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

Phase 3

Completed

Conditions: PFIC2
PFIC1

Interventions: Drug: A4250 (odevixibat)
Drug: Placebo

Registration Number: NCT03566238

Lead Sponsor: Albireo

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 62

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
A4250 low dose	A4250 (odevixibat)	Capsules for oral administration (40 ug/kg) once daily for 24 weeks
A4250 high dose	A4250 (odevixibat)	Capsules for oral administration (120 ug/kg) once daily for 24 weeks
Placebo	Placebo	Capsules for oral administration (to match active) once daily for 24 weeks

Primary Outcome Measures

Name	Time	Method
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)	Over 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 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.
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)	Over 24 weeks of treatment	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.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (45): Children's Hospital Los Angeles
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Los Angeles, California, United States
University of California, San Francisco
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San Francisco, California, United States
Children's Hospital Colorado
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Denver, Colorado, United States
Emory University School of Medicine
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Atlanta, Georgia, United States
Johns Hopkins School of Medicine
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Baltimore, Maryland, United States
Washington University School of Medicine
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Saint Louis, Missouri, United States
Icahn School of Medicine at Mount Sinai
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New York, New York, United States
Columbia University Medical Center - Presbyterian Hospital Building
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New York, New York, United States
Cleveland Clinic
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Cleveland, Ohio, United States
Children's Hospital of Philadelphia
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Philadelphia, Pennsylvania, United States
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Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States