Long Term Safety & Efficacy Study Evaluating The Effect of A4250 in Children With PFIC

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)

Open Label Extension Study to evaluate long term safety and persistence of effect of A4250 in children with PFIC.

Study Overview

• Status: Active, not recruiting
• Conditions: Progressive Familial Intrahepatic Cholestasis
• Intervention / Treatment: Drug: A4250 (odevixibat)

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia
    • The Royal Children's Hospital
• Belgium
  • Woluwe-Saint-Lambert, Belgium
    • Cliniques Universitaires Saint-Luc
• Canada
  • Toronto, Canada
    • The Hospital for Sick Children
• France
  • Bron, France
    • University and Pediatric Hospital of Lyon
  • Le Kremlin-Bicêtre, France
    • Universite Paris SUD - Hpitaux Universitaires Paris-Sud - Hopital Bicetre
  • Marseille, France
    • Hôspital de la Timone
  • Paris, France
    • Hospital Necker-Enfants Maladies
• Germany
  • Hannover, Germany
    • Medizinische Hochschule Hannover
  • Tübingen, Germany
    • Kinderklinik Tubingen, Universitatsklinikum Tubingen
  • Tübingen, Germany
    • Univesitatsklinikum Tubingen Klinik fur Kinder und Jugendmedizin
• Israel
  • 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 Zarowia Dziecka
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • 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
  • Colorado
    • Denver, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children - Riley Children's Specialists
  • 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
  • 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: 1 year to 98 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria Cohort 1:

1. Completion of the 24-week Treatment Period of Study A4250-005 or withdrawn from Study A4250-005 due to patient/caregiver judgment of intolerable symptoms after completing at least 12 weeks of treatment
2. Signed informed consent and assent as appropriate
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

Inclusion Criteria Cohort 2:

1. A male or female patient of any age, with a clinical diagnosis of PFIC, including episodic forms (i.e., BRIC), and with a body weight ≥5 kg at Visit S-1.
2. Patient must have clinical genetic confirmation of PFIC
3. Patients with PFIC, excluding BRIC, must have elevated serum bile acid concentration,specifically measured to be ≥100 μmol/L, taken as the average of 2 samples at least 7 days apart (Visits S-1 and S-2) prior to the Screening/Inclusion Visit (Visit 1).
4. Patients with PFIC, excluding BRIC, must have history of significant pruritus and a caregiver-reported observed scratching or patient-reported itching (for patients >18 with no caregiver-reported observed scratching) in the eDiary average of ≥2 (on 0 to 4 scale) in the 2 weeks prior to the Screening/Inclusion Visit (Visit 1).
5. Patients with episodic forms of PFIC (i.e., BRIC) must have an emerging flare characterized by clinically significant pruritus and elevated serum bile acid levels/cholestasis as judged by the investigator.
6. 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.
7. Age appropriate patients are expected to have a consistent caregiver for the duration of the study
8. Caregivers and age-appropriate patients (≥8 years of age) must be willing and able to use an eDiary device as required by the study

Exclusion Criteria Cohort 1:

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 hormonal contraception, intra-uterine device, or complete abstinence) throughout the duration of the study and 90 days thereafter
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

Exclusion Criteria Cohort 2:

1. Known pathologic variations of the ABCB11 gene that have been demonstrated to result in 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:

   1. Biliary atresia of any kind
   2. Suspected or proven liver cancer or metastasis to the liver on imaging studies
   3. Histopathology on liver biopsy is suggestive of alternate non-PFIC related etiology of cholestasis Note: Patients with clinically significant portal hypertension are allowed.
3. Patient with a past medical history or ongoing presence of any other disease or condition known to interfere with the absorption, distribution, metabolism (specifically bile acid metabolism), or excretion of drugs in the intestine, including but not limited to,inflammatory bowel disease.
4. Patient with past medical history or ongoing chronic (i.e., >3 months) diarrhea requiring intravenous fluid or nutritional intervention for treatment of the diarrhea and/or its sequelae.
5. Patient has a confirmed past diagnosis of infection with human immunodeficiency virus or other present and active, clinically significant, acute, or chronic infection, or past medical history of any major episode of infection requiring hospitalization or treatment with parenteral anti-infective treatment within 4 weeks of treatment start (Study Day 1) or completion of oral anti-infective treatment within 2 weeks prior to start of Screening Period.
6. Any patient with suspected or confirmed cancers except for basal cell carcinoma, and non-liver cancers treated at least 5 years prior to Screening with no evidence of recurrence.
7. Patient has had a liver transplant, or a liver transplant is planned within 6 months of the Screening/Inclusion Visit.
8. Decompensated liver disease, coagulopathy, history, or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
9. INR >1.4 (the patient may be treated with Vitamin K intravenously, and if INR is ≤1.4 at resampling the patient may be included).
10. Serum ALT >10 × upper limit of normal (ULN) at Screening.
11. Serum ALT >15 × ULN at any time point during the last 6 months unless an alternate etiology was confirmed for the elevation.
12. Total bilirubin >10 × ULN at Screening.

13. Patient suffers from uncontrolled, recalcitrant pruritic condition other than PFIC.

    Examples include, but not limited to, refractory atopic dermatitis or other primary pruritic skin diseases.

14. Any patient who is pregnant or lactating or who is planning to become pregnant within 72 weeks of the Screening/Inclusion Visit.
15. Sexually active males and females who are not using a reliable contraceptive method with ≤1% failure rate (such as hormonal contraception, intrauterine 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).
16. Patient with a past medical history of alcohol or substance abuse will be excluded. Patient must agree to refrain from illicit drug and alcohol use during the study.
17. Administration of bile acid or lipid binding resins and medications that slow GI motility.
18. Patient has had investigational exposure to a drug, biologic agent, or medical device within 30 days prior to Screening, or 5 half-lives of the study agent, whichever is longer.
19. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A4250; Capsules for oral administration (40 or 120 µg/kg) once daily for 72 weeks, or 40 µg/kg/day for the first 12 weeks followed by 120 µg/kg/day for the remaining 60 weeks"	Drug: A4250 (odevixibat); A4250 is a small molecule and selective inhibitor of IBAT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
US: Change in Pruritus	Change in pruritus as indexed by caregiver-reported (Albireo ObsRO instrument) observed scratching	From baseline over 72 weeks
EU and rest of world: Change in serum bile acids		From baseline up to week 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EU and rest of world: Proportion of positive pruritus assessments at the patient level over the 72-week treatment period using the Albireo ObsRO instrument.		72 weeks
US: Change from baseline in serum bile acids after 72 weeks of treatment.		72 weeks
All regions: 3. Change from baseline in serum bile acids at Weeks 4, 12, 22, 24, 36, 46, 48, 60, 70, 72, and 76		Weeks 4, 12, 22, 24, 36, 46, 48, 60, 70, 72, and 76
All regions: Proportion of individual assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument.		weeks 0-4, 0-12, 0-22, 0-24, 0-36, 0-46, 0-48, 0-60, 0-70, or the proportion of positive pruritus assessments at each 4-week interval between V1/Screening and V5/Week 24, then by each visit between V5/Week 24 to V12/Week 76
All regions: Proportion of individual AM assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument		weeks 0-4, 0-12, 0-22, 0-24, 0-36, 0-46, 0-48, 0-60, 0-70, or the proportion of positive pruritus assessments at each 4-week interval between V1/Screening and V5/Week 24, then by each visit between V5/Week 24 to V12/Week 76
All regions: Proportion of individual PM assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument		weeks 0-4, 0-12, 0-22, 0-24, 0-36, 0-46, 0-48, 0-60, 0-70, or the proportion of positive pruritus assessments at each 4-week interval between V1/Screening and V5/Week 24, then by each visit between V5/Week 24 to V12/Week 76
All regions. All-cause mortality		From baseline to weeks 24, 48, and 72
All regions: Number of patients undergoing biliary diversion surgery		From baseline to weeks 24, 48, and 72
All regions: Number of patients undergoing liver transplantation		From baseline to weeks 24, 48, and 72
All regions: Change in growth	The linear growth deficit compared to the standard growth curve	From baseline to weeks 24, 48, and 72
All regions: Change in AST to platelet ratio idex (APRI) score		From baseline to week 72
All regions: Change in Fib-4 score		From baseline to week 72
All regions: Change in pediatric end-stage liver disease (PELD)/model for end-stage liver disease (MELD) score		From baseline to week 72
All regions: Change in use of antipruritic medication		From baseline to weeks 24, 48, and 72

Collaborators and Investigators

• Sponsor: Albireo
• Investigators: Study Director: Ipsen Medical Director, Ipsen

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2018
• Primary Completion (Estimated): March 31, 2024
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: August 24, 2018
• First Submitted That Met QC Criteria: September 4, 2018
• First Posted (Actual): September 6, 2018

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Pediatric; Cholestasis
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis; Cholestasis, Intrahepatic
• Other Study ID Numbers: A4250-008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants.

Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board.

• IPD Sharing Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later.
• IPD Sharing Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available here (https://vivli.org/members/ourmembers/).

Drug and device information, study documents

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