Clinical Trials Register

Summary
EudraCT Number:	2015-002396-18
Sponsor's Protocol Code Number:	2015-602295-02
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-10-09
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2015-002396-18

A.3

Full title of the trial

ORODISPERSIBLE MINITABLETS OF ENALAPRIL IN YOUNG CHILDREN WITH HEART FAILURE DUE TO CONGENITAL HEART DISEASE

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

ORODISPERSIBLE MINITABLETS OF ENALAPRIL IN YOUNG CHILDREN WITH HEART FAILURE DUE TO CONGENITAL HEART DISEASE

A.3.2

Name or abbreviated title of the trial where available

ENACHD

A.4.1

Sponsor's protocol code number

2015-602295-02

A.5.4

Other Identifiers

Name:

Number:

602295

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/176/2015

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Ethicare GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	European Commission FP7 grant agreement 602295
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharmaplex bvba
B.5.2	Functional name of contact point	Lead Clinical Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Av St-Hubert 51
B.5.3.2	Town/ city	Wezembeek-Oppem
B.5.3.3	Post code	1970
B.5.3.4	Country	Belgium
B.5.4	Telephone number	003227843693
B.5.5	Fax number	003227843066
B.5.6	E-mail	iklingmann@pharmaplex.be

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Enalapril Orodispersible Minitablets (ODMT)
D.3.4	Pharmaceutical form	Orodispersible tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Enalapril Maleate
D.3.9.1	CAS number	76095-16-4
D.3.9.2	Current sponsor code	ENA10BA
D.3.9.3	Other descriptive name	ENALAPRIL MALEATE
D.3.9.4	EV Substance Code	SUB01884MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Enalapril Orodispersible Minitablet (ODMT)
D.3.4	Pharmaceutical form	Orodispersible tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Enalapril maleate
D.3.9.1	CAS number	76095-16-4
D.3.9.2	Current sponsor code	ENA10BA
D.3.9.3	Other descriptive name	ENALAPRIL MALEATE
D.3.9.4	EV Substance Code	SUB01884MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0,25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart Failure due to Congenital Heart Disease

E.1.1.1

Medical condition in easily understood language

heart failure

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10010495
E.1.2	Term	Congenital heart disease NOS
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

• To demonstrate safety, in particular renal safety, of enalapril ODMTs in children with CHD.
• To characterise the dose/safety relationship from a starting dose to an optimal maintenance dose.
• To explore the dose exposure/response relationship with pharmacodynamic parameters in the paediatric population with CHD.
• To investigate the Shortening Fraction (SF) of the heart muscle by echocardiography.
• To investigate the acceptability and palatability of enalapril ODMTs in the paediatric population with CHD.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

LENA Pharmacogenomics and metabolomics exploratory studies, V 1.0 date 22July2015

E.3

Principal inclusion criteria

• Age from birth to less than 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 ACE-Inhibitors (ACEI).
• Subjects already on ACE-Inhibitors willing to switch to Enalapril Orodispersable Minitablets.
• Patient and/or parent(s)/legal representative provided written informed consent.

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.

E.4

Principal 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. below P5
• 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 (Upper Limit of Normal) according to the hospital’s test methodology).
• History of Angioedema.
• Hypersensitivity to ACEI.
• Concomittant medication:
o Dual ACEI therapy
o Renin inhibitors
o Angiotensin II antagonists
o NSAIDs 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.

E.5 End points

E.5.1

Primary end point(s)

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

PK/PD profile sampling timepoints: Visit day 1: pre-dose, 0h, 2, 4, 6, 8, 12 hours

E.5.2

Secondary end point(s)

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.
8. Death due to worsening of the underlying disease.
9. Pharmacodynamic and efficacy endpoints analysis to differentiate high and low output disease.

E.5.2.1

Timepoint(s) of evaluation of this end point

Biochemistry, Urine and BNP collected during each visit in the hospital to monitor renal function.
PK and PD 1 sample collected during each visit, unless the patient
terminated use of the IMP, then only PD sample is collected.
Acceptability and Palatability questionnaire is completed during initial
visit, once stable dose is reached and during end of study visit.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Group 1: ACEI-pretreated patients. Group B: ACEI-naive patients

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Hungary

Netherlands

Serbia

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

children below 6 years

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

for next 10 months follow up study is performed to provide medication
for next 10 months and ensure safety of the patients. After the next
10months no further study treatment is planned. Patients will be
treated as per local standards.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-12-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-02-28

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