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

Heart Failure Clinical Trial

— LENA-WP08  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02652728
• Other study ID #: 2015-602295-01
• Secondary ID: 2015-002335-17
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• First received: January 3, 2016
• Last updated: January 8, 2016
• Start date: January 2016
• Est. completion date: June 2017

Study information

• Verified date: January 2016
• Source: Ethicare GmbH
• Contact: Stephanie Laeer, Prof,MD,PhD
• Phone: +49 211 8110740
• Email: Stephanie.Laeer[@]uni-duesseldorf.de
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyAustria: Austrian Medicines and Medical Devices AgencyNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Hungary: National Institute of PharmacySerbia: Medicines and Medical Devices Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: June 2017
• Est. primary completion date: June 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Month to 11 Years

Eligibility

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.

Study Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Dilated Cardiomyopathy
• Heart Failure

Intervention

Drug:
• Enalapril Orodispersible Minitablet
Weight-dependent dose titration and long-term treatment scheme with enalapril ODMTs of 0.25 mg and 1 mg strength

Locations

Country	Name	City	State
Austria	Medical University of Vienna	Vienna
Hungary	Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology	Budapest
Netherlands	Sophia Children's Hospital, Erasmus MC	Rotterdam
Netherlands	Wilhelmina Children's Hospital, University Medical Center Utrecht	Utrecht
Serbia	Univerzitetska Decja Klinika	Belgrade
United Kingdom	Great Ormond Street Hospital for Children NHS Trust	London

Sponsors (1)

Lead Sponsor	Collaborator
Ethicare GmbH

Countries where clinical trial is conducted

Austria,  Hungary,  Netherlands,  Serbia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure	Area under the Curve (AUC) of enalapril and enalaprilat are measured at first dose or at any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation	0 hours to 12 hours	Yes
Primary	Maximum Concentration (Cmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure	Maximum Concentration (Cmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation	0 hours to 12 hours	Yes
Primary	Time to Maximum Concentration (Tmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure	Time to Maximum Concentration (Tmax) of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy (1 month to less than 12 years); descriptive pharmacokinetic investigation	0 hours to 12 hours	Yes
Secondary	AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets	AUC of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 years; descriptive pharmacokinetic investigation	0 hours to 12 hours	Yes
Secondary	Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets	Cmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 years; descriptive pharmacokinetic investigation	0 hours to 12 hours	Yes
Secondary	Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets	Tmax of enalapril and enalaprilat are measured at first dose or any time during steady state to assess bioavailability of enalapril ODMTs in children with heart failure due to dilated cardiomyopathy in the age subsets 1 month to less than 1 year and 1 year to less than 12 years; descriptive pharmacokinetic investigation	0 hours to 12 hours	Yes
Secondary	Renin	Renin as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation	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)	Yes
Secondary	Angiotensin 1	Angiotensin 1 as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation	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)	Yes
Secondary	Aldosterone	Aldosterone as marker of the renin-angiotensin-aldosterone system at every study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation	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)	Yes
Secondary	Plasma Renin Activity	Plasma Renin Activity as marker of the renin-angiotensin-aldosterone system at each study visit up to the end of treatment at 8 weeks; exploratory pharmacodynamic investigation	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)	Yes
Secondary	Brain natriuretic peptides (BNP)	Brain natriuretic peptides measurement as indicator of disease severity measured at every visit up to the end of treatment at 8 weeks	At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (day 14, 28, 42), at Last Visit (day 56)	Yes
Secondary	Acceptability of the ODMTs	Acceptability assessment according to an age-appropriate scale	Assessment time points: at Initial Dose, at one Study Control Visit (at days 14, 28 or 42), at Last Visit (day 56)	Yes
Secondary	Palatability of the ODMTs	Palatability assessment according to an age-appropriate scale	Assessment time points: at Initial Dose, at one Study Control Visit (at days 14, 28 or 42), at Last Visit (day 56)	Yes
Secondary	Blood pressure	Safety monitoring parameter to decide on next dose prescription level	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)	Yes
Secondary	Serum potassium	Renal monitoring parameter to decide on next dose prescription level	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)	Yes
Secondary	Blood urea nitrogen (BUN)	Renal monitoring parameter to decide on next dose prescription level	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)	Yes
Secondary	Creatinine	Renal monitoring parameter to decide on next dose prescription level	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)	Yes
Secondary	Micro-albuminuria	Renal monitoring parameter to decide on next dose prescription level	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)	Yes
Secondary	Shortening fraction	Shortening Fraction in echocardiography	Assessment time points: at Screening Visit and at Last Visit (day 56)	Yes
Secondary	Number of patients experiencing rehospitalisation due to heart failure	Number of patients experiencing rehospitalisation due to heart failure including the need for heart transplantation or the institution of mechanical circulatory support	During 8 weeks of treatment	Yes
Secondary	Death due to worsening of the underlying disease	Death due to worsening of the underlying disease	During 8 weeks of treatment	Yes

External Links

•   FP7-funded "LENA" project, Grant Agreement 602295