Clinical Trials Register

Summary
EudraCT Number:	2010-021572-29
Sponsor's Protocol Code Number:	AMB114588
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-10-11
Trial results	View 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

France - ANSM

A.2

EudraCT number

2010-021572-29

A.3

Full title of the trial

An open-label, long term extension study for treatment of pulmonary arterial hypertension in paediatric patients aged 8 years up to 18 years who have participated in AMB112529 and in whom continued treatment with ambrisentan is desired

A.3.1

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

Testing medicines to treat children with pulmonary arterial hypertension (PAH)
Testing medicines to treat teens with pulmonary arterial hypertension (PAH)

A.3.2

Name or abbreviated title of the trial where available

Safety FU Study of Amb in 8-17yr olds

A.4.1

Sponsor's protocol code number

AMB114588

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01342952

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/224/2009

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GlaxoSmithKline Research & Development Limited
B.1.3.4	Country	United Kingdom
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	GlaxoSmithKline Research & Development Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline
B.5.2	Functional name of contact point	GSK Clinical Support Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	Iron Bridge Road, Stockley Park West
B.5.3.2	Town/ city	Uxbridge, Middlesex
B.5.3.3	Post code	UB11 1BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44(0)208990 4466
B.5.5	Fax number	+44(0)208990 4968
B.5.6	E-mail	GSKClinicalSupportHD@gsk.com

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	Yes
D.2.1.1.1	Trade name	VOLIBRIS® (ambrisentan)
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/273
D.3 Description of the IMP
D.3.1	Product name	ambrisentan
D.3.2	Product code	GSK1325760
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
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	AMBRISENTAN
D.3.9.1	CAS number	177036-94-1
D.3.9.2	Current sponsor code	GSK1325760
D.3.9.4	EV Substance Code	SUB25424
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	10
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	Yes
D.2.1.1.1	Trade name	VOLIBRIS® (ambrisentan)
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/273
D.3 Description of the IMP
D.3.1	Product name	ambrisentan
D.3.2	Product code	GSK1325760
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
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	AMBRISENTAN
D.3.9.1	CAS number	177036-94-1
D.3.9.2	Current sponsor code	GSK1325760
D.3.9.4	EV Substance Code	SUB25424
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	5
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: 3
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/273
D.3 Description of the IMP
D.3.1	Product name	ambrisentan
D.3.2	Product code	GSK1325760
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
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	AMBRISENTAN
D.3.9.1	CAS number	177036-94-1
D.3.9.2	Current sponsor code	GSK1325760
D.3.9.4	EV Substance Code	SUB25424
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	2.5
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

Pulmonary Arterial Hypertension

E.1.1.1

Medical condition in easily understood language

High blood pressure in the lungs

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	14.0
E.1.2	Level	PT
E.1.2	Classification code	10064911
E.1.2	Term	Pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10065150
E.1.2	Term	Associated with pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10065152
E.1.2	Term	Familial pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10065151
E.1.2	Term	Idiopathic pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is the long-term safety and tolerability of ambrisentan in the paediatric PAH population.

E.2.2

Secondary objectives of the trial

Efficacy

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

Cardiopulmonary Hemodynamic Sub-study (see Appendix 1 of protocol): The change from Study AMB112529 baseline in cardiopulmonary hemodynamic assessments data in subjects in whom hemodynamic data is considered part of the standard of care.

E.3

Principal inclusion criteria

1. Have participated in and complied, to the best of their ability, with the protocol for
AMB112529 and have met one of the following:
a. Completed the Week 24 visit in AMB112529;
b. Required additional targeted treatment for PAH due to inadequate response to the current treatment or worsening of their clinical condition prior to week 24 in AMB112529;
c. Required reduction in dose of baseline targeted treatment for PAH after ambrisentan was added to the treatment regimen;
d. In the opinion of the investigator, continued treatment with ambrisentan is warranted.
2. A female is eligible to participate in this study, as assessed by the investigator, if she is of:
a. Non-childbearing potential (i.e., physiologically incapable of becoming
pregnant); or,
b. Child-bearing potential - has a negative pregnancy test and is not lactating and,
if sexually active, agrees to continue to use 2 reliable methods of contraception
until study completion and for at least 30 days following the last dose of study
drug
3. Subject or subject’s legal guardian is able and willing to give written informed
consent. As part of the consent, female subjects of childbearing potential will be
informed of the risk of teratogenicity and will need to be counselled in a
developmentally appropriate manner on the importance of pregnancy prevention; and male subjects will need to be informed of potential risk of testicular tubular atrophy and aspermia.

E.4

Principal exclusion criteria

1. Subjects who were withdrawn from ambrisentan in Study AMB112529;
2. Subjects who did not comply with the protocol in Study AMB112529;
3. Female subjects who are pregnant or breastfeeding;
4. Subjects with severe renal impairment (estimated creatinine clearance <30 mL/min
assessed within the previous 45 days) at the point of transition from Study
AMB112529 into this study;
5. Subject with clinically significant fluid retention in the opinion of the investigator;
6. Subject with clinically significant anaemia in the opinion of the investigator;
7. Subjects who are to enter another clinical trial or be treated with another
investigational product after exiting Study AMB112529.

E.5 End points

E.5.1

Primary end point(s)

Safety as assessed by:
•Adverse Events;
• Serious Adverse Events;
• Clinical laboratory parameters;
• Physical examination (including height, weight, body mass index / body surface
area, oxygen saturation, jugular venous pressure, liver size, and presence of
peripheral oedema and/or ascites);
• Vital Signs;
• Pubertal development (change from Study AMB112529 baseline in endocrinology
assessments every six months and at 20 years of age);
• The time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events).

E.5.1.1

Timepoint(s) of evaluation of this end point

The above measurements and evaluations will be conducted during the trial.

Depending on the endpoint, evaluation of these endpoints can be at entry into the study, every three months, every six months, at the end of the study or as follow-up.

* View table 1 of the protocol "Time and Events Table"

E.5.2

Secondary end point(s)

Efficacy
• All cause mortality;
• The change from Study AMB112529 baseline in the 6 minute walking distance (6MWD) test evaluated every six months;
• The time to clinical worsening of PAH;
• The time to addition of another targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to the following reasons:
- Deterioration of clinical condition;
- Lack of beneficial effect with previous therapy (not reaching set treatment goals);
• The time to change in dose of ambrisentan or other targeted PAH therapeutic agents(prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition;
• The change from Study AMB112529 baseline in Subject Global Assessment every three months using the SF-10 health survey for children;
• The change from Study AMB112529 baseline in WHO functional class every six months;
• Change from Study AMB112529 baseline in N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) concentration every six months.

E.5.2.1

Timepoint(s) of evaluation of this end point

The above measurements and evaluations will be conducted during the trial.

Depending on the endpoint, evaluation of these endpoints can be at entry into the study, every six months, at the end of the study or as follow-up in patients who are withdrawn from ambrisentan.

* View table 1 of the protocol "Time and Events Table"

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

Yes

E.8.2.3.1

Comparator description

Different dose of same IMP

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

Japan

United States

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

Subjects can remain in the study until one of the following:
• Subject turns 18 years of age (when can receive marketed product);
• The product is approved and available for use in the subject’s age group;
• Development for use in the paediatric population is discontinued;
• The subject decides he/she no longer wants to participate in the study;
• The investigator considers it is in the best interest of the subject to discontinue
ambrisentan (e.g. for safety reasons).

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

E.8.9.2

In all countries concerned by the trial days

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)

F.1.1.4

Infants and toddlers (28 days-23 months)

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

F.3.3.2

Women of child-bearing potential using contraception

Yes

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 will give assent and their parents or legal guardian will give consent.

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)

Not applicable. The study may continue until subjects have turned 18;• product is proved and available for use in the subject’s age group; development for use in the paediatric population is discontinued; the subject decides he/she no longer wants to participate in the study; the investigator considers it is in the best interest of the subject to discontinue ambrisentan (e.g. for safety reasons).

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

2011-11-16

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-09

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