This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC Types 1 or 2 (PEDFIC 1)

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)

Double blind, randomized, placebo controlled, Phase 3 study to investigate the efficacy and safety of low doses and high doses of A4250 compared to placebo in children with progressive familial intrahepatic cholestasis (PFIC) types 1 and 2.

Study Overview

• Status: Completed
• Conditions: PFIC1; PFIC2
• Intervention / Treatment: Drug: A4250 (odevixibat); Drug: Placebo

Detailed Description

Up to 50 sites in the following countries will take part in this study:

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

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia
    • The Royal Children's Hospital
• Belgium
  • Leuven, Belgium
    • UZ Leuven
  • Woluwe-Saint-Lambert, Belgium
    • Cliniques Universitaires Saint-Luc
• Canada
  • Toronto, Canada
    • The Hospital for Sick Children
  • Vancouver, Canada
    • British Columbia Children's Hospital
• France
  • Bron, France
    • University and Pediatric Hospital of Lyon
  • Le Kremlin-Bicêtre, France
    • Universite Paris SUD - Hopitaux Universitaires Paris-Sud - Hopital Bicetre
  • Marseille, France
    • Hospital De La Timone
  • Paris, France
    • Hospital Necker-Enfants Maladies
• Germany
  • Essen, Germany
    • Uniklinikum Essen- Kinderklinik II
  • Hanover, Germany
    • Medizinische Hochschule Hannover
  • Tübingen, Germany
    • Kinderklinik Tubingen, Universitatsklinikum Tubingen
• Israel
  • Haifa, Israel
    • Rambam Medical Centre
  • Jerusalem, Israel
    • Shaare-Zedek Mc
  • Petah Tikva, Israel
    • Schneider Children's Medical Center of Israel
• Italy
  • Bergamo, Italy
    • Azienda Ospedaliera Papa Giovanni XXIII
  • Padua, Italy
    • University Hospital Of Padova
  • Torino, Italy
    • Ospedale Regina Margherita
• Netherlands
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Utrecht, Netherlands
    • Universitair Medisch Centrum (UMC) Utrecht
• Poland
  • Warsaw, Poland
    • Instytut Pomnik - Centrum Zdrowia Dziecka
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • King Faisal Specialist Hospital & Research Centre
• Spain
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain
    • Hospital Universitario La Paz
• Sweden
  • Solna, Sweden
    • Astrid Lindgren Children's Hospital, Karolinska University Hospital
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye)
    • Gazi University
  • Ankara, Turkey (Türkiye)
    • Hacettepe University Faculty of Medicine
  • Antalya, Turkey (Türkiye)
    • Akdeniz University
  • Istanbul, Turkey (Türkiye)
    • Istanbul University Medical Faculty
  • Malatya, Turkey (Türkiye)
    • Inonu University Medical Faculty
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Women's and Children's NHS Foundation Trust
  • Leeds, United Kingdom
    • Leeds General Infirmary
  • London, United Kingdom
    • Institute of Liver Studies - Kings College Hospital
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Colorado
    • Denver, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins School of Medicine
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10029
      • Icahn School Of Medicine At Mount Sinai
    • New York, New York, United States, 10032
      • Columbia University Medical Center - Presbyterian Hospital Building
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine - Texas Children's Liver Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 14 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• A male or female participant with a clinical diagnosis of PFIC Type 1 or 2 and with a body weight above 5 kg
• Participant must have clinical genetic confirmation of PFIC-1 or PFIC-2
• Participant must have elevated serum bile acid (s-BA) concentration
• Participant must have history of significant pruritus and a caregiver reported observed scratching in the eDiary
• Participant and/or legal guardian must sign informed consent (and assent) as appropriate.
• Participants will be expected to have a consistent caregiver(s) for the duration of the study
• Caregivers and age-appropriate participants (≥8 years of age) must be willing and able to use an eDiary device as required by the study

Key Exclusion Criteria:

• Participant with pathologic variations of the ABCB11 gene that predict complete absence of the bile salt export pump (BSEP) protein

• Participant with past medical history or ongoing presence of other types of liver disease including, but not limited to, the following:

  1. Biliary atresia of any kind
  2. Benign recurrent intrahepatic cholestasis, indicated by any history of normal s BAs
  3. Suspected or proven liver cancer or metastasis to the liver on imaging studies
  4. Histopathology on liver biopsy that is suggestive of alternate non-PFIC related etiology of cholestasis
• Participant with past medical history or ongoing chronic diarrhea
• Any participant with suspected or confirmed cancers except for basal cell carcinoma
• Participant with a past medical history of chronic kidney disease with an impaired renal function and a glomerular filtration rate <70 mL/min/1.73 m^2
• Participant with surgical history of disruption of the enterohepatic circulation (biliary diversion surgery) within 6 months prior to start of Screening Period
• Participant has had a liver transplant or a liver transplant is planned within 6 months of randomization
• Decompensated liver disease
• Participant suffers from uncontrolled, recalcitrant pruritic condition other than PFIC
• Participant who has been previously treated with an IBAT inhibitor whose pruritus has not responded to treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A4250 low dose; Capsules for oral administration (40 ug/kg) once daily for 24 weeks	Drug: A4250 (odevixibat); A4250 is a small molecule and selective inhibitor of ileal bile acid transporter (IBAT).
Experimental: A4250 high dose; Capsules for oral administration (120 ug/kg) once daily for 24 weeks	Drug: A4250 (odevixibat); A4250 is a small molecule and selective inhibitor of ileal bile acid transporter (IBAT).
Placebo Comparator: Placebo; Capsules for oral administration (to match active) once daily for 24 weeks	Drug: Placebo; Placebo identical in appearance to active drug (A4250).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With at Least a 70% Reduction in Fasting Serum Bile Acid (s-BA) Concentration From Baseline to the End of Treatment or Reaching a Level <=70 Micromoles Per Liter (Mcmol/L) After 24 Weeks of Treatment	Fasting s-BA baseline was calculated as the average of the last 2 values prior to the first dose. The end value was the average of the values at Weeks 22 and 24 after the start of double-blind treatment. Participants who had at least 70% reduction in fasting s-BA from baseline to the end of treatment or reached <=70 mcmol/L after 24 weeks of treatment were considered as responder. Participants with missing average at the end of treatment were classified as non-responder. Percentages are rounded to hundredth decimal.	From Baseline (Day 1) up to Week 24
Percentage of Positive Pruritus Assessments at the Participant Level Based on the Albireo Observer-Reported Outcome (ObsRO) Instrument Over the 24-Week Treatment Period	A positive pruritus assessment was defined as a scratching score of <=1 or at least 1 point drop from baseline. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100.	From Baseline (Day 1) up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Serum Bile Acid at Weeks 12 and 24	Blood samples for analysis of s-BA were drawn at all visits. Participants were to fast (water intake only was permissible) for at least 4 hours prior to the collection of samples. Exceptions could be made for infants <12 months of age if they were unable to fast for the full 4 hours. Baseline was the average of the last 2 non-missing values of fasting s-BA concentration prior to the first dose of study treatment.	Baseline (Day 1) and Weeks 12 and 24
Change From Baseline in Serum Alanine Aminotransferase (ALT) Concentration at Weeks 12 and 24	Blood samples were collected to determine the ALT concentration. Baseline was the last available assessment before the first dose of study treatment.	Baseline (Day 1) and Weeks 12 and 24
Change From Baseline in Growth Parameters at Weeks 12 and 24	The change in the growth parameters was assessed using linear growth deficit [height (centimeter), weight (kilogram) and body mass index (BMI) (kg/meter square)] compared to standard growth curve (Z-score) calculated by using the software or methods from the centers for disease control (CDC) website for participants with age >=2 years old and from the world health organization website for participants with age <2 years old. Participants whose accurate age was not available, Z-score was not calculated. A Z-score indicated how many standard deviation's (SD) a participant's measurement (like height, weight and BMI), was from the average for their age and sex. A Z-score of 0 represents the median or 50th percentile, while positive or negative values show how far above or below average a measurement was. Baseline was the last available assessment before the first dose of study treatment.	Baseline (Day 1) and Weeks 12 and 24
Percentage of Responders for Pruritus Assessments Based on Bi-Weekly and Monthly Scores Using the Albireo Observer-Reported Outcome Instrument at Weeks 12 and 24	The responder for pruritus scores was defined as a participant who achieved at least a 1-point reduction in the ObsRO pruritus score. Percentages are rounded to hundredth decimal.	Weeks 12 and 24
Change From Baseline in Sleep Parameters Based on the Albireo Observer-reported Outcome Instrument Over the 24-Week Treatment Period	The sleep disturbance were recorded twice daily via the electronic diary (eDiary). Participants and/or caregivers completed the eDiary every day in the morning and in the evening. The morning diary was completed shortly after the participant woke up and was used to record nighttime itching and scratching severity, aspects of sleep disturbance, and tiredness upon waking (AM scores). The evening/bedtime diary was completed just before the participant went to bed and recorded participant's itching and scratching severity, and tiredness during the day (PM scores). Both morning and bedtime diaries included Albireo ObsRO and PRO items. Baseline was the average of 14-day scores before the first dose of study treatment.	Baseline (Day 1) and Weeks 1 to 4, Weeks 5 to 8, Weeks 9 to 12, Weeks 13 to 16, Weeks 17 to 20, and Weeks 21 to 24
Change From Baseline in Sleep Parameters Based on the Albireo Patient-Reported Outcome (PRO) Instrument Over the 24-Week Treatment Period	The ObsRO and electronic diary (eDiary) PRO scale called PRUCISION was used to assess pruritus and sleep outcomes. Participants and/or caregivers completed the eDiary every day in the morning (AM scores) and in the evening (PM scores). Specifically, for difficulty falling or staying asleep, the following 2 respective questions were asked in the Morning Daily eDiary: 1) How hard was it to fall asleep last night because of your itching. and 2) How hard was it to stay asleep last night because of your itching. The PRO was a 5-point scale, and scores ranged from 0 (no itching) to 28 (the worst itching), where higher scores indicated a greater amount of itching, sleep disturbance, and tiredness. No subscales were used. Change in sleep parameters measured with the Albireo PRO and ObsRO instruments by each 4-week interval over the 24-week treatment period was assessed. Baseline was the average of 14-day scores before the first dose of study treatment.	Baseline (Day 1) and Weeks 1 to 4, Weeks 5 to 8, Weeks 9 to 12, Weeks 13 to 16, Weeks 17 to 20, and Weeks 21 to 24
Percentage of Individual Assessments Meeting the Definition of a Positive Pruritus Assessment at the Participant Level Using the Albireo ObsRO Instrument Over the 24-Week Treatment Period	A positive pruritus assessment was defined as a scratching score of <=1 or at least 1 point drop from baseline based on the Albireo ObsRO instrument. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively.	From Baseline (Day 1) up to Week 24
Percentage of Individual Assessments Meeting the Definition of a Positive Pruritus Assessment at the Participant Level Using the Albireo PRO Instrument Over the 24-Week Treatment Period	A positive pruritus assessment was defined as a scratching score of <=1 or at least 1 point drop from baseline based on the Albireo PRO instrument, only participants >=8 years of age completed the Albireo PRO instrument. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively.	From Baseline (Day 1) up to Week 24
Percentage of Individual Assessments Meeting the Definition of a Positive Pruritus Assessment at the Participant Level Using the Albireo ObsRO Instrument Over the 24-Week Treatment Period	A positive pruritus assessment was defined as a scratching score of <=1 or at least 1 point drop from baseline based on the Albireo ObsRO instrument. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively.	Baseline (Day 1) and Weeks 1 to 4, Weeks 5 to 8, Weeks 9 to 12, Weeks 13 to 16, Weeks 17 to 20, and Weeks 21 to 24
Number of Participants Underwent Biliary Diversion Surgery and Liver Transplantation	The number of participants underwent biliary diversion surgery and liver transplantation was determined.	From Baseline (Day 1) up to Week 24
Number of Participants Achieved Positive Pruritus Assessment for >50% of the Time Based on the Albireo ObsRO and PRO Instruments Over the 24-Week Treatment Period	A positive pruritus assessment was defined as a scratching score of <=1 or at least 1 point drop from baseline based on the Albireo ObsRO and PRO instruments. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100.	From Baseline (Day 1) up to Week 24

Collaborators and Investigators

• Sponsor: Albireo

Publications and helpful links

General Publications

• Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, D'Antiga L, Durmaz O, Fischler B, Gonzales E, Grammatikopoulos T, Gupte G, Hardikar W, Houwen RHJ, Kamath BM, Karpen SJ, Kjems L, Lacaille F, Lachaux A, Lainka E, Mack CL, Mattsson JP, McKiernan P, Ozen H, Rajwal SR, Roquelaure B, Shagrani M, Shteyer E, Soufi N, Sturm E, Tessier ME, Verkade HJ, Horn P. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2022 Sep;7(9):830-842. doi: 10.1016/S2468-1253(22)00093-0. Epub 2022 Jul 1.
• Gwaltney C, Ivanescu C, Karlsson L, Warholic N, Kjems L, Horn P. Validation of the PRUCISION Instruments in Pediatric Patients with Progressive Familial Intrahepatic Cholestasis. Adv Ther. 2022 Nov;39(11):5105-5125. doi: 10.1007/s12325-022-02262-7. Epub 2022 Sep 6.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2018
• Primary Completion (Actual): July 27, 2020
• Study Completion (Actual): July 28, 2020

Study Registration Dates

• First Submitted: May 25, 2018
• First Submitted That Met QC Criteria: June 20, 2018
• First Posted (Actual): June 25, 2018

Study Record Updates

• Last Update Posted (Estimated): November 28, 2025
• Last Update Submitted That Met QC Criteria: November 17, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Pediatric; Cholestasis
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis; odevixibat
• Other Study ID Numbers: A4250-005

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No