Follow-up Safety Trial in Children With Chronic Heart Failure Therapy Receiving Orodispersible Minitablets of Enalapril (LENA-WP10)

Paediatric long-term safety follow-up clinical trial in maximum 100 children with heart failure due to dilated cardiomyopathy or congenital heart disease, from 1 day to less than 12 years of age at recruitment into the preceding short-term pharmacokinetic (PK)/pharmacodynamic (PD) trials. Pharmacodynamic measurements and renal monitoring in all children after 1 , 4, 7 and 10 months of follow-up; in addition PK assessments as well as acceptability and palatability assessments in children still under enalapril Orodispersible Minitablet (ODMT) treatment.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; Dilated Cardiomyopathy; Congenital Heart Disease
• Intervention / Treatment: Drug: Enalapril Orodispersible Minitablet

Detailed Description

This clinical trial is one of three clinical trials of the European Commission (FP7)-funded "LENA" (Labeling of Enalapril from Neonates 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 this 10 months Safety Follow-up Study (LENA-WP10 Trial).

Reliable data on the long-term safety of enalapril in paediatric patients are currently not available. By conducting this long-term Safety Follow-up Trial in children who received or still receive enalapril Orodispersible Minitablets at the end of the 8-weeks PK/PD LENA-Work Package (WP)08 (children with heart failure due to dilated cardiomyopathy) and LENA-WP09 (children with heart failure due to congenital heart disease) Trials using sensitive and highly specific assay methodology, it will be possible to add to the generation of reliable PK and PD data in the whole paediatric age range from birth to 12 years. In addition, this follow-up study will allow to systematically collect follow-up information over 10 more months, so in total 12 months, in paediatric patients under long-term enalapril ODMT treatment and in paediatric patients who had received at least 3 days of ODMT treatment but then stopped for any reason.

The End-of-study Visit of the WP08 and WP09 Trials is also the First Visit of the Follow-up Study. Further Visits occur after 1 month, 4 months, 7 months and 10 months.

At each Visit blood pressure and renal monitoring as well as pharmacodynamic parameters and adverse events are assessed. In children under ongoing enalapril ODMT treatment, single PK sampling as well as acceptability and palatability assessments are made at each Visit.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Stephanie Laeer, Prof,MD,PhD; Phone Number: +49 211 8110740; Email: stephanie.laeer@uni-duesseldorf.de
• Study Contact Backup: Name: Ingrid Klingmann, MD,PhD; Phone Number: +32 2 784 3693; Email: iklingmann@pharmaplex.be

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna
    • Contact: Christoph Male, Prof,MD,PhD; Phone Number: + 43 1 40400 32320; Email: christoph.male@meduniwien.ac.at
    • Contact: Vanessa Swoboda, MD; Phone Number: + 43 1 40400 32320; Email: v.swoboda@live.at
    • Principal Investigator: Christoph Male, Prof,MD,PhD
    • Sub-Investigator: Vanessa Swoboda, MD
• Hungary
  • Budapest, Hungary, 1095
    • Hungarian Paediatric Heart Centre,Göttsegen Gyorgy Hungarian Institute of Cardiology
    • Contact: Andras Szatmari, Prof,MD,PhD; Phone Number: +36 1 215 1220; Email: szatmari@kardio.hu
    • Principal Investigator: Andras Szatmari, Prof,MD,Phd
    • Sub-Investigator: Laszlo Ablonczy, MD
    • Contact: Laszlo Ablonczy, MD; Phone Number: +36 1 215 1220; Email: 'Laszlo Ablonczy' <ablonczyl@gmail.com>
• Netherlands
  • Rotterdam, Netherlands, 3015 CN
    • Sophia Children's Hospital Erasmus MC
    • Principal Investigator: Michiel Dalinghaus, MD,PhD
    • Contact: Saskia N. de Wildt, MD,PhD; Phone Number: +31 10 7040704; Email: s.dewildt@erasmusmc.nl
    • Contact: Tjitske van der Zanden; Phone Number: +31 10 7040704; Email: t.vanderzanden@erasmusmc.nl
    • Sub-Investigator: Marijke Van der Meulen, MD,PhD
  • Utrecht, Netherlands, 3584 CX
    • Wilhelmina Children's Hospital, University Medical Center Utrecht
    • Contact: J.M.P. J. Breur, MD,PhD; Phone Number: + 31 8875 540 02; Email: h.breur@umcutrecht.nl
    • Principal Investigator: J.M.P. J. Breur, MD,PhD
• Serbia
  • Belgrade, Serbia, 11129
    • Univerzitetska Dečja Klinika
    • Contact: Ida Jovanovic, Prof,MD,PhD; Phone Number: + 38 1112060716; Email: idaj@rcub.bg.ac.rs
    • Principal Investigator: Ida Jovanovic, Prof,MD,PhD
    • Contact: Milica Bajcetic, Prof,MD,PhD; Phone Number: +38 1112060716; Email: milica.bajcetic@udk.bg.ac.rs
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital for Children NHS Trust
    • Contact: Michael Burch, Prof,MD,PhD; Phone Number: +44 020 7405 9200; Email: michael.burch@gosh.nhs.uk
    • Principal Investigator: Michael Burch, Prof,MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients from the WP08 and WP09 Trials who have been treated with enalapril Orodispersible Minitablets and are still under ODMT treatment.
• Patients from the WP08 and WP09 Trials who have been treated for at least 3 days with enalapril Orodispersible Minitablets and are no longer under ODMT treatment.
• Written informed consent from parent(s)/legal representative provided written informed consent for participation in this long term follow-up study and assent from the patient according to national legislation and as far as achievable from the child.

Exclusion Criteria:

Patients who have been enrolled and treated in the WP08 or WP09 Trials have fulfilled the respective in- and exclusion criteria of those protocols. As it is the aim of this Follow-up Study to observe the safety of all patients exposed to enalapril ODMT treatment, no additional exclusion criteria are defined in this protocol. However, adapted to the health situation of the patient, the investigator will decide whether planned study activities can be performed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Enalapril Orodispersible Minitablets; Individually adapted dose of enalapril consisting of 1 to maximum 4 enalapril ODMTs of 0.25 mg and/or 1 mg and/or other prescribed treatment of heart failure.	Drug: Enalapril Orodispersible Minitablet; Weight-dependent long-term treatment scheme with enalapril ODMTs of 0.25 and/or 1 mg strength; Other Names: Enalapril ODMT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with Adverse Reactions	Adverse Reaction definition according to European Directive 2001/20/EC, assessed at each Visit concerning intensity and causality	up to month 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure	Measurement pre-dose after 5 minutes at rest at every Visit up to end of treatment at Month 10	At every Visit: (day 0, month 1, 4, 7, 10)
Renin	Renin to assess the Renin-angiotensin-aldosterone system (RAAS) measured at every Visit up to end of treatment at Month 10	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Angiotensin 1	Angiotensin 1to assess the Renin-angiotensin-aldosterone system (RAAS) measured at every Visit up to end of treatment at Month 10	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Aldosterone	Aldosterone to assess the Renin-angiotensin-aldosterone system (RAAS) measured at every Visit up to end of treatment at Month 10	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Plasma Renin Activity	Plasma renin activity to assess the Renin-angiotensin-aldosterone system (RAAS) measured at every Visit up to end of treatment at Month 10	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Creatinine	Creatinine for renal monitoring measured at every Visit up to end of treatment at Month 10	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Urea nitrogen	Urea nitrogen for renal monitoring measured at every Visit up to end of treatment at Month 10	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Serum potassium	Serum potassium for renal monitoring measured at every Visit up to end of treatment at Month 10	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Brain-Natriuretic-Peptides (BNP)	BNP measured at every visit up to end of treatment at Month 10 to observe disease severity	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Micro-albuminuria	Measurement of micro-albuminuria for renal monitoring measured at every Visit up to end of treatment at Month 10	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Clinical haematology	Assessment at First and Last Study Visit at the end of treatment at Month 10	Day 0 and Month 10
ECG	Assessment at First and Last Study Visit at the end of treatment at Month 10	Day 0 and Month 10
Plasma concentration of enalapril and its active metabolite enalaprilat under long-term treatment	At each Visit in children under enalapril ODMT treatment a single blood sample will be collected to measure the enalapril and enalaprilat plasma levels during long-term treatment; population-kinetic investigation	Pre-dose at each Visit: (day 0, month 1, 4, 7, 10)
Acceptability assessment of enalapril ODMTs	Acceptability assessment at each Visit up to end of treatment at 10 months in children under enalapril ODMT treatment according to an age-appropriate scale	At each Visit: (day 0, month 1, 4, 7, 10)
Palatability assessment of enalapril ODMTs	Palatability assessment at each Visit up to end of treatment at Month 10 in children under enalapril ODMT treatment according to an age-appropriate scale	At each Visit: (day 0, month 1, 4, 7, 10)

Collaborators and Investigators

• Sponsor: Ethicare GmbH
• Investigators: Principal Investigator: Ida Jovanovic, Prof,MD,PhD, Univerzitetska Dečja Klinika Belgrade; Study Chair: Saskia N. de Wildt, MD,PhD, Sophia Children's Hospital, Erasmus MC; Principal Investigator: Michiel Dalinghaus, MD,PhD, Sophia Children's Hospital, Erasmus MC; Principal Investigator: J.M.P. J. Breur, MD,PhD, Wilhelmina Children's Hospital, University Medical Center Utrecht; Principal Investigator: Christoph Male, Prof,MD,PhD, Medical University of Vienna; Principal Investigator: Michael Burch, Prof,MD,PhD, Great Ormond Street Hospital for Children NHS Trust London; Principal Investigator: András Szatmári, Prof,MD,PhD, Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Anticipated): April 1, 2018
• Study Completion (Anticipated): April 1, 2018

Study Registration Dates

• First Submitted: January 4, 2016
• First Submitted That Met QC Criteria: January 12, 2016
• First Posted (Estimate): January 13, 2016

Study Record Updates

• Last Update Posted (Estimate): January 13, 2016
• Last Update Submitted That Met QC Criteria: January 12, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Cardiovascular Abnormalities; Cardiomegaly; Laminopathies; Heart Failure; Heart Diseases; Cardiomyopathies; Cardiomyopathy, Dilated; Heart Defects, Congenital; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Enalapril
• Other Study ID Numbers: 2015-602295-03; 2015-002397-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Serious Adverse Event information