Orodispersible Minitablets of Enalapril in Children With Heart Failure Due to Dilated Cardiomyopathy

Study Overview
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Brief Summary
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Paediatric clinical trial in 50 children, from 1 month to less than 12 years of age, suffering from heart failure due to dilated cardiomyopathy, 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 up to Adolescents) project: 50 children with heart failure due to dilated cardiomyopathy (LENA-Work Package (WP) 08 Trial) and 50 children with heart failure due to congenital heart disease (LENA-WP09 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 WP08 Trial children between 1 month and less than 12 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 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 protocol a target dose similar to the adult target dose (20 mg of 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 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 ACE-inhibition on cardiac outcome and renal function.

Official Title
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Orodispersible Minitablets of Enalapril in Children With Heart Failure Due to Dilated Cardiomyopathy

Conditions
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Heart Failure, Dilated Cardiomyopathy

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 presenting with heart failure with signs of left ventricular (LV) systolic dysfunction who are eligible to receive ACE-Inhibitors in addition to standard therapy (e.g., digitalis and diuretics) can be enrolled into this trial. Patients who previously presented with LV systolic dysfunction and who have already been treated with ACE-Inhibitors, and currently still have an indication for the use of an ACE-Inhibitor can be switched to an equivalent starting dose of enalapril ODMT. Patients fulfilling the following inclusion criteria can be enrolled Age 1 month to less than 12 years. Male and female patients. Diagnosis of dilated cardiomyopathy presenting with LV end-diastolic dimension > P95 and/or LV shortening fraction (SF) < 25% Subjects may be naïve to ACE-Inhibitor. Subjects already on ACE-Inhibitor willing to switch to enalapril Orodispersible Minitablets. Written informed consent from parent(s)/legal representative 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: Severe heart failure and/or end stage heart failure precluding introduction or continuation of ACE-Inhibitor. Too low blood pressure, e.g. ˂P5 Restrictive and hypertrophic cardiomyopathies. Obstructive valvular disease (peak echocardiographic gradient more than 30 mm Hg). 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-Inhibitor. Concomitant 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 Month
Maximum Age: 11 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>* Weight-dependent dose titration and long-term treatment scheme with enalapril ODMTs of 0.25 mg and 1 mg strength<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 bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation | 0 hours to 12 hours | 
| Maximum Concentration (Cmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure | Maximum Concentration (Cmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation | 0 hours to 12 hours | 
| Time to Maximum Concentration (Tmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure | Time to Maximum Concentration (Tmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 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 children with heart failure of two age-subsets | AUC of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 years; descriptive pharmacokinetic investigation | 0 hours to 12 hours | 
| Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets | Cmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 years; descriptive pharmacokinetic investigation | 0 hours to 12 hours | 
| Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets | Tmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 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 (day 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 (day 14, 28, 42) up to Last Visit after 8 (day 56) | 
| Aldosterone | Aldosterone as marker of the renin-angiotensin-aldosterone system at every 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 (day 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 (day 14, 28, 42) up to Last Visit (day 56) | 
| Brain natriuretic peptides (BNP) | Brain natriuretic peptides measurement as indicator of disease severity measured at every visit up to the end of treatment at 8 weeks | At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (day 14, 28, 42), at Last Visit (day 56) | 
| Acceptability of the ODMTs | Acceptability assessment according to an age-appropriate scale | Assessment time points: at Initial Dose, at one Study Control Visit (at days 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, at one Study Control Visit (at days 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), over 2 hours after all other Titration Visits, pre-dose at all Study Control Visits (at days 14, 28 and 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 |