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
  • Marseille, France
    • Hospital De La Timone
  • Paris, France
    • Hospital Necker-Enfants Maladies
  • le Kremlin Bicetre, France
    • Universite Paris SUD - Hopitaux Universitaires Paris-Sud - Hopital Bicetre
• Germany
  • Essen, Germany
    • Uniklinikum Essen- Kinderklinik II
  • Hannover, Germany
    • Medizinische Hochschule Hannover
  • Tubingen, Germany
    • Kinderklinik Tubingen, Universitatsklinikum Tubingen
• Israel
  • Haifa, Israel
    • Rambam Medical Centre
  • Jerusalem, Israel
    • Shaare-Zedek Mc
  • Petach-Tikva, Israel
    • Schneider Children's Medical Center of Israel
• Italy
  • Bergamo, Italy
    • Azienda Ospedaliera Papa Giovanni XXIII
  • Padova, 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
  • Ankara, Turkey
    • Gazi University
  • Ankara, Turkey
    • Hacettepe University Faculty of Medicine
  • Antalya, Turkey
    • Akdeniz University
  • Istanbul, Turkey
    • Istanbul University Medical Faculty
  • Malatya, Turkey
    • 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
    • Saint 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: 10 months to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

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
Proportion of Positive Pruritus Assessments at the Participant Level Over the 24-week Treatment Period Based on the Albireo Observer-reported Outcome (ObsRO) Instrument (United States Primary Endpoint)	ObsRO instrument was used to assess severity of observed scratching twice a day (AM and PM) with score from 0 to 4 where 0 is no scratching and 4 is worst possible scratching. A positive pruritus assessment was defined as a scratching score of <= 1 or at least one point drop from baseline. At each post baseline assessment over the 24-week treatment period, the AM score was compared to the baseline AM average and the PM score was compared to the baseline PM average. Both AM and PM pruritus assessments were included in the analysis. Any intermittently missing assessment or missing planned assessment after premature treatment discontinuation, death, or initiation of rescue treatment was classified as negative assessment. Proportion of positive pruritus assessments at the participant level over the 24-week was then calculated. Full analysis set was used for the analysis.	Over 24 weeks of treatment
Percentage of Participants Experiencing at Least a 70% Reduction in Fasting s-BA Concentration From Baseline to the End of Treatment or Reaching a Level <= 70 μmol/L After 24 Weeks of Treatment (European Union and Rest of the World Primary Endpoint)	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 μmol/L after 24 weeks of treatment were considered as responder. Participants with missing average at the end of treatment were classified as non-responder. Full analysis set was used for the analysis.	Over 24 weeks of treatment

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.

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 (Actual): September 5, 2021
• Last Update Submitted That Met QC Criteria: August 10, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Pediatric; Cholestasis
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis
• 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