Clinical Trials Register

Summary
EudraCT Number:	2010-019547-19
Sponsor's Protocol Code Number:	AMB112529
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:	2010-07-15
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

2010-019547-19

A.3

Full title of the trial

Estudio abierto, aleatorizado, para comparar parámetros de seguridad y eficacia para una dosis alta y una baja de ambrisentan (ajustadas al peso corporal), como tratamiento para la hipertensión arterial pulmonar en pacientes pediátricos entre 8 y 18 años.
A randomized, open label study comparing safety and efficacy parameters for a high and a low dose of ambrisentan (adjusted for body weight) for the treatment of pulmonary arterial hypertension in paediatric patients aged 8 years up to 18 years.

A.4.1

Sponsor's protocol code number

AMB112529

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	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.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	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.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

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	PT
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.1.3

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 de este estudio es evaluar la seguridad y la tolerabilidad del ambrisentan en la población de niños (entre 8 y 18 años de edad) con HAP.

E.2.2

Secondary objectives of the trial

Farmacocinética:
• Evaluación de la farmacocinética poblacional a partir de una muestra de plasma por paciente en las semanas 4, 8, 12, 16, 20, y 24.
• Desarrollo de un modelo farmacocinético/farmacodinámico.
Eficacia
• Variación con respecto al basal de la distancia recorrida en el Test de la Marcha de los 6 minutos (TM6M) después de 24 semanas de tratamiento.
• Variación media con respecto al basal de la prueba de la TM6M en las semanas 4, 8, 12, 16 y 20.
• Tiempo transcurrido hasta el empeoramiento clínico de la HAP.
• Variación con respecto al basal de la evaluación global por el paciente realizada con el cuestionario de salud SF-10 para niños hasta la semana 24.
• Variación con respecto al basal de la clase funcional de la OMS hasta la semana 24.
• Variación con respecto al basal de la concentración plasmática del N-Terminal tipo pro-B péptido natriurético (NT-proBNP) en la semana 24.

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

Sub-estudio de hemodinámica cardiopulmonar: Las evaluaciones hemodinámicas se efectuarán en el momento basal y en la semana 24 o en la retirada prematura en un subgrupo de pacientes reclutados en centros donde la recogida de datos hemodinámicos forma parte de la asistencia habitual.

E.3

Principal inclusion criteria

1. Varón o mujer de 8 años de edad como mínimo y que no hayan cumplido los 18 años en el momento de la aleatorización.
2. Diagnóstico actual de HAP (grupo 1 la OMS) con síntomas de clase II o III de la OMS de una de las siguientes categorías:
• Idiopática
• Heredable [familiar]
• Secundaria a enfermedades del tejido conectivo (como esclerodermia limitada, esclerodermia difusa, enfermedad mixta del tejido conjuntivo, lupus eritematoso sistémico o síndrome de superposición).
• HAP persistente a pesar de la reparación quirúrgica (al menos 6 meses antes de la visita de selección) de defectos del septo o tabique atrial, defectos del septo o tabique ventricular, defectos del septo o tabique atrio-ventricular y conducto arterial persistente.
3. Cuando el cateterismo cardíaco derecho (CCD) se realice como parte del diagnóstico o la asistencia habituales, cumplir los criterios hemodinámicos siguientes (véase Apéndice 1):
• presión arterial pulmonar media (PAPm) ≥ 25 mmHg
• resistencia vascular pulmonar (RVP) ≥ 240 din. s/cm5
• presión telediastólica del ventrículo izquierdo (PTDVI) o presión de enclavamiento capilar pulmonar (PECP) ≤ 15 mmHg.
4. Los sujetos podrán no haber recibido tratamiento previo (i.e. naïve), o deberán haber suspendido el tratamiento con otro ARE (por ejemplo, bosentan) al menos un mes antes debido a elevación de los parámetros de las pruebas de función hepática (PFH), o deberán haber recibido una dosis estable de medicación específica para la HAP (por ejemplo, sildenafilo o prostaciclina) durante al menos un mes antes de la visita de selección. El tratamiento de base de la medicación específica para la HAP, en su caso, no debe modificarse desde la visita de selección hasta el final de todas las evaluaciones del periodo de tratamiento.
5. En los sujetos en los que se haya suspendido el tratamiento con un ARE debido a la elevación en las PFH, los resultados de las PFH deberán ser < 3 veces el límite superior de la normalidad (LSN).
6. Una mujer podrá para participar en este estudio, tras la evaluación por el investigador, en caso de que:
a. no sea potencialmente fértil (es decir, que sea fisiológicamente incapaz de concebir) ; o,
b. si es potencialmente fértil, tenga un resultado negativo en la prueba de embarazo y no se encuentre en período de lactancia en las visitas de selección y basal/ de aleatorización y si es sexualmente activa y se comprometa a utilizar dos métodos anticonceptivos fiables desde la visita de selección hasta la finalización del estudio y durante al menos 30 días después de la última dosis del fármaco del estudio (los métodos anticonceptivos fiables se enumeran en el Apéndice 2).
7. El sujeto o su tutor legal es capaz y está dispuesto a dar su consentimiento informado por escrito. Como parte del consentimiento, las mujeres potencialmente fértiles serán informadas del riesgo de teratogenia y deberán recibir información, adecuada a su grado de madurez, acerca de la importancia evitar el embarazo; los varones deberán ser informados del riesgo de sufrir atrofia de los túbulos testiculares y aspermia.

E.4

Principal exclusion criteria

1. Sujetos en tratamiento con un ARE.
2. Sujetos en tratamiento con ciclosporina A.
3. Sujetos con un peso corporal inferior a 20 kg.
4. Sujetos que no toleraron el tratamiento para la HAP debido a efectos adversos posiblemente relacionados con su mecanismo de acción (como prostanoides, ARE, inhibidores de la PDE-5), con la excepción de las anomalías hepáticas en los sujetos que recibían otro ARE.
5. Mujeres embarazadas o en período de lactancia.
6. Sujetos con un diagnóstico de hepatitis activa (anticuerpos contra el antígeno de superficie del virus de la hepatitis B y anticuerpos contra el virus de la hepatitis C) o una elevación clínicamente importante de las enzimas hepáticas (ALT, AST o FA > 3 veces el LSN) en la visita de selección.
7. Sujetos con insuficiencia renal grave (aclaramiento de creatinina < 30 ml/min) en la visita de selección.
8. Sujetos con una retención de líquidos clínicamente importante en opinión del investigador.
9. Sujetos con anemia clínicamente importante en opinión del investigador.
10. Sujetos con hipersensibilidad conocida al fármaco del estudio, sus metabolitos o a los excipientes de la formulación.
11. Sujetos que hayan participado en otro ensayo o hayan recibido otro producto en investigación en los 30 días anteriores.
12. Alcoholismo, consumo de drogas en el año anterior.
13. Cualquier enfermedad concurrente o uso concomitante de medicación que, en opinión del investigador, pueda afectar a la seguridad del sujeto.

E.5 End points

E.5.1

Primary end point(s)

Seguridad:
• 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 de los resultados de la evaluación endocrinológica de las semanas 12 y 24 con respecto al basal).

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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)

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

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

Diferentes dosis del mismo MI

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

No aplicable
Nota: Los pacientes que participen en el estudio y en los que es adecuado continuar tratamiento con ambrisentan serán elegibles para participar en un estudio de seguimiento a largo plazo.

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 2010-07-15.

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

Los padres o tutores legales darán consentimiento (niños de 8 a 11). Particpante y padres/tutores Darán Consentimiento (12 a 17). Los de 18 darán consentimiento ellos mismos.

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 pacientes que participen en el estudio y en los que es adecuado continuar tratamiento con ambrisentan serán elegibles para participar en un estudio de seguimiento a largo plazo.

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

2010-10-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-09-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-02-11

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