Clinical Trials Register

Summary
EudraCT Number:	2017-002325-38
Sponsor's Protocol Code Number:	A4250-008
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-09-17
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

Spain - AEMPS

A.2

EudraCT number

2017-002325-38

A.3

Full title of the trial

An Open-label Extension Study to Evaluate Long-term Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 2)

Estudio abierto de extensión para evaluar la eficacia y la seguridad a largo plazo de A4250 en niños con colestasis intrahepática familiar progresiva de tipo 1 y 2 (PEDFIC 2)

A.3.1

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

A study to determine the long term effect and safety of A4250 in treatment of children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2.

Estudio para determinar los efectos y la seguridad a largo plazo del A4250 en el tratamiento de niños con colestasis intrahepática familiar progresiva de tipo 1 y 2.

A.4.1

Sponsor's protocol code number

A4250-008

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/306/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Albireo AB
B.1.3.4	Country	Sweden
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	Albireo AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Albireo AB
B.5.2	Functional name of contact point	Clinical Operations Department
B.5.3	Address:
B.5.3.1	Street Address	Arvid Wallgrens backe 20
B.5.3.2	Town/ city	Göteborg
B.5.3.3	Post code	41346
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+34675781547
B.5.5	Fax number	+4631820223
B.5.6	E-mail	jquintero@vhebron.net

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/12/1028
D.3 Description of the IMP
D.3.2	Product code	A4250
D.3.4	Pharmaceutical form	Capsule, hard
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	Not applicable
D.3.9.3	Other descriptive name	A4250 (1200 μg)
D.3.9.4	EV Substance Code	SUB126128
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1200
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/12/1028
D.3 Description of the IMP
D.3.2	Product code	A4250
D.3.4	Pharmaceutical form	Capsule, hard
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	Not applicable
D.3.9.3	Other descriptive name	A4250 (600 μg)
D.3.9.4	EV Substance Code	SUB126128
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	600
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/3/12/1028
D.3 Description of the IMP
D.3.2	Product code	A4250
D.3.4	Pharmaceutical form	Capsule, hard
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	Not applicable
D.3.9.3	Other descriptive name	A4250 (400 μg)
D.3.9.4	EV Substance Code	SUB126128
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
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: 4
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/3/12/1028
D.3 Description of the IMP
D.3.2	Product code	A4250
D.3.4	Pharmaceutical form	Capsule, hard
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	Not applicable
D.3.9.3	Other descriptive name	A4250 (200 μg)
D.3.9.4	EV Substance Code	SUB126128
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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

Progressive Familial Intrahepatic Cholestasis Types 1 and 2

Colestasis intrahepática familiar progresiva de tipo 1 y 2

E.1.1.1

Medical condition in easily understood language

An inherited condition causing reduced bile acid flow and progressive
liver disease in children and young people.

Se trata de una enfermedad heredada que reduce el flujo de ácidos biliares y provoca una enfermedad progresiva del hígado en niños y jóvenes.

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10076033
E.1.2	Term	Progressive familial intrahepatic cholestasis
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic 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 of this study is to demonstrate a sustained effect of A4250 on serum bile acid (s-BAs) and pruritus in children with PFIC Types 1 and 2.

El objetivo principal de este estudio es demostrar el efecto continuado de A4250 sobre los ácidos biliares séricos (ABs) y el prurito en niños con colestasis intrahepática familiar progresiva (CIFP) de tipo 1 o 2.

E.2.2

Secondary objectives of the trial

• To evaluate the long-term safety and tolerability of repeated daily doses of A4250
• To evaluate the effect of A4250 on growth
• To evaluate the effect of A4250 on biliary diversion and/or listing for liver transplantation
• To evaluate the effect of A4250 on biochemical markers of cholestasis and liver disease

• Evaluar la seguridad y tolerabilidad a largo plazo de dosis diarias repetidas de A4250
• Evaluar el efecto de A4250 sobre el crecimiento
• Evaluar el efecto de A4250 en la derivación biliar o en la lista de espera para un trasplante de hígado
• Evaluar el efecto de A4250 en los marcadores bioquímicos de colestasis y hepatopatía

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Completion of the 24-week Treatment Period of Study A4250-005 or withdrawn from Study A4250-005 due to patient/caregiver judgment of lack of improvement/intolerable symptoms after completing at least 12 weeks of treatment
2. Signed informed consent and assent as appropriate. Patients who turn 18 years of age (or legal age per country) during the study will be required to re-consent to remain on the study
3. Patients expected to have a consistent caregiver for the duration of the study
4. Caregivers (and age appropriate patients) must be willing and able to use an eDiary device as required by the study

1. Haber completado el período de tratamiento de 24 semanas del estudio A4250-005 o haberse retirado del estudio A4250-005 debido a la ausencia de mejoría/síntomas intolerables, a juicio del paciente o su cuidador, tras completar al menos una tanda de 12 semanas.
2. Haber firmado el consentimiento informado y el asentimiento, según corresponda. Los pacientes que cumplan 18 años de edad (o la mayoría de edad que corresponda a cada país) durante el estudio deberán volver a firmar un consentimiento para permanecer en el estudio.
3. Se espera que los pacientes tengan un mismo cuidador durante todo el transcurso del estudio.
4. De acuerdo con los requisitos del estudio, los cuidadores (y los pacientes de la edad apropiada) deben estar dispuestos a usar un diario electrónico (eDiary) y ser capaces de hacerlo.

E.4

Principal exclusion criteria

Patients meeting any of the following criteria at Visit 1 will not be eligible for study participation:
1. Decompensated liver disease: coagulopathy, history, or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
2. Sexually active males and females who are not using a reliable contraceptive method with ≤1% failure rate (such as barrier protection, hormonal contraception, intra-uterine device, or complete abstinence) throughout the duration of the study and 90 days thereafter (from signed informed consent through 90 days after last dose of study drug).
3. Patients not compliant with treatment in study A4250-005
4. Any other conditions or abnormalities which, in the opinion of the investigator or Medical Monitor, may compromise the safety of the patient, or interfere with the patient participating in or completing the study

Los pacientes que cumplan cualquiera de los criterios siguientes en la visita 1 no serán aptos para participar en el estudio:
1. Hepatopatía descompensada: coagulopatía, antecedentes o presencia de ascitis clínicamente relevante, hemorragia por varices o encefalopatía
2. Varones y mujeres sexualmente activos que no estén utilizando un método anticonceptivo fiable con ≤ 1 % de fallos (como los métodos de barrera, anticoncepción hormonal, dispositivo intrauterino o abstinencia total) durante toda la duración del estudio y durante los 90 días posteriores (desde la firma del consentimiento informado hasta 90 días después de la última administración del fármaco en estudio)
3. Pacientes que no hayan cumplido con el tratamiento en el estudio A4250-005
4. Cualquier otra patología o alteración que, en opinión del investigador o el monitor médico, pueda poner en peligro la seguridad del paciente o interferir con la participación del paciente en el estudio o impedir que lo finalice

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is:
Change from baseline in s-BA after 72 weeks of treatment.

El criterio principal de valoración de la eficacia es: cambio en los niveles de ABs con respecto a los valores basales tras 72 semanas de tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

Screening/ Inclusion Visit and week 72

Selección/ Visita de inclusión y semana 72

E.5.2

Secondary end point(s)

Secondary efficacy endpoints include:
• All-cause mortality, number of patients undergoing biliary diversion
surgery, or being listed for liver transplantation.
• Change in growth after initiation of A4250 treatment
• Change in AST to platelet ratio index (APRI) score and Fib-4 score
from baseline to Week 72
• Change in pediatric end-stage liver disease (PELD)/model for endstage
liver disease (MELD) score from baseline to Week 72
• Change in use of antipruritic medication

Los Criterios secundarios de valoración de la eficacia incluyen:
• Mortalidad por cualquier causa, número de pacientes sometidos a cirugía de derivación biliar o que se añaden a la lista de espera para trasplante de hígado.
• Cambio en el crecimiento tras el inicio del tratamiento con A4250
• Cambio en la puntuación del índice APRI (aspartato-aminotransferasa/plaquetas) y la puntuación FIB-4 entre el valor basal y la semana 72
• Cambio en la puntuación para la hepatopatía pediátrica en etapa terminal (PELD —Pediatric End-stage Liver Disease)/modelo para la hepatopatía en fase terminal (MELD —Model for End-stage Liver Disease) entre el valor basal y la semana 72
• Cambio en el uso de medicación antiprurítica

E.5.2.1

Timepoint(s) of evaluation of this end point

• Weeks 24, 48, and 72

Semanas 24, 48 y 72

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of Life Assessment (using PedsQL)

Evaluación de calidad de vida (usando PedsQL)

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

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.8.2.4

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

Australia

Belgium

Canada

France

Germany

Israel

Italy

Netherlands

Poland

Saudi Arabia

Spain

Sweden

Turkey

United Kingdom

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

End of study in one country: last patient last visit (LPLV) and sites are closed.
End of study globally: LPLV globally and all sites closed

Final del estudio en un país: última visita del último paciente (UVUP), habiéndose cerrado los centros.
Final del estudio global: UVUP en términos globales, habiéndose cerrado todos los centros

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)

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

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

Minors unable to speak and read will be enrolled onto this study.
Parents' consent will be sought.

Los menores que no puedan hablar y leer serán inscritos en este
estudio. Se solicitará el consentimiento de los padres.

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)

None

Ninguno

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

2018-12-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-13

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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