E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart Failure due to Dilated Cardiomyopathy |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056419 |
E.1.2 | Term | Dilated cardiomyopathy |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To obtain paediatric pharmacokinetic data of enalapril and its active metabolite enalaprilat in paediatric patients treated with enalapril
ODMTs to describe the dose exposure in the paediatric population with DCM. |
|
E.2.2 | Secondary objectives of the trial |
1. To demonstrate safety, in particular renal safety, of enalapril ODMTs
in children with DCM.
2. To characterise the dose/safety relationship from a starting dose to
an optimal maintenance dose.
3. To explore the dose exposure/response relationship with
pharmacodynamic parameters in the paediatric population with DCM.
4. To investigate the Shortening Fraction (SF) of the heart muscle by
echocardiography.
5. To investigate the acceptability and palatability of enalapril ODMTs in
the paediatric population with DCM. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
LENA Pharmacogenomics and metabolomics exploratory studies V 2.0 date 25Jan2016 |
|
E.3 | Principal inclusion criteria |
• Age 1 month to <12 years.
• Male and female patients.
• Diagnosis of DCM presenting with LV end-diastolic dimension ˃ P95 and/or LV shortening fraction ˂ 25% in patients, resulting from different types of underlying cardiac diseases with signs of decreased systolic LV function, and without ACE Inhibitor treatment; patients with ACE inhibitor pre-treatment must have documented
evidence of having fulfilled these criteria before start of
the ACE Inhibitor therapy.
• Subjects already on ACEI willing to switch to enalapril Orodispersable Minitablets.
• Patient and/or parent(s)/legal representative provided written
informed consent.
Permitted:
Other CHF medications will be allowed, at the discretion of the treating
physician. These include but are not limited to diuretics, beta-blockers,
digoxin, mineralocorticoid receptor antagonist, aspirin and paracetamol. |
|
E.4 | Principal exclusion criteria |
• Severe HF and/or end stage heart failure precluding introduction or
continuation of ACEI.
• 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 ULN (Upper Limit
of Normal) according to the hospital's test methodology).
• History of angioedema.
• Hypersensitivity to ACEI.
• Concomittant medication:
o Dual ACEI therapy
o Renin inhibitors
o Angiotensin II antagonists
o NSAIDs except acetylsalicylic acid only for antiplatelet therapy
• Already enrolled in an interventional trial with an investigational
drug, unless no interference with the current study can be shown. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The bioavailability of enalapril and its active metabolite enalaprilat in the
paediatric population (AUC from 0 to time of last sampling point, Cmax
and Tmax); descriptive pharmacokinetic investigation. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK/PD profile sampling timepoint: Visit day 1: pre-dose, 0h, 2, 4, 6, 8, 12
hours |
|
E.5.2 | Secondary end point(s) |
1. The bioavailability of enalapril and its active metabolite enalaprilat in
the different age subsets (1 months to ˂12 months, 12 months to ˂6
years, 6 years to ˂12 years) of the paediatric population (AUC from 0 to
time of last sampling point, Cmax and Tmax); descriptive
pharmacokinetic investigation.
2. Markers of the renin-angiotensin-aldosterone system as exploratory
pharmacodynamic investigation.
3. Brain natriuretic peptides (BNPs).
4. Acceptability and palatability of the novel formulation.
5. Safety parameters including blood pressure and renal function.
6. Echocardiography (Shortening Fraction)
7. Rehospitalisation due to heart failure.
8. Death due to worsening of the underlying disease
9. Pharmacodynamic and efficacy endpoints analysis to differentiate
high and low output disease |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Biochemistry and Urine collected during each visit in the hospital to ensure renal function.
PK and PD 1 sample collected during each visit, unless the patient terminated use of the IMP, then only PD sample is collected.
Acceptability and Palatability questionnaire is completed during initial visit, once stable dose is reached and during end of study visit. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Group 1: ACEI-pretreated patients. Group B: ACEI-naive patients |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Germany |
Hungary |
Netherlands |
Serbia |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |