Clinical Trials Register

Summary
EudraCT Number:	2010-021572-29
Sponsor's Protocol Code Number:	AMB114588
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-11-17
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

Spain - AEMPS

A.2

EudraCT number

2010-021572-29

A.3

Full title of the trial

Estudio de extensión abierto y a largo plazo sobre el tratamiento de la hipertensión arterial pulmonar en pacientes pediátricos de 8 a 18 años de edad que han participado en el estudio AMB112529 y para los que se desea tratamiento continuo con ambrisentan.
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.4.1

Sponsor's protocol code number

AMB114588

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GlaxoSmithKline, S.A
B.1.3.4	Country	Spain
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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 10 mg comprimidos recubiertos con película
D.2.1.1.2	Name of the Marketing Authorisation holder	GLAXO GROUP LTD.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.9.3	Other descriptive name	AMBRISENTAN
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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 5 mg comprimidos recubiertos con película
D.2.1.1.2	Name of the Marketing Authorisation holder	GLAXO GROUP LTD.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.9.3	Other descriptive name	AMBRISENTAN
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Information not present in EudraCT
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.3.9.2	Current sponsor code	GSK1325760
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

Hipertensión Arterial Pulmonar
Pulmonary Arterial Hypertension

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13
E.1.2	Level	LLT
E.1.2	Classification code	10064911
E.1.2	Term	Hipertensión arterial pulmonar

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13
E.1.2	Level	LLT
E.1.2	Classification code	10065150
E.1.2	Term	Hipertensión pulmonar arterial primaria asociada

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13
E.1.2	Level	LLT
E.1.2	Classification code	10065151
E.1.2	Term	Hipertensión pulmonar arterial primaria idiopática

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13
E.1.2	Level	LLT
E.1.2	Classification code	10065152
E.1.2	Term	Hipertensión pulmonar arterial primaria familiar

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13
E.1.2	Level	PT
E.1.2	Classification code	10064911
E.1.2	Term	Hipertensión arterial pulmonar

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

El objetivo principal es la seguridad y la tolerabilidad a largo plazo de ambrisentan en la población de pediátrica con HAP (véase Seguridad).
The primary objective is the safety and tolerability of ambrisentan in the paediatric PAH population.

E.2.2

Secondary objectives of the trial

Eficacia
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

Subestudio de hemodinámica cardiopulmonar: Variación con respecto al periodo basal del estudio AMB112529 de los datos de evaluaciones hemodinámicas cardiopulmonares en sujetos en quienes los datos hemodinámicos se consideren parte de la asistencia habitual (véase el Apéndice 1 del protocolo).
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 consider

E.3

Principal inclusion criteria

1. El paciente tendrá que haber participado en el estudio AMB112529 y haber cumplido el protocolo lo mejor posible, y deberá satisfacer uno de estos requisitos:
a. Completó la visita de la semana 24 del estudio AMB112529;
b. Necesitó tratamiento dirigido adicional para la HAP debido a una respuesta insuficiente al tratamiento que recibía o al empeoramiento de su estado clínico antes de la semana 24 en el estudio AMB112529;
c. Precisó una reducción de la dosis del tratamiento basal específico para la HAP después de la adición de ambrisentan al régimen de tratamiento;
d. En opinión del investigador, está justificado continuar el tratamiento con ambrisentan.
2. Una adolescente podrá para participar en este estudio, previa evaluación por el investigador, en caso de que:
a. no sea potencialmente fértil (es decir, que fisiológicamente no pueda quedarse embarazada); o,
b. si es potencialmente fértil, tenga un resultado negativo en una prueba de embarazo y no se encuentre en periodo de lactancia y, si es sexualmente activa, se comprometa a seguir usando dos métodos anticonceptivos fiables hasta la finalización del estudio y durante al menos 30 días después de recibir la última dosis del fármaco del estudio.
3. El sujeto (o su tutor legal) es capaz y está dispuesto a dar su consentimiento informado por escrito. Como parte del consentimiento, las pacientes en edad fértil serán informadas del riesgo de teratogenia y deberán recibir información, adecuada a su grado de madurez, acerca de la importancia de evitar el embarazo; los varones deberán ser informados del riesgo de sufrir atrofia de los túbulos testiculares y aspermia.
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. Sujetos que dejaron de recibir ambrisentan en el estudio AMB112529.
2. Sujetos que no cumplieron el protocolo del estudio AMB112529.
3. Pacientes embarazadas o en periodo de lactancia.
4. Pacientes con insuficiencia renal grave (aclaramiento de creatinina calculado <30ml/min evaluado en los 45 días previos) en el momento de transición del estudio AMB112529 a este estudio.
5. Sujetos con retención de fluidos de importancia clínica en opinión del investigador.
6. Sujetos con anemia de importancia clínica en opinión del investigador.
7. Sujetos que vayan a participar en otro ensayo clínico o a recibir tratamiento con otro producto en investigación tras el estudio AMB112529.
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)

- Acontecimientos adversos.
- Acontecimientos adversos graves.
- Parámetros de laboratorio clínico.
- Exploración física (talla, peso, índice de masa corporal / superficie corporal, saturación de oxígeno, presión venosa yugular, tamaño hepático y presencia de edema periférico o ascitis).
- Constantes vitales.
- Desarrollo puberal (variación con respecto al periodo basal del estudio AMB112529 de las evaluaciones endocrinológicas realizadas cada seis meses y a los 20 años de edad).
- Tiempo transcurrido hasta la modificación de la dosis de ambrisentan o de otros medicamentos específicos para la HAP (prostanoides, inhibidores de la PDE-5) debido a problemas de tolerabilidad (por ejemplo, acontecimientos adversos)
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.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

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

Diferent dose of same IMP

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

Information not present in EudraCT

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

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

Los sujetos podrán continuar en el estudio de extensión hasta se cumpla una de las condiciones siguientes:
- El sujeto cumple 18 años
- Se aprueba el producto y está disponible para usarse en el grupo en edad del sujeto
- Se suspende el desarrollo del producto para uso en la población pediátrica.
- El sujeto decide que no desea seguir participando en el estudio.
- El investigador considera que lo más conveniente para el sujeto es dejar de recibir ambrisentan.

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.1.1.1

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.1.1.6

Adolescents (12-17 years)

Yes

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2010-11-17.

Yes

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

Que los niños sean capaces de dar su consentimiento así como los padres o representantes legales. 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)

Los sujetos podrán continuar en el estudio de extensión hasta que el sujeto cumple 18 años, que se apruebe el producto y está disponible para usarse en el grupo en edad del sujeto, que se suspenda el desarrollo del producto para uso en la población pediátrica, que el sujeto decida que no desea seguir participando en el estudio o que el investigador considera que lo más conveniente para el sujeto es dejar de recibir ambrisentan (por ejemplo, por motivos de seguridad).

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

2011-01-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-01-11

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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