Primary:To obtain paediatric pharmacokinetic data of enalapril and its active metabolite enalaprilat in patients treated with enalapril ODMTs to describe the dose exposure in the paediatric population with CHD. Secondary:1. To demonstrate safety of…
ID
Source
Brief title
Condition
- Congenital cardiac disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The bioavailability of enalapril and its active metabolite enalaprilat in young
children (AUC from 0 to time of last sampling point, Cmax and Tmax);
descriptive pharmacokinetic investigation.
Secondary outcome
1. The bioavailability of enalapril and its active metabolite enalaprilat in
the different age subsets (0 to *12 months and 12 months to *6 years) of the
paediatric study 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
pharmaco-dynamic 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 including the need for heart
transplantation or the institution of mechanical circulatory support.
8. Death due to worsening of the underlying disease.
9. Pharmacodynamic and efficacy endpoints analysis to differentiate high and
low output disease.
Background summary
Enalapril maleate has established medical use having been marketed in Europe
since 1983. Its safety and efficacy in adults are therefore well understood,
although less so in paediatric patients since few clinical studies have been
conducted in this population. The European Medicines Agency Expert Group
Meeting on Paediatric Heart Failure considers enalapril a first-line treatment
for chronic heart failure in children (EMA, 2010a).
There is currently no licensed formulation of enalapril available in Europe
suitable for use in children with heart failure, resulting in the
administration of extemporaneous oral preparations.
This study will enable the development of a novel clinically relevant
age-appropriate and acceptable enalapril formulation, with improved method of
administration and ease of dosing compared to products currently available.
Study objective
Primary:
To obtain paediatric pharmacokinetic data of enalapril and its active
metabolite enalaprilat in patients treated with enalapril ODMTs to describe the
dose exposure in the paediatric population with CHD.
Secondary:
1. To demonstrate safety of enalapril ODMTs in children with CHD.
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 CHD.
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 CHD.
Study design
Phase II/III prospective, open-label, single and multiple dose pharmacokinetic
bridging study with exploratory pharmacodynamic assessments in patients from
birth to less than 6 years of age.
Intervention
GROUP A
First dose: clinically comparable dosing of ACEI previously used
GROUP B
First dose of one or two 0.25 mg ODMTs in accordance with the dose banding
dosing regimen provided in this protocol, administered orally. If there is no
sustained hypotension as determined by common clinical practice during the 8
hours blood pressure surveillance period under the initial dose, daily
administration of the first dose will be continued for one week or shorter if
the clinical condition of the child requires more rapid up-titration. Daily
doses will be increased until the individually defined long-term dose is
reached as long as there is no sustained hypotension and serum creatinine and
potassium are acceptable as determined by common clinical practice before each
dose increase, respecting the agreed stopping rules.
First and second titration doses in children below 7 kg will be administered in
dispersed form if deemed appropriate by the investigator.
Study burden and risks
nvt
Wiecherstr. 3
Haltern am See 45721
DE
Wiecherstr. 3
Haltern am See 45721
DE
Listed location countries
Age
Inclusion criteria
- Age from birth to 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 ACEI.
- Subjects already on ACEI willing to switch to Enalapril Orodispersable Minitablets.
- Patient and/or parent(s)/legal representative provided written informed consent and assent from the patient received according to national legislation and as far as achievable from the child.
- Permitted: other CHF medications are allowed, at the discretion of the investigator. These include but are not limited to diuretics, beta-blockers, digoxin, mineralocorticoid receptor antagonist, aspirin and paracetamol.
Exclusion criteria
- Neonates if born < 37 weeks gestation.
- Severe HF and/or end stage heart failure requiring ICU support precluding introduction or continuation of ACEI.
- Too low blood pressure, e.g. - 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 ULN.
- History of Angioedema.
- Hypersensitivity to ACEI.
- Concomittant medication:
o Dual ACEI therapy
o Renin inhibitors
o Angiotensin II antagonists
o NSAIDs (including ibuprofen) 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-002396-18-NL |
| CCMO | NL54738.078.15 |