Paediatric clinical trial in 50 children, from newborn to less than 6 years of age, suffering from heart failure due to congenital heart disease, to obtain paediatric pharmacokinetic and pharmacodynamic data of enalapril and its active metabolite enalaprilat while treated for 8 weeks with enalapril in form of Orodispersible Minitablets (ODMTs), to describe the dose exposure in this patient population.
This clinical trial is one of three clinical trials of the European Commission (FP7)-funded "LENA" (Labeling of Enalapril from Neonates to Adolescents) project: 50 children with heart failure due to congenital heart disease (LENA-Work Package (WP)09 Trial), and 50 children with heart failure due to dilated cardiomyopathy (LENA-WP08 Trial) get treated with an optimal dose of enalapril ODMTs for up to 8 weeks after thorough, individualised titration and get invited to join the 10 months Safety Follow-up Study (LENA-WP10 Trial). In this WP09 Trial children from age of newborn to less than 6 years, naive to enalapril treatment or switched from an Angiotensin-Converting-Enzyme (ACE)-Inhibitor pre-treatment, receive an Initial Dose to investigate the reaction over 8 hours before a decision on the first dose level is made. Always up to 7 days later a next higher dose is given at the hospital, the patient is supervised for 4 and then always 2 hours before a decision on the prescribed dose for the next dosing period is made. In this study a target dose similar to the adult target dose (20 mg enalapril in a 70 year old adult result in 0.282 mg/kg/day enalapril) is defined. Enalapril ODMTs of 0.25 mg and 1 mg strength are available to allow for an individual dose titration scheme. Weight-dependently, pharmacokinetic (PK) and pharmacodynamic (PD) data are collected once in a full PK/PD day over 12, respectively 6 hours, and single PK/PD samples at each Dose Titration Visit and each bi-weekly Study Control Visit until the Last Visit after 8 weeks of treatment. Blood pressure and renal monitoring is performed at each visit before deciding on the dose level for the next treatment period. Pharmacogenomics and metabolomics exploratory studies are added as a sub-study to better understand the underlying disease, its progression as well as the impact of the ACE-inhibition on cardiac outcome and renal function.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
8-weeks treatment, open, uncontrolled, PK/PD, acceptability and palatability assessments and safety assessments after Enalapril intake in form of 0.25 mg or 1 mg ODMTs
Medical University of Vienna
Vienna, Austria
Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology
Budapest, Hungary
Sophia Children's Hospital, Erasmus MC
Rotterdam, Netherlands
Wilhelmina Children's Hospital, University Medical Center Utrecht
Utrecht, Netherlands
Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
Area under the Curve (AUC) of enalapril and enalaprilat are measured at first dose or at any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation
Time frame: 0 hours to 12 hours
Maximum Concentration (Cmax) of enalapril and its active metabolite
Maximum Concentration (Cmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation
Time frame: 0 hours to 12 hours
Time to Maximum Concentration (Tmax) of enalapril and its active metabolite
Time to Maximum Concentration (Tmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease (newborn to less than 6 years); descriptive pharmacokinetic investigation
Time frame: 0 hours to 12 hours
AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure
AUC of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease in the age su-sets newborn to less than 1 year and 1 to less than 6 years; descriptive pharmacokinetic investigation
Time frame: 0 hours to 12 hours
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Univerzitetska Dečja Klinika
Belgrade, Serbia
Great Ormond Street Hospital for Children NHS Trust
London, United Kingdom
Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure
Cmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease in the age su-sets newborn to less than 1 year and 1 to less than 6 years; descriptive pharmacokinetic investigation
Time frame: 0 hours to 12 hours
Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in two age-subsets of children with heart failure
Tmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess the bioavailability of enalapril ODMTs in young children with heart failure due to congenital heart disease in the age su-sets newborn to less than 1 year and 1 to less than 6 years; descriptive pharmacokinetic investigation
Time frame: 0 hours to 12 hours
Renin
Renin as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation
Time frame: Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56)
Angiotensin 1
Angiotensin 1 as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation
Time frame: Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56)
Aldosterone
Aldosterone as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation
Time frame: Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56)
Plasma Renin Activity
Plasma Renin Activity as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation
Time frame: Pre-dose, 4 h post first dose, pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56)
Brain natriuretic peptides (BNPs).
Brain natriuretic peptides measurement as indicator of disease severity at every visit up to end of treatment at 8 weeks
Time frame: At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (days 14, 28, 42) up to Last Visit (day 56)
Acceptability of the ODMTs
Acceptability assessment according to an age-appropriate scale
Time frame: Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56)
Palatability of the ODMTs
Palatability assessment according to an age-appropriate scale
Time frame: Assessment time points: at Initial Dose Visit, at one Study Control Visit (day 14, 28 or 42), at Last Visit (day 56)
Blood pressure
Safety monitoring parameter to decide on next dose prescription level
Time frame: Pre-dose at each Visit, over 8 hours at Initial Dose Visit, over 4 hours at First Titration Visit (day 3 to 7), for 2 hours after all following Titration Visits, pre-dose at all Study Control Visits (day 14, 28, 42), at last Visit (day 56)
Serum potassium
Renal monitoring parameter to decide on next dose prescription level
Time frame: Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56)
Blood urea nitrogen (BUN)
Renal monitoring parameter to decide on next dose prescription level
Time frame: Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56)
Creatinine
Renal monitoring parameter to decide on next dose prescription level
Time frame: Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56)
Micro-albuminuria
Renal monitoring parameter to decide on next dose prescription level
Time frame: Pre-dose at each Visit: Screening Visit, Initial Dose Visit, all Titration Visits, all Study Control Visits (day 14, 28, 42) up to Last Visit (day 56)
Shortening Fraction
Shortening Fraction in echocardiography
Time frame: Assessment time points: at Screening Visit and at Last Visit (day 56)
Number of patients experiencing rehospitalisation due to heart failure
Number of patients experiencing rehospitalisation due to heart failure including the need for heart transplantation or the institution of mechanical circulatory support
Time frame: During 8 weeks of treatment
Death due to worsening of the underlying disease
Death due to worsening of the underlying disease
Time frame: During 8 weeks of treatment