Clinical trial NCT02652728: Orodispersible Minitablets of Enalapril in Children With Heart Failure Due to Dilated Cardiomyopathy
Official title: Orodispersible Minitablets of Enalapril in Children With Heart Failure Due to Dilated Cardiomyopathy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Heart Failure
Dilated Cardiomyopathy
Lead sponsor: Ethicare GmbH
Sponsor class: INDUSTRY
First posted: 2016-01-12
Enrollment: 50
Sex: ALL
Minimum age (years): 1
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Primary outcomes:
measure: Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
timeFrame: 0 hours to 12 hours
measure: Maximum Concentration (Cmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
timeFrame: 0 hours to 12 hours
measure: Time to Maximum Concentration (Tmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure
timeFrame: 0 hours to 12 hours
Secondary outcomes:
measure: AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets
timeFrame: 0 hours to 12 hours
measure: Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets
timeFrame: 0 hours to 12 hours
measure: Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets
timeFrame: 0 hours to 12 hours
measure: Renin
timeFrame: 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)
measure: Angiotensin 1
timeFrame: 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)
measure: Aldosterone
timeFrame: 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)
measure: Plasma Renin Activity
timeFrame: 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)
measure: Brain natriuretic peptides (BNP)
timeFrame: At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (day 14, 28, 42), at Last Visit (day 56)
measure: Acceptability of the ODMTs
timeFrame: Assessment time points: at Initial Dose, at one Study Control Visit (at days 14, 28 or 42), at Last Visit (day 56)
measure: Palatability of the ODMTs
timeFrame: Assessment time points: at Initial Dose, at one Study Control Visit (at days 14, 28 or 42), at Last Visit (day 56)
measure: Blood pressure
timeFrame: 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)
measure: Serum potassium
timeFrame: 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)
measure: Blood urea nitrogen (BUN)
timeFrame: 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)
measure: Creatinine
timeFrame: 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)
measure: Micro-albuminuria
timeFrame: 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)
measure: Shortening fraction
timeFrame: Assessment time points: at Screening Visit and at Last Visit (day 56)
measure: Number of patients experiencing rehospitalisation due to heart failure
timeFrame: During 8 weeks of treatment
measure: Death due to worsening of the underlying disease
timeFrame: During 8 weeks of treatment
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Budapest
country: Hungary
facility: Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology
city: Rotterdam
country: Netherlands
facility: Sophia Children's Hospital, Erasmus MC
city: Utrecht
country: Netherlands
facility: Wilhelmina Children's Hospital, University Medical Center Utrecht
city: Belgrade
country: Serbia
facility: Univerzitetska Dečja Klinika
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Trust
Study officials:
affiliation: Sophia Children's Hospital Erasmus MC Rotterdam
name: Michiel Dalinghaus, MD, PhD
role: STUDY_CHAIR
affiliation: Wilhelmina Children's Hosptial University Medical Center Utrecht
name: J.M.P. J. Breur, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Univerzitetska Decja Klinika Belgrade
name: Ida Jovanovic, Prof,MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Vienna
name: Christoph Male, Prof, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Great Ormond Street Hospital for Children London
name: Michael Burch, Prof,MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hungarian Paediatric Heart Institute, Göttsegen Gyorgy Hungarian Institute of Cardiology Budapest
name: András Szatmári, Prof,MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: