-141 days from enrollment) | To assess the frequency of patients who exit from the study within 16 weeks of follow-up |
| Time (days) from start of ivabradine therapy and new episode of acute heart failure, and/or implantation of mechanical assist device at the end of follow up | At the end of the 16 weeks follow-up period (129-141 days from enrollment) | To assess the period within main cardiological events would occur after the start of ivabradine therapy |
Countries
Italy
Outcome results
None listed