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

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.

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.

Eligibility Criteria:
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.