Back to results

Orodispersible Minitablets of Enalapril in Children With Heart Failure Due to Dilated Cardiomyopathy (LENA-WP08)

Primary Purpose

Heart Failure, Dilated Cardiomyopathy

Status

Unknown status

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Enalapril Orodispersible Minitablet

About this trial

This is an interventional treatment trial for Heart Failure

Eligibility Criteria

1 Month - 11 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Medical University of Vienna
Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology
Sophia Children's Hospital, Erasmus MC
Wilhelmina Children's Hospital, University Medical Center Utrecht
Univerzitetska Dečja Klinika
Great Ormond Street Hospital for Children NHS Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Drug administration

Arm Description

Enalapril Orodispersible Minitablet (ODMT), 0.25 mg or 1 mg, administered 1x/day or 2x/day for up to 8 weeks

Outcomes

Primary Outcome Measures

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

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

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

Secondary Outcome Measures

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

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

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

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

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

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

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

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

Acceptability of the ODMTs

Acceptability assessment according to an age-appropriate scale

Palatability of the ODMTs

Palatability assessment according to an age-appropriate scale

Blood pressure

Safety monitoring parameter to decide on next dose prescription level

Serum potassium

Renal monitoring parameter to decide on next dose prescription level

Blood urea nitrogen (BUN)

Renal monitoring parameter to decide on next dose prescription level

Creatinine

Renal monitoring parameter to decide on next dose prescription level

Micro-albuminuria

Renal monitoring parameter to decide on next dose prescription level

Shortening fraction

Shortening Fraction in echocardiography

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

Death due to worsening of the underlying disease

Full Information

NCT ID

NCT02652728

First Posted

January 3, 2016

Last Updated

January 8, 2016

Sponsor

Ethicare GmbH

1. Study Identification

Unique Protocol Identification Number

NCT02652728

Brief Title

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

Acronym

LENA-WP08

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2016

Overall Recruitment Status

Unknown status

Study Start Date

January 2016 (undefined)

Primary Completion Date

June 2017 (Anticipated)

Study Completion Date

June 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Ethicare GmbH

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure, Dilated Cardiomyopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Drug administration

Arm Type

Experimental

Arm Description

Enalapril Orodispersible Minitablet (ODMT), 0.25 mg or 1 mg, administered 1x/day or 2x/day for up to 8 weeks

Intervention Type

Drug

Intervention Name(s)

Enalapril Orodispersible Minitablet

Other Intervention Name(s)

Enalapril ODMT

Intervention Description

Weight-dependent dose titration and long-term treatment scheme with enalapril ODMTs of 0.25 mg and 1 mg strength

Primary Outcome Measure Information:

Title

Area under the Curve (AUC) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure

Description

Time Frame

0 hours to 12 hours

Title

Maximum Concentration (Cmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure

Description

Time Frame

0 hours to 12 hours

Title

Time to Maximum Concentration (Tmax) of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure

Description

Time Frame

0 hours to 12 hours

Secondary Outcome Measure Information:

Title

AUC of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets

Description

Time Frame

0 hours to 12 hours

Title

Cmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets

Description

Time Frame

0 hours to 12 hours

Title

Tmax of enalapril and its active metabolite enalaprilat after administration of enalapril ODMTs in children with heart failure of two age-subsets

Description

Time Frame

0 hours to 12 hours

Title

Renin

Description

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

Time Frame

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)

Title

Angiotensin 1

Description

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

Time Frame

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)

Title

Aldosterone

Description

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

Time Frame

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)

Title

Plasma Renin Activity

Description

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

Time Frame

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)

Title

Brain natriuretic peptides (BNP)

Description

Brain natriuretic peptides measurement as indicator of disease severity measured at every visit up to the end of treatment at 8 weeks

Time Frame

At Screening Visit and then pre-dose at each Titration Visit and Study Control Visit (day 14, 28, 42), at Last Visit (day 56)

Title

Acceptability of the ODMTs

Description

Acceptability assessment according to an age-appropriate scale

Time Frame

Assessment time points: at Initial Dose, at one Study Control Visit (at days 14, 28 or 42), at Last Visit (day 56)

Title

Palatability of the ODMTs

Description

Palatability assessment according to an age-appropriate scale

Time Frame

Assessment time points: at Initial Dose, at one Study Control Visit (at days 14, 28 or 42), at Last Visit (day 56)

Title

Blood pressure

Description

Safety monitoring parameter to decide on next dose prescription level

Time Frame

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)

Title

Serum potassium

Description

Renal monitoring parameter to decide on next dose prescription level

Time Frame

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)

Title

Blood urea nitrogen (BUN)

Description

Renal monitoring parameter to decide on next dose prescription level

Time Frame

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)

Title

Creatinine

Description

Renal monitoring parameter to decide on next dose prescription level

Time Frame

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)

Title

Micro-albuminuria

Description

Renal monitoring parameter to decide on next dose prescription level

Time Frame

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)

Title

Shortening fraction

Description

Shortening Fraction in echocardiography

Time Frame

Assessment time points: at Screening Visit and at Last Visit (day 56)

Title

Number of patients experiencing rehospitalisation due to heart failure

Description

Number of patients experiencing rehospitalisation due to heart failure including the need for heart transplantation or the institution of mechanical circulatory support

Time Frame

During 8 weeks of treatment

Title

Death due to worsening of the underlying disease

Description

Death due to worsening of the underlying disease

Time Frame

During 8 weeks of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Month

Maximum Age & Unit of Time

11 Years

Accepts Healthy Volunteers

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Stephanie Laeer, Prof,MD,PhD

Phone

+49 211 8110740

Stephanie.Laeer@uni-duesseldorf.de

First Name & Middle Initial & Last Name or Official Title & Degree

Ingrid Klingmann, MD, PhD

Phone

+32 2 7843692

iklingmann@pharmaplex.be

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michiel Dalinghaus, MD, PhD

Organizational Affiliation

Sophia Children's Hospital Erasmus MC Rotterdam

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

J.M.P. J. Breur, MD, PhD

Organizational Affiliation

Wilhelmina Children's Hosptial University Medical Center Utrecht

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Ida Jovanovic, Prof,MD,PhD

Organizational Affiliation

Univerzitetska Decja Klinika Belgrade

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Christoph Male, Prof, MD,PhD

Organizational Affiliation

Medical University of Vienna

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Michael Burch, Prof,MD,PhD

Organizational Affiliation

Great Ormond Street Hospital for Children London

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

András Szatmári, Prof,MD,PhD

Organizational Affiliation

Hungarian Paediatric Heart Institute, Göttsegen Gyorgy Hungarian Institute of Cardiology Budapest

Official's Role

Principal Investigator

Facility Information:

Facility Name

Medical University of Vienna

City

Vienna

ZIP/Postal Code

1090

Country

Austria

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Christoph Male, Prof,MD,PhD

Phone

+ 43 1 40400 32320

christoph.male@meduniwien.ac.at

First Name & Middle Initial & Last Name & Degree

Vanessa Swoboda, MD

Phone

+ 43 1 40400 32320

v.swoboda@live.at

First Name & Middle Initial & Last Name & Degree

Christoph Male, Prof,MD,PhD

First Name & Middle Initial & Last Name & Degree

Vanessa Swoboda, MD

Facility Name

Hungarian Paediatric Heart Centre, Göttsegen Gyorgy Hungarian Institute of Cardiology

City

Budapest

ZIP/Postal Code

1095

Country

Hungary

Facility Contact:

First Name & Middle Initial & Last Name & Degree

András Szatmári, Prof,MD,PhD

Phone

+36 1 215 1220

szatmari@kardio.hu

First Name & Middle Initial & Last Name & Degree

Laszlo Ablonczy, MD

Phone

+36 1 215 1220

ablonczyl@gmail.com

First Name & Middle Initial & Last Name & Degree

András Szatmári, Prof,MD,PhD

First Name & Middle Initial & Last Name & Degree

Laszlo Ablonczy, MD

Facility Name

Sophia Children's Hospital, Erasmus MC

City

Rotterdam

ZIP/Postal Code

3015 CN

Country

Netherlands

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michiel Dalinghaus, MD,PhD

Phone

+3110-7040704

'Michiel Dalinghaus' <m.dalinghaus@erasmusmc.nl>

First Name & Middle Initial & Last Name & Degree

Tjitske van der Zanden

Phone

+3110-7040704

t.vanderzanden@erasmusmc.nl

First Name & Middle Initial & Last Name & Degree

Michiel Dalinghaus, MD,PhD

First Name & Middle Initial & Last Name & Degree

Marijke Van der Meulen, MD,PjD

Facility Name

Wilhelmina Children's Hospital, University Medical Center Utrecht

City

Utrecht

ZIP/Postal Code

3584 CX

Country

Netherlands

Facility Contact:

First Name & Middle Initial & Last Name & Degree

J.M.P. J. Breur, MD,PhD

Phone

+ 31 8875 540 02

h.breur@umcutrecht.nl

First Name & Middle Initial & Last Name & Degree

J.M.P. J. Breur, MD,PhD

Facility Name

Univerzitetska Dečja Klinika

City

Belgrade

ZIP/Postal Code

11129

Country

Serbia

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Milica Bajcetic, Prof,MD,PhD

Phone

+ 38 1112060716

milica.bajcetic@udk.bg.ac.rs

First Name & Middle Initial & Last Name & Degree

Ida Jovanovic, Prof,MD,PhD

Phone

+ 38 1112060716

idaj@rcub.bg.ac.rs

First Name & Middle Initial & Last Name & Degree

Ida Jovanovic, Prof,MD,PhD

Facility Name

Great Ormond Street Hospital for Children NHS Trust

City

London

ZIP/Postal Code

WC1N 3JH

Country

United Kingdom

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michael Burch, Prof,MD,PhD

Phone

+44 020 7405 9200

michael.burch@gosh.nhs.uk

First Name & Middle Initial & Last Name & Degree

Michael Burch, Prof,MD,PhD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Serious Adverse Event information

Links:

URL

http://www.lena-med.eu/

Description

FP7-funded "LENA" project, Grant Agreement 602295

Learn more about this trial

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

We'll reach out to this number within 24 hrs