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

Primary Purpose

PFIC1, PFIC2

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
A4250 (odevixibat)
Placebo
Sponsored by
Albireo
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for PFIC1 focused on measuring Pediatric, Cholestasis

Eligibility Criteria

6 Months - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Hospital Los Angeles
  • University of California, San Francisco
  • Children's Hospital Colorado
  • Emory University School of Medicine
  • Johns Hopkins School of Medicine
  • Washington University School of Medicine
  • Icahn School of Medicine at Mount Sinai
  • Columbia University Medical Center - Presbyterian Hospital Building
  • Cleveland Clinic
  • Children's Hospital of Philadelphia
  • Children's Hospital of Pittsburgh
  • Baylor College of Medicine - Texas Children's Liver Center
  • The Royal Children's Hospital
  • UZ Leuven
  • Cliniques Universitaires Saint-Luc
  • The Hospital for Sick Children
  • British Columbia Children's Hospital
  • University and Pediatric Hospital of Lyon
  • Universite Paris SUD - Hopitaux Universitaires Paris-Sud - Hopital Bicetre
  • Hospital de la Timone
  • Hospital Necker-Enfants maladies
  • Uniklinikum Essen- Kinderklinik II
  • Medizinische Hochschule Hannover
  • Kinderklinik Tübingen, Universitätsklinikum Tübingen
  • Rambam Medical Centre
  • Shaare-Zedek Mc
  • Schneider Children's Medical Center Of Israel
  • Azienda Ospedaliera Papa Giovanni XXIII
  • University Hospital Of Padova
  • Ospedale Regina Margherita
  • University Medical Center Groningen
  • Universitair Medisch Centrum (UMC) Utrecht
  • Instytut Pomnik - Centrum Zdrowia Dziecka
  • King Faisal Specialist Hospital & Research Centre
  • Hospital Universitari Vall d'Hebron
  • Hospital Universitario La Paz
  • Astrid Lindgren Children's Hospital, Karolinska University Hospital
  • Gazi University
  • Hacettepe University Faculty of Medicine
  • Akdeniz University
  • Istanbul University Medical Faculty
  • Inonu University Medical Faculty
  • Birmingham Women's and Children's NHS Foundation Trust
  • Leeds General Infirmary
  • Institute of Liver Studies - Kings College Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

A4250 low dose

A4250 high dose

Placebo

Arm Description

Capsules for oral administration (40 ug/kg) once daily for 24 weeks

Capsules for oral administration (120 ug/kg) once daily for 24 weeks

Capsules for oral administration (to match active) once daily for 24 weeks

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

Full Information

First Posted
May 25, 2018
Last Updated
August 10, 2021
Sponsor
Albireo
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1. Study Identification

Unique Protocol Identification Number
NCT03566238
Brief Title
This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC Types 1 or 2
Acronym
PEDFIC 1
Official 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)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
May 16, 2018 (Actual)
Primary Completion Date
July 27, 2020 (Actual)
Study Completion Date
July 28, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Albireo

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
PFIC1, PFIC2
Keywords
Pediatric, Cholestasis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Double-Blind, Randomized, Placebo-Controlled
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
62 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A4250 low dose
Arm Type
Experimental
Arm Description
Capsules for oral administration (40 ug/kg) once daily for 24 weeks
Arm Title
A4250 high dose
Arm Type
Experimental
Arm Description
Capsules for oral administration (120 ug/kg) once daily for 24 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Capsules for oral administration (to match active) once daily for 24 weeks
Intervention Type
Drug
Intervention Name(s)
A4250 (odevixibat)
Intervention Description
A4250 is a small molecule and selective inhibitor of ileal bile acid transporter (IBAT).
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo identical in appearance to active drug (A4250).
Primary Outcome Measure Information:
Title
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)
Description
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.
Time Frame
Over 24 weeks of treatment
Title
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)
Description
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.
Time Frame
Over 24 weeks of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: Biliary atresia of any kind Benign recurrent intrahepatic cholestasis, indicated by any history of normal s BAs Suspected or proven liver cancer or metastasis to the liver on imaging studies 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
Facility Information:
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Children's Hospital Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Emory University School of Medicine
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30329
Country
United States
Facility Name
Johns Hopkins School of Medicine
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Columbia University Medical Center - Presbyterian Hospital Building
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Baylor College of Medicine - Texas Children's Liver Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
The Royal Children's Hospital
City
Melbourne
Country
Australia
Facility Name
UZ Leuven
City
Leuven
Country
Belgium
Facility Name
Cliniques Universitaires Saint-Luc
City
Woluwe-Saint-Lambert
Country
Belgium
Facility Name
The Hospital for Sick Children
City
Toronto
Country
Canada
Facility Name
British Columbia Children's Hospital
City
Vancouver
Country
Canada
Facility Name
University and Pediatric Hospital of Lyon
City
Bron
Country
France
Facility Name
Universite Paris SUD - Hopitaux Universitaires Paris-Sud - Hopital Bicetre
City
le Kremlin Bicetre
Country
France
Facility Name
Hospital de la Timone
City
Marseille
Country
France
Facility Name
Hospital Necker-Enfants maladies
City
Paris
Country
France
Facility Name
Uniklinikum Essen- Kinderklinik II
City
Essen
Country
Germany
Facility Name
Medizinische Hochschule Hannover
City
Hannover
Country
Germany
Facility Name
Kinderklinik Tübingen, Universitätsklinikum Tübingen
City
Tubingen
Country
Germany
Facility Name
Rambam Medical Centre
City
Haifa
Country
Israel
Facility Name
Shaare-Zedek Mc
City
Jerusalem
Country
Israel
Facility Name
Schneider Children's Medical Center Of Israel
City
Petach-Tikva
Country
Israel
Facility Name
Azienda Ospedaliera Papa Giovanni XXIII
City
Bergamo
Country
Italy
Facility Name
University Hospital Of Padova
City
Padova
Country
Italy
Facility Name
Ospedale Regina Margherita
City
Torino
Country
Italy
Facility Name
University Medical Center Groningen
City
Groningen
Country
Netherlands
Facility Name
Universitair Medisch Centrum (UMC) Utrecht
City
Utrecht
Country
Netherlands
Facility Name
Instytut Pomnik - Centrum Zdrowia Dziecka
City
Warsaw
Country
Poland
Facility Name
King Faisal Specialist Hospital & Research Centre
City
Riyadh
ZIP/Postal Code
11211
Country
Saudi Arabia
Facility Name
Hospital Universitari Vall d'Hebron
City
Barcelona
Country
Spain
Facility Name
Hospital Universitario La Paz
City
Madrid
Country
Spain
Facility Name
Astrid Lindgren Children's Hospital, Karolinska University Hospital
City
Solna
Country
Sweden
Facility Name
Gazi University
City
Ankara
Country
Turkey
Facility Name
Hacettepe University Faculty of Medicine
City
Ankara
Country
Turkey
Facility Name
Akdeniz University
City
Antalya
Country
Turkey
Facility Name
Istanbul University Medical Faculty
City
Istanbul
Country
Turkey
Facility Name
Inonu University Medical Faculty
City
Malatya
Country
Turkey
Facility Name
Birmingham Women's and Children's NHS Foundation Trust
City
Birmingham
Country
United Kingdom
Facility Name
Leeds General Infirmary
City
Leeds
Country
United Kingdom
Facility Name
Institute of Liver Studies - Kings College Hospital
City
London
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
35780807
Citation
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.
Results Reference
derived

Learn more about this trial

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

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