Clinical Trials Register

Summary
EudraCT Number:	2017-002325-38
Sponsor's Protocol Code Number:	A4250-008
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-10-11
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

Italy - Italian Medicines Agency

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)

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.

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	+46317411480
B.5.5	Fax number	+4631820223
B.5.6	E-mail	medinfo@albireopharma.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	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

Studio di estensione in aperto per valutare l’efficacia e la sicurezza a lungo termine di A4250 in bambini con colestasi intraepatica progressiva familiare di tipo 1 e 2 (PEDFIC 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.

Studio per determinare l'effetto a lungo termine e la sicurezza di A4250 nel trattamento di bambini affetti da Colestasi Intraepatica Progressiva Familiare

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.

L'obiettivo primario di questo studio è dimostrare un effetto prolungato di A4250 sugli acidi biliarisierici (s-BA) e sul prurito nei bambini con PFIC di tipo 1 e 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

Valutare la sicurezza e la tollerabilità a lungo termine di dosi giornaliere ripetute di A4250
- Valutare l'effetto di A4250 sulla crescita
- Valutare l'effetto di A4250 sulla diversione biliare e/o sull'inserimento in lista di attesa per il trapianto di fegato
- Valutare l'effetto di A4250 sui marcatori biochimici della colestasi e dell'insufficienza epatica

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.Completamento del Periodo di trattamento di 24 settimane dello studio A4250-005 o ritiro dallo studio A4250-005 a causa di
assenza di miglioramento/sintomi intollerabili come giudicato dal paziente/caregiver dopo aver completato almeno 12 settimane di
trattamento
2.Firma del consenso informato e dell'assenso come appropriato. I pazienti che compiono 18 anni (o la maggiore età legale del
paese) durante lo studio dovranno firmare un nuovo consenso per rimanere nello studio
3.I pazienti dovranno avere sempre lo stesso caregiver per tutta la durata dello studio
4.I caregiver (e i pazienti dell'età appropriata) devono acconsentire ed essere in grado di utilizzare un diario elettronico come
richiesto dallo studio

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

I pazienti che soddisfano uno qualsiasi dei seguenti criteri alla Visita 1 non saranno idonei alla partecipazione allo studio:
1.Patologia epatica scompensata: coagulopatia, anamnesi o presenza di ascite clinicamente significativa, emorragia da varici e/o
encefalopatia
2.Soggetti di sesso maschile e femminile sessualmente attivi che non utilizzano un metodo contraccettivo affidabile con
percentuale di fallimento ≤1% (come metodi di barriera, contraccezione ormonale, dispositivo intrauterino o astinenza completa)
per tutta la durata dello studio e per 90 giorni successivamente (dalla firma del consenso informato e per 90 giorni dopo l'ultima
dose di farmaco dello studio).
3.Pazienti che non si attengono al trattamento nello studio A4250-005
4.Qualsiasi altra patologia o anormalità che, secondo il giudizio dello sperimentatore o del Monitor clinico, potrebbe
compromettere la sicurezza del paziente o interferire con la partecipazione o il completamento dello studio da parte del paziente

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.

L'endopoint primario di efficacia è:
Variazione dal basale di s-BA dopo 72 settimane di trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

Screening/ Inclusion Visit and week 72

Screening/visita di arruolamento e settimana 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

E.5.2 End point secondario (ripetere se necessario): Gli endpoint secondari di efficacia comprendono:
- Mortalità per qualsiasi causa, numero di pazienti che si sottopongono a intervento chirurgico di diversione biliare o che vengono
inseriti in lista per il trapianto di fegato
- Variazioni nella crescita dopo l'inizio del trattamento con A4250
- Variazioni del rapporto tra AST e piastrine (indice APRI) e punteggio Fib-4 dal basale alla Settimana 72
- Variazioni del punteggio dell'insufficienza epatica pediatrica di stadio terminale (PELD)/modello per insufficienza epatica
terminale (MELD) dal basale alla Settimana 72
- Variazioni nell'uso di farmaci contro il prurito

E.5.2.1

Timepoint(s) of evaluation of this end point

• Weeks 24, 48, and 72

settimane 24, 48, e 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)

valutazioni Quality of Life (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

Ultima visita dell'ultimo paziente (LPLV) e i centri vengono chiusi. LPLV a livello internazionale e tutti i centri chiusi

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.

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

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

2018-11-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-12

P. End of Trial
P.	End of Trial Status	Ongoing

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