A study to determine if A4250 is safe and can be used to treat children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2.

• Register: EUCTR
• Last refreshed on: 23 November 2020
• Main ID: EUCTR2017-002338-21-NL
• Date of registration: 19/02/2018
• Prospective Registration: Yes
• Primary sponsor: Albireo AB
• Public title: A study to determine if A4250 is safe and can be used to treat children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2.
• Scientific title: A Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study to Demonstrate Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 1)
• Date of first enrolment: 28/05/2018
• Target sample size: 60
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002338-21
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Poland, Saudi Arabia, Spain, Sweden, Turkey, United Kingdom, United States

Contacts

• Name: Clinical Operations Department
• Affiliation: Albireo AB

• Name: Clinical Operations Department
• Affiliation: Albireo AB

Key inclusion & exclusion criteria

Inclusion criteria:
1. A male or female patient, with clinical diagnosis of PFIC Type 1 or 2, between the ages of =6 months and =18 years at Visit 1 with a body weight above 5 kg
2. Patient must have clinical genetic confirmation of PFIC-1 or PFIC-2 through identification of biallelic pathogenic variants in either the ATP8B1 or ABCB11 genes
3. Patient must have elevated s-BA concentration, specifically measured
to be =100 µmol/L, taken as the average of 2 samples at least 7 days apart (Visits 1 and 2) prior to randomization
4. Patient must have history of significant pruritus and a caregiver-reported observed scratching in the eDiary in the 2 weeks prior
to randomization
5. Patient and/or legal guardian must sign 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 in order to remain in the study
6. Patients will be expected to have a consistent caregiver for the duration of the study
7. Caregivers and age-appropriate patients (=8 years of age) must be willing and able to use an eDiary device as required by the study
Are the trial subjects under 18? yes
Number of subjects for this age range: 60
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 2
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Patient with pathologic variations of the ABCB11 gene that predict complete absence of the BSEP protein
2. Patient with past medical history or ongoing presence of other types of liver disease including, but not limited to, the following:
a) Biliary atresia of any kind
b) Benign recurrent intrahepatic cholestasis
c) Suspected or proven liver cancer or metastasis to the liver on imaging studies
d) Histopathology on liver biopsy is suggestive of alternate non-PFIC related etiology of cholestasis
3. Patient with past medical history of ongoing chronic diarrhea
4. Any patient with suspected or confirmed cancers except for basal cell carcinoma
5. Patient with a past medical history of chronic kidney disease with an impaired renal function and a glomerular filtration rate <70 mL/min/1.73 m2
6. Patient with surgical history of disruption of the enterohepatic circulation (biliary diversion surgery) within 6 months prior to start of Screening period)
7. Patient has had a liver transplant or a liver transplant is planned
within 6 months of randomization
8. Decompensated liver disease, coagulopathy, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
9. Patient suffers from uncontrolled, recalcitrant pruritic condition other than PFIC.
10. Patient who has been previously treated with an IBAT inhibitor whose pruritus has not responded to treatment


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Progressive Familial Intrahepatic Cholestasis Types 1 and 2
MedDRA version: 20.0 Level: PT Classification code 10076033 Term: Progressive familial intrahepatic cholestasis System Organ Class: 10010331 - Congenital, familial and genetic disorders

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

Intervention(s)

Product Code: A4250
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not applicable
Other descriptive name: A4250 (1200 µg)
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 1200-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Code: A4250
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not applicable
Other descriptive name: A4250 (600 µg)
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 600-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Code: A4250
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not applicable
Other descriptive name: A4250 (400 µg)
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 400-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Code: A4250
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not applicable
Other descriptive name: A4250 (200 µg)
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To demonstrate the efficacy of repeated daily doses of 40 µg/kg and 120 µg/kg A4250 in children with PFIC Types 1 and 2, as determined by the following:
• The proportion of patients experiencing at least a 70% reduction in fasting s-BA concentration from baseline to end of treatment or a reduction to a specified level, compared to placebo after 24 weeks of treatment
• To proportion of positive pruritus assessments at the subject level over the 24-week Treatment Period

Primary end point(s): The proportion of patients experiencing at least a 70% reduction in fasting s-BA concentration from baseline to end of treatment or a reduction to a specified level, compared to placebo after 24 weeks of treatment

Timepoint(s) of evaluation of this end point: Randomization (baseline), Week 24, follow-up visit

Secondary Objective: • To evaluate the effect of A4250 on serum ALT concentration
• To evaluate the effect of A4250 on growth
• To evaluate the effect of A4250 on sleep disturbance
• To evaluate the effect of A4250 on the need for surgical treatment (biliary diversion or liver transplantation)
• To assess the safety and tolerability of repeated daily doses of A4250 for 24 weeks

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy endpoints include the following:
EU and RoW: Proportion of positive pruritus assessments at the subject
level over the 24-week Treatment Period. A positive pruritus assessment
is defined as a scratching score of =1 or at least a one-point drop from
baseline on the Albireo ObsRO instrument.
All Regions
All secondary endpoints are compared to placebo.
o Change from baseline to Week 12 and to Week 24 in fasting serum bile
acids
o Change from baseline to Week 12 and to Week 24 in serum ALT
concentration
o Change in growth from baseline to Week 12 and to Week 24
o Proportion of responders for pruritus scores at Weeks 12 and 24 based
on the Albireo PRO and ObsRO instruments
o Change in sleep parameters measured with the Albireo PRO and ObsRO
instruments from baseline over the 24-week Treatment Period
o Proportion of individual assessments meeting the definition of a
positive pruritus assessment at the subject level over the 24-week
Treatment Period; only patients =8 years of age will complete the
Albireo PRO instrument
o Proportion of individual assessments meeting the definition of a
positive pruritus assessment at the subject level from Weeks 0-4, Weeks
0-8, Weeks 0-12, Weeks 0-18, Weeks 0-24, respectively, or the
proportion of positive pruritus assessments at each 4-week interval.
o Proportion of individual AM assessments meeting the definition of a
positive pruritus assessment at the subject level from Weeks 0-4, Weeks
0-8, Weeks 0-12, Weeks 0-18, Weeks 0-24, respectively, or the
proportion of positive pruritus assessments at each 4-week interval.
o Proportion of individual PM assessments meeting the definition of a
positive pruritus assessment at the subject level from Weeks 0-4, Weeks
0-8, Weeks 0-12, Weeks 0-18, Weeks 0-24, respectively, or the
proportion of positive pruritus assessments at each 4-week interval.
o Number of patients undergoing biliary diversion surgery or liver transplantation

Timepoint(s) of evaluation of this end point: Week 12 and Week 24

Secondary ID(s)

A4250-005

2017-002338-21-SE

Source(s) of Monetary Support

Albireo AB

Ethics review

Status: Approved
Approval date: 28/05/2018
Contact: