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

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.

Eligibility Criteria:
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.