Orodispersible Minitablets of Enalapril in Young Children With Heart Failure Due to Congenital Heart Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Orodispersible Minitablets of Enalapril in Young Children With Heart Failure Due to Congenital Heart Disease

Conditions
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Heart Failure, Congenital Heart Disease

Intervention / Treatment
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* Drug: Enalapril Orodispersible Minitablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients fulfilling the following Inclusion Criteria can be enrolled: Age from birth to less than 6 years. Male and female patients. Weight greater than 2.5 kg. Diagnosis of heart failure due to congenital heart disease requiring after-load reduction by drug therapy. Subjects may be naïve to ACE-Inhibitors. Subjects already on ACE-Inhibitors willing to switch to enalapril Orodispersible Minitablets. Patient and/or parent(s)/legal representative provided written informed consent and assent from the patient according to national legislation and as far as achievable from the child. Exclusion Criteria: Patients fulfilling any of the following Exclusion Criteria cannot be enrolled into this trial: Neonates if born < 37 weeks of gestation. Severe heart failure and/or end stage heart failure precluding introduction or continuation of ACE-Inhibitor. Too low blood pressure, e.g. ˂P5 Uncorrected primary obstructive valvular disease, or significant systemic ventricular outflow obstruction, dilated restrictive or hypertrophic cardiomyopathy. Uncorrected severe peripheral stenosis of large arteries including severe coarctation of the aorta. Severe renal impairment with serum creatinine >2x Upper Limit of Normal (ULN) (according to the hospital's test methodology) History of angioedema. Hypersensitivity to ACE-Inhibitors. Concommitant medication: Dual ACE-Inhibitor therapy Renin inhibitors Angiotensin II antagonists Non-Steroidal Anti-Inflammatory Drugs (including ibuprofen) except for aspirin and paracetamol Already enrolled in an interventional trial with an investigational drug, unless no interference with the current study can be shown.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug administration<br>Enalapril Orodispersible Minitablet (ODMT), 0.25 mg or 1 mg, administered 1x/day or 2x/day for up to 8 weeks | Drug: Enalapril Orodispersible Minitablet<br>* 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<br>* Other names: Enalapril ODMT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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 | 0 hours to 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 0 hours to 12 hours | 
| 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | During 8 weeks of treatment | 
| Death due to worsening of the underlying disease | Death due to worsening of the underlying disease | During 8 weeks of treatment |