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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    		 2017-002338-21
    Trial protocol
    		 SE   DE   FR   GB   NL   ES   BE   PL   IT  
    Global end of trial date
    28 Jul 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    23 Oct 2025
    First version publication date
    29 Apr 2021
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of Secondary Outcome Results

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A4250-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03566238
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Albireo AB, An Ipsen Company
    Sponsor organisation address
    Arvid Wallgrens backe 20, Göteborg, Sweden, 413 46
    Public contact
    Patrick Horn, MD, PhD , Albireo AB, An Ipsen Company, +1 (857) 378-2035, medinfo@albireopharma.com
    Scientific contact
    Patrick Horn, MD, PhD , Albireo AB, An Ipsen Company, +1 (857) 378-2035 , medinfo@albireopharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002054-PIP01-16
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of repeated daily doses of 40 microgram per kilogram (mcg/kg) per day and 120 mcg/kg/day odevixibat in children with progressive familial intrahepatic cholestasis Types 1 and 2 (PFIC1 and PFIC2), as determined by the following: • Proportion of participants experiencing at least a 70% reduction in serum bile acid (s-BA) concentration from baseline to end of treatment or reaching a level <=70 micromoles per liter (mcmol/L). • Proportion of positive pruritus assessments at the participant level over the 24-week treatment period.
    Protection of trial subjects
    Safety was evaluated throughout the study, including monitoring for adverse events (AEs) and concomitant medications, physical examinations, vital signs, laboratory tests (including chemistry, hematology, urinalysis, vitamins A and E, 25-hydroxy vitamin D, and international normalized ratio), and abdominal ultrasound at regularly scheduled and ad-hoc meetings. Hepatic events underwent review and adjudication of etiology by an independent Data Safety Monitoring Board.
    Background therapy
    		 Eligible participants were randomized on Day 0 (Visit 3) in a 1:1:1 fashion to receive 40 mcg/kg/day or 120 mcg/kg/day of odevixibat, or matching placebo. Odevixibat was administered orally, once daily at doses of 40 mcg/kg/day or 120 mcg/kg/day based on randomized treatment. Odevixibat was supplied in 2 capsule sizes and 4 strengths: capsule size 0 (200 or 600 mcg strength) that could be opened and sprinkled on food and capsule size 3 (400 or 1200 mcg strength) to be swallowed intact but could be opened for participants unable to swallow the capsules whole. Treatment duration was 24 weeks with the possibility to continue treatment with odevixibat 120 mcg/kg/day in the open label extension study.
    Evidence for comparator
    		 Placebo controlled
    Actual start date of recruitment
    16 May 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 19 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Saudi Arabia: 3
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    United Kingdom: 13
    Worldwide total number of subjects
    62
    EEA total number of subjects
    22
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    23
    Children (2-11 years)
    34
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase 3, double-blind, placebo-controlled study was conducted in children with PFIC at 33 study centers in 12 countries between 16 May 2018 and 28 July 2020.

    Pre-assignment
    Screening details
    		 The study included up to an 8-week screening period, a 24-week treatment period, and a 4-week follow-up period. A total of 62 participants were enrolled in the study.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Capsules for oral administration (to match active) once daily for 24 weeks. Placebo: Placebo identical in appearance to active drug (A4250).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was orally administered once daily in the morning for 24 weeks. For young children or in case of difficulties swallowing the capsules, capsules could be opened and the content sprinkled on soft foods.

    Arm title
    		 A4250 Low Dose
    Arm description
    		 Capsules for oral administration (40 mcg/kg) once daily for 24 weeks. A4250 (odevixibat): A4250 is a small molecule and selective inhibitor of ileal bile acid transporter (IBAT).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Odevixibat
    Investigational medicinal product code
    A4250
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    40 mcg/kg/day was orally administered once daily in the morning for 24 weeks. For young children or in case of difficulties swallowing the capsules, capsules could be opened and the content sprinkled on soft foods.

    Arm title
    		 A4250 High Dose
    Arm description
    		 Capsules for oral administration (120 mcg/kg) once daily for 24 weeks. A4250 (odevixibat): A4250 is a small molecule and selective inhibitor of IBAT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Odevixibat
    Investigational medicinal product code
    A4250
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    120 mcg/kg/day was orally administered once daily in the morning for 24 weeks. For young children or in case of difficulties swallowing the capsules, capsules could be opened and the content sprinkled on soft foods.

    Number of subjects in period 1
    		Placebo A4250 Low Dose A4250 High Dose
    Started
    20
    23
    19
    Received treatment
    20
    23
    19
    Completed
    15
    18
    16
    Not completed
    5
    5
    3
         Adverse event, non-fatal
    -
    -
    1
         Unspecified
    -
    1
    -
         Lack of efficacy
    5
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Capsules for oral administration (to match active) once daily for 24 weeks. Placebo: Placebo identical in appearance to active drug (A4250).

    Reporting group title
    A4250 Low Dose
    Reporting group description
    		 Capsules for oral administration (40 mcg/kg) once daily for 24 weeks. A4250 (odevixibat): A4250 is a small molecule and selective inhibitor of ileal bile acid transporter (IBAT).

    Reporting group title
    A4250 High Dose
    Reporting group description
    		 Capsules for oral administration (120 mcg/kg) once daily for 24 weeks. A4250 (odevixibat): A4250 is a small molecule and selective inhibitor of IBAT.

    Reporting group values
    		 Placebo A4250 Low Dose A4250 High Dose Total
    Number of subjects
    		 20 23 19 62
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 8 9 6 23
        Children (2-11 years)
    		 11 13 10 34
        Adolescents (12-17 years)
    		 1 1 3 5
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.75 ( 3.853 ) 3.86 ( 3.660 ) 5.24 ( 4.188 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 12 11 31
        Male
    		 12 11 8 31
    Type of PFIC
    PFIC Type 1: Familial intrahepatic cholestasis-1 (FIC1) protein deficiency, PFIC Type 2: Bile salt export pump (BSEP) deficiency.
    Units: Subjects
        Type 1
    		 5 7 5 17
        Type 2
    		 15 16 14 45
    Age Category 1
    Age Category 1
    Units: Subjects
        6 months to 5 years
    		 16 17 14 47
        6 to 12 years
    		 3 5 4 12
        13 to 18 years
    		 1 1 1 3
    Race
    Units: Subjects
        White
    		 17 18 17 52
        Black or African American
    		 0 2 0 2
        Asian
    		 1 0 1 2
        American Indian or Alaska Native
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Other
    		 2 3 1 6
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 0 1
        Not Hispanic or Latino
    		 19 23 19 61
    Region of Enrollment
    Units: Subjects
        United States
    		 3 2 3 8
        United Kingdom
    		 5 6 2 13
        Saudi Arabia
    		 1 0 2 3
        Canada
    		 1 1 0 2
        Netherlands
    		 1 0 2 3
        Turkey
    		 1 7 3 11
        Poland
    		 2 0 1 3
        Italy
    		 1 1 0 2
        Israel
    		 1 0 1 2
        France
    		 1 3 1 5
        Australia
    		 1 0 0 1
        Germany
    		 2 3 4 9

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Capsules for oral administration (to match active) once daily for 24 weeks. Placebo: Placebo identical in appearance to active drug (A4250).

    Reporting group title
    A4250 Low Dose
    Reporting group description
    		 Capsules for oral administration (40 mcg/kg) once daily for 24 weeks. A4250 (odevixibat): A4250 is a small molecule and selective inhibitor of ileal bile acid transporter (IBAT).

    Reporting group title
    A4250 High Dose
    Reporting group description
    		 Capsules for oral administration (120 mcg/kg) once daily for 24 weeks. A4250 (odevixibat): A4250 is a small molecule and selective inhibitor of IBAT.

    Primary: Percentage of Participants With at least a 70% Reduction in Fasting Serum Bile Acid Concentration From Baseline to the End of Treatment or Reaching a Level <=70 mcmol/L After 24 Weeks of Treatment

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    End point title
    		 Percentage of Participants With at least a 70% Reduction in Fasting Serum Bile Acid Concentration From Baseline to the End of Treatment or Reaching a Level <=70 mcmol/L After 24 Weeks of Treatment
    End point 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 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. The FAS included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    From Baseline (Day 1) up to Week 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    20
    23
    19
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0.00 to 16.84)
    43.5 (23.19 to 65.51)
    21.1 (6.05 to 45.57)
    Statistical analysis title
    		 Fasting s-BA Concentration
    Statistical analysis description
    Analysis was based on the Cochran Mantel Haenszel test adjusting PFIC type. A pooled analysis for the closed testing procedure was applied to control multiplicity. The 1-sided adjusted p-value for an individual dose was calculated as the maximum value of the unadjusted p-value for the pooled analysis and the unadjusted p-value for the individual doses. 1-sided adjusted p-value was reported.
    Comparison groups
    Placebo v A4250 Low Dose
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 percentage difference
    Point estimate
    0.435
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2195
         upper limit
    		 0.6551
    Statistical analysis title
    		 Fasting s-BA Concentration
    Statistical analysis description
    Analysis was based on the Cochran Mantel Haenszel test adjusting PFIC type. A pooled analysis for the closed testing procedure was applied to control multiplicity. The 1-sided adjusted p-value for an individual dose was calculated as the maximum value of the unadjusted p-value for the pooled analysis and the unadjusted p-value for the individual doses. 1-sided adjusted p-value was reported.
    Comparison groups
    Placebo v A4250 High Dose
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0174
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 percentage difference
    Point estimate
    0.211
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.021
         upper limit
    		 0.4557

    Primary: Proportion of Positive Pruritus Assessments at the Participant Level Based on the Albireo Observer-Reported Outcome (ObsRO) Instrument Over the 24-Week Treatment Period

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    End point title
    		 Proportion of Positive Pruritus Assessments at the Participant Level Based on the Albireo Observer-Reported Outcome (ObsRO) Instrument Over the 24-Week Treatment Period
    End point description
    A positive pruritus assessment was defined as a scratching score of <=1 or at least 1 point drop from baseline. The proportion 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. The FAS included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    From Baseline (Day 1) up to Week 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    20
    23
    19
    Units: proportion of pruritus-participant-level
        arithmetic mean (standard error)
    28.74 ( 5.209 )
    58.31 ( 6.205 )
    47.69 ( 8.110 )
    Statistical analysis title
    		 Proportion of Positive Pruritus Assessments
    Statistical analysis description
    Analysis of the Proportion of Positive Pruritus Assessments at Participant Level over the 24-Week Treatment Period - Albireo ObsRO Instrument (AM and PM Scores).
    Comparison groups
    Placebo v A4250 Low Dose
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0019
    Method
    		 ANCOVA
    Parameter type
    		 Least Square (LS) mean difference
    Point estimate
    28.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.83
         upper limit
    		 46.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.182
    Notes
    [1] - Analysis of Covariance (ANCOVA) model including treatment, baseline pruritus score at AM and PM, PFIC type, and age category was used for treatment comparisons. A pooled analysis for the closed testing procedure was applied to control multiplicity. The 1-sided adjusted p-value for an individual dose was calculated as the maximum value of the unadjusted p-value for the pooled analysis and the unadjusted p-value for the individual doses. 1-sided adjusted p-value was reported.
    Statistical analysis title
    		 Proportion of Positive Pruritus Assessments
    Statistical analysis description
    Analysis of the Proportion of Positive Pruritus Assessments at Participant Level over the 24-Week Treatment Period - Albireo ObsRO Instrument (AM and PM Scores).
    Comparison groups
    Placebo v A4250 High Dose
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0163
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    21.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.87
         upper limit
    		 41.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.892
    Notes
    [2] - An ANCOVA model including treatment, baseline pruritus score at AM and PM, PFIC type, and age category was used for treatment comparisons. A pooled analysis for the closed testing procedure was applied to control multiplicity. The 1-sided adjusted p-value for an individual dose was calculated as the maximum value of the unadjusted p-value for the pooled analysis and the unadjusted p-value for the individual doses. 1-sided adjusted p-value was reported.

    Secondary: Change From Baseline in Fasting Serum Bile Acid at Weeks 12 and 24

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    End point title
    		 Change From Baseline in Fasting Serum Bile Acid at Weeks 12 and 24
    End point description
    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. The FAS included all randomized participants who received at least 1 dose of study treatment. Here, n= number of participants with data collected at Baseline and Weeks 12 and 24.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 12 and 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    17
    20
    16
    Units: mcmol/L
    arithmetic mean (standard error)
        Week 12 (n=17,20,16)
    7.44 ( 24.588 )
    -113.70 ( 38.011 )
    -106.44 ( 41.201 )
        Week 24 (n=11,17,15)
    18.64 ( 31.559 )
    -145.03 ( 41.951 )
    -72.90 ( 52.617 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Alanine Aminotransferase (ALT) Concentration at Weeks 12 and 24

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    End point title
    		 Change From Baseline in Serum Alanine Aminotransferase (ALT) Concentration at Weeks 12 and 24
    End point description
    Blood samples were collected to determine the ALT concentration. Baseline was the last available assessment before the first dose of study treatment. The FAS included all randomized participants who received at least 1 dose of study treatment. Here, n= number of participants with data collected at Baseline and Weeks 12 and 24.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 12 and 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    18
    22
    18
    Units: units/L
    arithmetic mean (standard error)
        Week 12 (n=18,22,18)
    1.7 ( 10.50 )
    -25.9 ( 23.36 )
    -13.8 ( 19.42 )
        Week 24 (n=11,17,15)
    3.7 ( 4.95 )
    -27.9 ( 17.97 )
    -25.3 ( 22.47 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Growth Parameters at Weeks 12 and 24

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    End point title
    		 Change From Baseline in Growth Parameters at Weeks 12 and 24
    End point description
    The summary was based on linear growth deficit [height (centimeter), weight (kilogram) and body mass index (BMI) (kg/meter square] for age compared to a standard growth curve (Z-score, standard deviation from median or 50th percentile standard growth curve), calculated by using the software or methods from the Centers for Disease Control and Prevention (CDC) website for participants with age >=2 years old and from the World Health Organization website for participants with age <2 years old. Baseline was the last available assessment before the first dose of study treatment. The FAS included all randomized participants who received at least 1 dose of study treatment. Here, n= number of participants with data collected at Baseline and Weeks 12 and 24.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 12 and 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    18
    22
    16
    Units: z-score
    arithmetic mean (standard error)
        Height deficit: Week 12 (n=18,22,16)
    -0.03 ( 0.127 )
    0.01 ( 0.108 )
    -0.06 ( 0.100 )
        Height deficit: Week 24 (n=12,17,15)
    -0.16 ( 0.104 )
    0.05 ( 0.105 )
    0.00 ( 0.163 )
        Weight deficit: Week 12 (n=18,22,16)
    0.13 ( 0.066 )
    0.20 ( 0.078 )
    0.00 ( 0.100 )
        Weight deficit: Week 24 (n=12,18,15)
    0.10 ( 0.102 )
    0.29 ( 0.106 )
    0.15 ( 0.124 )
        BMI deficit: Week 12 (n=18,22,16)
    0.18 ( 0.148 )
    0.23 ( 0.114 )
    0.08 ( 0.147 )
        BMI deficit: Week 24 (n=12,17,15)
    0.26 ( 0.156 )
    0.36 ( 0.113 )
    0.20 ( 0.203 )
    No statistical analyses for this end point

    Secondary: 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

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    End point title
    		 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
    End point description
    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. The FAS included all randomized participants who received at least 1 dose of study treatment. Here, n= number of participants with data collected at specific timepoints.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    20 [3]
    23 [4]
    19 [5]
    Units: percentage of participants
    number (confidence interval 95%)
        AM and PM scores combined:Week 12(Bi-weekly score)
    5.0 (0.13 to 24.87)
    60.9 (38.54 to 80.29)
    42.1 (20.25 to 66.50)
        AM and PM scores combined:Week 12(Monthly score)
    10.0 (1.23 to 31.70)
    52.2 (30.59 to 73.18)
    42.1 (20.25 to 66.50)
        AM and PM scores combined:Week 24(Bi-weekly score)
    11.8 (1.46 to 36.44)
    43.5 (23.19 to 65.51)
    33.3 (13.34 to 59.01)
        AM and PM scores combined:Week 24(Monthly score)
    10.5 (1.30 to 33.14)
    52.2 (30.59 to 73.18)
    31.6 (12.58 to 56.55)
        AM score: Week 12 (Bi-weekly score)
    10.0 (1.23 to 31.70)
    60.9 (38.54 to 80.29)
    42.1 (20.25 to 66.50)
        AM score: Week 12 (Monthly score)
    10.0 (1.23 to 31.70)
    56.5 (34.49 to 76.81)
    42.1 (20.25 to 66.50)
        AM score: Week 24 (Bi-weekly score)
    11.8 (1.46 to 36.44)
    39.1 (19.71 to 61.46)
    33.3 (13.34 to 59.01)
        AM score: Week 24 (Monthly score)
    15.8 (3.38 to 39.58)
    52.2 (30.59 to 73.18)
    42.1 (20.25 to 66.50)
        PM score: Week 12 (Bi-weekly score)
    10.0 (1.23 to 31.70)
    65.2 (42.73 to 83.62)
    36.8 (16.29 to 61.64)
        PM score: Week 12 (Monthly score)
    10.0 (1.23 to 31.70)
    60.9 (38.54 to 80.29)
    36.8 (16.29 to 61.64)
        PM score: Week 24 (Bi-weekly score)
    11.8 (1.46 to 36.44)
    56.5 (34.49 to 76.81)
    33.3 (13.34 to 59.01)
        PM score: Week 24 (Monthly score)
    10.5 (1.30 to 33.14)
    52.2 (30.59 to 73.18)
    31.6 (12.58 to 56.55)
    Notes
    [3] - n=20,20,17,19,20,20,17,19,20,20,17,19.
    [4] - n=23,23,23,23,23,23,23,23,23,23,23,23.
    [5] - n=19,19,18,19,19,19,18,19,19,19,18,19.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sleep Parameters Based on the Albireo Observer-reported Outcome Instrument Over the 24- Week Treatment Period

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    End point title
    		 Change From Baseline in Sleep Parameters Based on the Albireo Observer-reported Outcome Instrument Over the 24- Week Treatment Period
    End point description
    The sleep disturbance were recorded twice daily via electronic diary (eDiary). Participants and/or caregivers completed eDiary every day in the morning and evening. Morning diary was completed shortly after participant woke up and was used to record nighttime itching and scratching severity, aspects of sleep disturbance, and tiredness upon waking (AM scores). Evening/bedtime diary was completed just before 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. The FAS included all randomized participants who received at least 1 dose of study treatment. Here, n=number of participants with data collected at specific timepoints. SBS=Seeing blood due to scratching; HFA=Help falling asleep; SwC=Sleeping with the caregiver; TMIS=Taking medications to induce sleep.
    End point type
    Secondary
    End point timeframe
    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
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    20
    23
    19
    Units: percentage of days
    arithmetic mean (standard error)
        SBS: Weeks 1 to 4 (n=20,23,19)
    -15.79 ( 4.700 )
    -14.42 ( 5.854 )
    -12.97 ( 6.036 )
        SBS: Weeks 5 to 8 (n=20,22,19)
    -12.10 ( 6.353 )
    -26.22 ( 7.427 )
    -13.99 ( 7.770 )
        SBS: Weeks 9 to 12 (n=20,23,18)
    -13.49 ( 6.320 )
    -29.22 ( 7.593 )
    -16.89 ( 9.258 )
        SBS: Weeks 13 to 16 (n=17,19,16)
    -15.75 ( 6.264 )
    -33.38 ( 8.219 )
    -18.16 ( 9.403 )
        SBS: Weeks 17 to 20 (n=15,20,16)
    -22.02 ( 7.999 )
    -32.14 ( 8.531 )
    -18.02 ( 9.967 )
        SBS: Weeks 21 to 24 (n=14,19,16)
    -23.72 ( 8.563 )
    -30.82 ( 8.184 )
    -15.52 ( 10.465 )
        HFA: Weeks 1 to 4 (n=20,23,19)
    -0.91 ( 1.596 )
    -14.73 ( 5.683 )
    -20.37 ( 6.390 )
        HFA: Weeks 5 to 8 (n=20,22,19)
    -2.35 ( 2.397 )
    -25.03 ( 7.527 )
    -31.49 ( 10.209 )
        HFA: Weeks 9 to 12 (n=20,23,18)
    -0.90 ( 1.152 )
    -31.03 ( 8.061 )
    -36.72 ( 11.154 )
        HFA: Weeks 13 to 16 (n=17,19,16)
    -0.86 ( 1.392 )
    -46.10 ( 9.677 )
    -37.76 ( 12.013 )
        HFA: Weeks 17 to 20 (n=15,20,16)
    -6.27 ( 3.862 )
    -45.65 ( 9.524 )
    -40.51 ( 12.566 )
        HFA: Weeks 21 to 24 (n=14,19,16)
    -3.19 ( 2.890 )
    -51.75 ( 9.857 )
    -32.58 ( 14.573 )
        Soothing: Weeks 1 to 4 (n=20,23,19)
    -1.15 ( 1.338 )
    -12.92 ( 5.911 )
    -21.88 ( 6.228 )
        Soothing: Weeks 5 to 8 (n=20,22,19)
    -3.76 ( 2.773 )
    -17.89 ( 7.562 )
    -35.97 ( 9.795 )
        Soothing: Weeks 9 to 12 (n=20,23,18)
    -5.00 ( 2.819 )
    -29.79 ( 8.570 )
    -41.21 ( 10.796 )
        Soothing: Weeks 13 to 16 (n=17,19,16)
    -2.12 ( 3.006 )
    -42.79 ( 10.364 )
    -40.23 ( 11.611 )
        Soothing: Weeks 17 to 20 (n=15,20,16)
    -4.73 ( 3.742 )
    -44.96 ( 10.485 )
    -40.13 ( 12.324 )
        Soothing: Weeks 21 to 24 (n=14,19,16)
    -7.64 ( 6.182 )
    -51.48 ( 10.323 )
    -34.87 ( 13.369 )
        SwC: Weeks 1 to 4 (n=20,23,19)
    -4.49 ( 1.961 )
    -15.30 ( 6.396 )
    -24.57 ( 7.024 )
        SwC: Weeks 5 to 8 (n=20,22,19)
    -5.93 ( 3.649 )
    -19.73 ( 7.061 )
    -35.58 ( 10.053 )
        SwC: Weeks 9 to 12 (n=20,23,18)
    -5.74 ( 3.585 )
    -26.12 ( 9.543 )
    -36.00 ( 10.361 )
        SwC: Weeks 13 to 16 (n=17,19,16)
    -4.96 ( 3.481 )
    -40.55 ( 10.501 )
    -37.52 ( 11.083 )
        SwC: Weeks 17 to 20 (n=15,20,16)
    -2.59 ( 3.688 )
    -42.20 ( 10.247 )
    -35.14 ( 11.563 )
        SwC: Weeks 21 to 24 (n=14,19,16)
    -5.45 ( 4.844 )
    -49.35 ( 10.466 )
    -33.14 ( 11.801 )
        TMIS: Weeks 1 to 4 (n=20,23,19)
    -1.78 ( 1.921 )
    -0.61 ( 1.913 )
    0.98 ( 2.320 )
        TMIS: Weeks 5 to 8 (n=20,22,19)
    1.44 ( 4.292 )
    0.18 ( 3.018 )
    -2.43 ( 3.036 )
        TMIS: Weeks 9 to 12 (n=20,23,18)
    2.40 ( 4.271 )
    1.31 ( 3.656 )
    -5.74 ( 4.967 )
        TMIS: Weeks 13 to 16 (n=17,19,16)
    0.16 ( 4.647 )
    -1.61 ( 2.556 )
    -4.58 ( 4.681 )
        TMIS: Weeks 17 to 20 (n=15,20,16)
    3.53 ( 5.384 )
    -1.99 ( 2.141 )
    -3.26 ( 6.403 )
        TMIS: Weeks 21 to 24 (n=14,19,16)
    5.50 ( 5.307 )
    -0.03 ( 2.251 )
    2.04 ( 8.413 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sleep Parameters Based on the Albireo Patient-Reported Outcome (PRO) Instrument Over the 24-Week Treatment Period

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    End point title
    		 Change From Baseline in Sleep Parameters Based on the Albireo Patient-Reported Outcome (PRO) Instrument Over the 24-Week Treatment Period
    End point description
    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. The FAS included all randomized participants who received at least 1 dose of study treatment. Here, n= number of participants with data collected at specific timepoints.
    End point type
    Secondary
    End point timeframe
    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
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    2
    2
    5
    Units: scores on a scale
    arithmetic mean (standard error)
        Difficulty falling asleep: Weeks 1 to 4
    -0.46 ( 0.143 )
    -0.72 ( 0.494 )
    -0.59 ( 0.394 )
        Difficulty falling asleep: Weeks 5 to 8
    -0.34 ( 0.018 )
    -1.40 ( 1.009 )
    -0.65 ( 0.571 )
        Difficulty falling asleep: Weeks 9 to 12
    -0.38 ( 0.339 )
    -2.31 ( 0.499 )
    -0.95 ( 0.650 )
        Difficulty falling asleep: Weeks 13 to 16
    -0.16 ( 0.268 )
    -2.07 ( 0.863 )
    -1.01 ( 0.665 )
        Difficulty falling asleep: Weeks 17 to 20
    -0.52 ( 0.228 )
    -2.12 ( 0.974 )
    -1.02 ( 0.710 )
        Difficulty falling asleep: Weeks 21 to 24
    -0.25 ( 0.179 )
    -2.22 ( 0.823 )
    -0.82 ( 0.658 )
        Difficulty staying asleep: Weeks 1 to 4
    -0.13 ( 0.411 )
    -0.70 ( 0.548 )
    -0.43 ( 0.440 )
        Difficulty staying asleep: Weeks 5 to 8
    0.09 ( 0.518 )
    -1.48 ( 0.932 )
    -0.50 ( 0.553 )
        Difficulty staying asleep: Weeks 9 to 12
    0.02 ( 0.661 )
    -2.51 ( 0.352 )
    -0.77 ( 0.670 )
        Difficulty staying asleep: Weeks 13 to 16
    0.13 ( 0.625 )
    -2.46 ( 0.464 )
    -0.89 ( 0.626 )
        Difficulty staying asleep: Weeks 17 to 20
    -0.15 ( 0.147 )
    -2.36 ( 0.637 )
    -0.95 ( 0.644 )
        Difficulty staying asleep: Weeks 21 to 24
    0.25 ( 0.429 )
    -2.55 ( 0.448 )
    -0.78 ( 0.633 )
    No statistical analyses for this end point

    Secondary: Proportion 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

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    End point title
    		 Proportion 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
    End point description
    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 proportion 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. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively. The FAS included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    20
    23
    19
    Units: proportion of pruritus-participant-level
    arithmetic mean (standard error)
        AM and PM scores combined: Weeks 0 to 4
    33.48 ( 5.881 )
    51.40 ( 5.818 )
    42.48 ( 7.508 )
        AM and PM scores combined: Weeks 0 to 8
    32.72 ( 5.871 )
    54.23 ( 5.887 )
    48.21 ( 7.479 )
        AM and PM scores combined: Weeks 0 to 12
    32.35 ( 5.945 )
    58.85 ( 5.738 )
    49.15 ( 7.428 )
        AM and PM scores combined: Weeks 0 to 16
    30.67 ( 5.522 )
    58.83 ( 5.925 )
    48.31 ( 7.624 )
        AM and PM scores combined: Weeks 0 to 18
    29.88 ( 5.462 )
    58.80 ( 6.004 )
    48.25 ( 7.809 )
        AM and PM scores combined: Weeks 0 to 20
    29.45 ( 5.376 )
    58.68 ( 6.079 )
    48.10 ( 7.975 )
        AM score: Weeks 0 to 4
    31.07 ( 5.436 )
    48.14 ( 6.161 )
    47.37 ( 8.439 )
        AM score: Weeks 0 to 8
    31.07 ( 5.213 )
    51.16 ( 6.129 )
    51.79 ( 8.001 )
        AM score: Weeks 0 to 12
    31.07 ( 5.374 )
    56.06 ( 5.922 )
    52.26 ( 7.693 )
        AM score: Weeks 0 to 16
    29.91 ( 5.246 )
    56.41 ( 6.183 )
    50.47 ( 7.660 )
        AM score: Weeks 0 to 18
    28.93 ( 5.224 )
    56.35 ( 6.249 )
    49.92 ( 7.800 )
        AM score: Weeks 0 to 20
    28.50 ( 5.206 )
    56.27 ( 6.293 )
    49.74 ( 7.993 )
        AM score: Weeks 0 to 24
    28.17 ( 5.276 )
    55.73 ( 6.396 )
    48.92 ( 8.197 )
        PM score: Weeks 0 to 4
    35.89 ( 7.055 )
    54.66 ( 6.594 )
    37.59 ( 7.629 )
        PM score: Weeks 0 to 8
    34.38 ( 7.290 )
    57.30 ( 6.478 )
    44.64 ( 7.804 )
        PM score: Weeks 0 to 12
    33.63 ( 7.404 )
    61.65 ( 6.330 )
    46.05 ( 7.884 )
        PM score: Weeks 0 to 16
    31.43 ( 7.006 )
    61.26 ( 6.205 )
    46.15 ( 8.178 )
        PM score: Weeks 0 to 18
    30.83 ( 6.898 )
    61.25 ( 6.225 )
    46.57 ( 8.363 )
        PM score: Weeks 0 to 20
    30.39 ( 6.812 )
    61.09 ( 6.284 )
    46.47 ( 8.434 )
        PM score: Weeks 0 to 24
    29.31 ( 6.592 )
    60.89 ( 6.385 )
    46.47 ( 8.456 )
    No statistical analyses for this end point

    Secondary: Proportion 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

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    End point title
    		 Proportion 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
    End point description
    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 proportion 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. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively. The FAS included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    2
    2
    5
    Units: proportion of pruritus-participant-level
    arithmetic mean (standard error)
        AM and PM scores combined: Weeks 0 to 4
    64.29 ( 8.929 )
    43.75 ( 25.893 )
    38.93 ( 15.272 )
        AM and PM scores combined: Weeks 0 to 8
    46.88 ( 12.946 )
    52.68 ( 25.893 )
    41.96 ( 16.178 )
        AM and PM scores combined: Weeks 0 to 12
    41.96 ( 10.417 )
    63.39 ( 18.155 )
    45.00 ( 16.939 )
        AM and PM scores combined: Weeks 0 to 16
    38.62 ( 3.348 )
    66.74 ( 18.080 )
    46.96 ( 17.477 )
        AM and PM scores combined: Weeks 0 to 18
    37.50 ( 0.198 )
    67.66 ( 18.849 )
    47.14 ( 17.558 )
        AM and PM scores combined: Weeks 0 to 20
    34.82 ( 0.179 )
    67.32 ( 20.179 )
    48.07 ( 18.010 )
        AM and PM scores combined: Weeks 0 to 24
    31.70 ( 1.637 )
    68.88 ( 19.772 )
    47.65 ( 17.997 )
        AM score: Weeks 0 to 4
    55.36 ( 8.929 )
    41.07 ( 23.214 )
    37.86 ( 16.115 )
        AM score: Weeks 0 to 8
    39.29 ( 14.286 )
    50.00 ( 21.429 )
    38.93 ( 16.243 )
        AM score: Weeks 0 to 12
    33.93 ( 10.119 )
    61.31 ( 11.310 )
    41.43 ( 16.562 )
        AM score: Weeks 0 to 16
    31.70 ( 1.339 )
    65.18 ( 12.500 )
    42.68 ( 16.554 )
        AM score: Weeks 0 to 18
    31.35 ( 1.190 )
    66.67 ( 13.492 )
    42.22 ( 16.343 )
        AM score: Weeks 0 to 20
    28.93 ( 0.357 )
    66.07 ( 15.357 )
    43.71 ( 16.860 )
        AM score: Weeks 0 to 24
    26.19 ( 1.190 )
    66.72 ( 16.718 )
    43.24 ( 16.835 )
        PM score: Weeks 0 to 4
    73.21 ( 8.929 )
    46.43 ( 28.571 )
    40.00 ( 15.042 )
        PM score: Weeks 0 to 8
    54.46 ( 11.607 )
    55.36 ( 30.357 )
    45.00 ( 16.545 )
        PM score: Weeks 0 to 12
    50.00 ( 10.714 )
    65.48 ( 25.000 )
    48.57 ( 17.715 )
        PM score: Weeks 0 to 16
    45.54 ( 5.357 )
    68.30 ( 23.661 )
    51.25 ( 18.751 )
        PM score: Weeks 0 to 18
    43.65 ( 1.587 )
    68.65 ( 24.206 )
    52.06 ( 19.230 )
        PM score: Weeks 0 to 20
    40.71 ( 0.000 )
    68.57 ( 25.000 )
    52.43 ( 19.568 )
        PM score: Weeks 0 to 24
    37.20 ( 2.083 )
    71.04 ( 22.825 )
    52.06 ( 19.595 )
    No statistical analyses for this end point

    Secondary: Proportion 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

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    End point title
    		 Proportion 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
    End point description
    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 proportion 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. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively. The FAS included all randomized participants who received at least 1 dose of study treatment. Here, n= number of participants with data collected at specific timepoints.
    End point type
    Secondary
    End point timeframe
    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
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    20
    23
    19
    Units: proportion of pruritus-participant level
    arithmetic mean (standard error)
        AM and PM scores combined:Weeks 1 to 4(n=20,23,19)
    33.48 ( 5.881 )
    51.40 ( 5.818 )
    42.48 ( 7.508 )
        AM and PM scores combined:Weeks 5 to 8(n=20,23,19)
    31.96 ( 6.515 )
    57.07 ( 6.714 )
    53.95 ( 8.423 )
        AM and PM scores combined:Weeks 9 to12(n=20,23,18)
    31.61 ( 6.794 )
    68.09 ( 6.357 )
    53.67 ( 9.404 )
        AM and PM scores combined:Weeks 13to16(n=17,20,16)
    28.36 ( 7.534 )
    67.59 ( 7.779 )
    54.35 ( 9.802 )
        AM and PM scores combined:Weeks 17to20(n=15,20,16)
    32.62 ( 8.583 )
    66.79 ( 7.805 )
    56.14 ( 10.655 )
        AM and PM scores combined:Weeks 21to24(n=14,19,16)
    35.42 ( 8.783 )
    68.57 ( 6.926 )
    55.12 ( 10.047 )
        AM score: Weeks 1 to 4 (n=20,23,19)
    31.07 ( 5.436 )
    48.14 ( 6.161 )
    47.37 ( 8.439 )
        AM score: Weeks 5 to 8 (n=20,23,19)
    31.07 ( 5.812 )
    54.19 ( 6.783 )
    56.20 ( 8.483 )
        AM score: Weeks 9 to 12 (n=20,23,18)
    31.07 ( 6.747 )
    65.84 ( 6.854 )
    55.95 ( 9.383 )
        AM score: Weeks 13 to 16 (n=17,20,16)
    29.62 ( 8.502 )
    66.07 ( 8.042 )
    53.57 ( 9.550 )
        AM score: Weeks 17 to 20 (n=15,20,16)
    30.24 ( 8.733 )
    64.11 ( 8.121 )
    55.58 ( 11.171 )
        AM score: Weeks 21 to 24 (n=14,19,16)
    37.30 ( 10.909 )
    64.37 ( 7.324 )
    54.35 ( 10.801 )
        PM score: Weeks 1 to 4 (n=20,23,19)
    35.89 ( 7.055 )
    54.66 ( 6.594 )
    37.59 ( 7.629 )
        PM score: Weeks 5 to 8 (n=20,23,19)
    32.86 ( 8.138 )
    59.94 ( 7.355 )
    51.69 ( 9.051 )
        PM score: Weeks 9 to 12 (n=20,23,18)
    32.14 ( 8.078 )
    70.34 ( 6.816 )
    51.39 ( 10.015 )
        PM score: Weeks 13 to 16 (n=17,20,16)
    27.10 ( 8.997 )
    69.11 ( 7.783 )
    55.13 ( 10.664 )
        PM score: Weeks 17 to 20 (n=15,20,16)
    35.00 ( 10.323 )
    69.46 ( 7.848 )
    56.70 ( 10.554 )
        PM score: Weeks 21 to 24 (n=14,19,16)
    33.54 ( 9.699 )
    72.76 ( 7.185 )
    55.90 ( 9.976 )
    No statistical analyses for this end point

    Secondary: Number of Participants Underwent Biliary Diversion Surgery and Liver Transplantation

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    End point title
    		 Number of Participants Underwent Biliary Diversion Surgery and Liver Transplantation
    End point description
    The number of participants underwent biliary diversion surgery and liver transplantation was determined. The FAS included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    20
    23
    19
    Units: participants
        Biliary diversion surgery
    0
    0
    0
        Liver transplantation
    0
    0
    0
    No statistical analyses for this end point

    Secondary: 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

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    End point title
    		 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
    End point description
    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 proportion 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. The FAS included all randomized participants who received at least 1 dose of study treatment. Here, n= number of participants with data collected for each specific instrument.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 24
    End point values
    		 Placebo A4250 Low Dose A4250 High Dose
    Number of subjects analysed
    20 [6]
    23 [7]
    19 [8]
    Units: participants
        Albireo ObsRO Instrument:AM and PM scores combined
    4
    17
    9
        Albireo ObsRO Instrument: AM score
    3
    13
    10
        Albireo ObsRO Instrument: PM score
    5
    16
    9
        Albireo PRO Instrument: AM and PM scores combined
    0
    1
    3
        Albireo PRO Instrument: AM score
    0
    1
    3
        Albireo PRO Instrument: PM score
    0
    1
    3
    Notes
    [6] - n=20,20,20,2,2,2.
    [7] - n=23,23,23,2,2,2.
    [8] - n=19,19,19,5,5,5.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All serious and non-serious AEs were collected once the caregiver/participant had signed the informed consent form (ICF) and until the post-treatment follow-up (Visit 10) or 28 days after the last dose of study treatment, approximately 28 weeks
    Adverse event reporting additional description
    Treatment emergent adverse events (TEAEs) were defined as any AE that occurred after first dose or AE occurred before first dose but worsened in severity on or after first dose. Treatment emergent serious adverse events and treatment emergent non-serious AEs are reported here.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Capsules for oral administration (to match active) once daily for 24 weeks. Placebo: Placebo identical in appearance to active drug (A4250).

    Reporting group title
    A4250 Low Dose
    Reporting group description
    		 Capsules for oral administration (40 mcg/kg) once daily for 24 weeks. A4250 (odevixibat): A4250 is a small molecule and selective inhibitor of IBAT.

    Reporting group title
    A4250 High Dose
    Reporting group description
    		 Capsules for oral administration (120 mcg/kg) once daily for 24 weeks. A4250 (odevixibat): A4250 is a small molecule and selective inhibitor of IBAT.

    Serious adverse events
    		 Placebo A4250 Low Dose A4250 High Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 20 (25.00%)
    0 / 23 (0.00%)
    3 / 19 (15.79%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Liver function test increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Auricular haematoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Neurodermatitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis adenovirus
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight gain poor
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo A4250 Low Dose A4250 High Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 20 (85.00%)
    19 / 23 (82.61%)
    16 / 19 (84.21%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Surgical and medical procedures
    Cardiac ablation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site swelling
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    5 / 20 (25.00%)
    7 / 23 (30.43%)
    5 / 19 (26.32%)
         occurrences all number
    7
    10
    13
    Reproductive system and breast disorders
    Genital rash
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    2
    Epistaxis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Nasal obstruction
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    4
    Selective eating disorder
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 23 (13.04%)
    3 / 19 (15.79%)
         occurrences all number
    1
    3
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 23 (8.70%)
    1 / 19 (5.26%)
         occurrences all number
    1
    2
    1
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    3
    Blood bilirubin increased
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 23 (13.04%)
    2 / 19 (10.53%)
         occurrences all number
    2
    4
    3
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    1
    Blood creatinine decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    0
    Liver palpable
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet count increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    1
    Product residue present
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Vitamin E increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count increased
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Injury, poisoning and procedural complications
    Auricular haematoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Scar
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Scratch
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Tibia fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Splenomegaly
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Otorrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Eye discharge
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Constipation
         subjects affected / exposed
    4 / 20 (20.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    4
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
    9 / 23 (39.13%)
    4 / 19 (21.05%)
         occurrences all number
    1
    11
    10
    Frequent bowel movements
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Toothache
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 23 (17.39%)
    3 / 19 (15.79%)
         occurrences all number
    0
    5
    4
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hepatomegaly
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Jaundice
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Nail discolouration
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Neurodermatitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    1
    Rash
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    4
    0
    0
    Rash vesicular
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Neck mass
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    0
    H1N1 influenza
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Klebsiella infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    2
    Otitis media
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Parotitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Post procedural infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    0 / 19 (0.00%)
         occurrences all number
    0
    3
    0
    Sinusitis bacterial
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin candida
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    0
    Viral diarrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    5
    Viral rash
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
    3 / 23 (13.04%)
    5 / 19 (26.32%)
         occurrences all number
    5
    4
    7
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Vitamin A deficiency
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Vitamin E deficiency
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2017
    Number of participants: 15. • Original protocol under which participants were first enrolled.
    10 May 2018
    Number of participants: 16. •Clarified that enrolment of participants with PFIC1 was targeted to 15%. •Exclusion criterion 9 was revised to clarify that participants listed for liver transplant was not excluded if primary reason for listing was symptomatic pruritus and not disease progression. •Guidelines for contraceptive requirements were updated that required participants to use reliable contraceptive methods throughout duration of study and 90 days thereafter. •Additional examples of prohibited medications, including erythromycin and 4-phenylbutyrate were added. •Requirement for genetic testing at screening was removed for participants with prior genotyping results confirming PFIC1 or 2. •Procedure for breaking randomization code was clarified. •Calculation to determine participant eligibility relating to ObsRO data collection was revised. •Primary efficacy endpoint for US (and secondary endpoint for EU and RoW) was revised to include more data collected in analysis. Statistical analyses were modified to align with that change. •All secondary and exploratory endpoints referring to patient-related outcome/ObsRO instrument using a reference time point of Week 24 were revised to include a specified duration over treatment period, for example over first of last 3 or 5 months of treatment period. •Assessment of change in gamma-glutamyl transferase was added to exploratory endpoint. •Clarification was made to include all laboratory tests related to safety including vitamins, and alpha-fetoprotein. •Additional assessments for physical examination, vitamins, urine pregnancy test and blood sampling for Pharmacokinetic analysis were added. •Approach to calculate baseline weekly itching and scratching scores was revised. •Requirement of cholestatic marker elevations without alternative explanation was removed; alkaline phosphatase was removed from list of repeat liver profile assessments; The criterion of international normalized ratio increase was revised.
    22 Nov 2018
    Number of participants: 6. • Exclusion criterion 17 was revised to remove barrier protection as an acceptable contraceptive method. • Exclusion criterion 9 was revised to specify that participants will be excluded if their liver transplant is planned within 6 months of randomization. • Statistical methodology to analyze the primary efficacy endpoint for United States (and secondary endpoint of EU and ROW) of change in pruritus between active and placebo arms was revised. • Secondary endpoints of change from baseline to Week 24 in s-BA, alanine transaminase (ALT), and growth were updated to include additional assessments at Week 12. As a result, change from baseline in ALT and s-BA at Week 12 were removed from the list of exploratory endpoints. • The secondary endpoint of percentage of participants achieving meaningful reduction in caregiver-reported observed scratching was revised to include assessment of patient-reported outcomes and to indicate how “meaningful reduction” was defined. An additional assessment timepoint of Week 12 was also added. • The secondary endpoint of change from baseline in sleep parameters was updated so multiple timepoints were evaluated in the study period rather than a single timepoint at end of therapy. • The following additional secondary endpoints were added for all regions: - Proportion of individual assessments and of individual AM and PM assessments meeting the definition of a positive pruritus assessment at the participant level from Weeks 0-4, Weeks 0-8, Weeks 0-12, Weeks 0-18, Weeks 0-24, respectively, or the proportion of positive pruritus assessments at each 4-week interval. • The exploratory efficacy endpoint of change in patient-reported and observer-reported night-time itching and scratching severity scores was revised so both morning and evening scores were analyzed rather than a single daily score.
    01 Mar 2019
    Number of participants: 8. • Exclusion criterion 8 was updated so participants post biliary diversion surgery were eligible for the study. • Clarification was made to the secondary endpoint to assess liver transplantation events. • Revised baseline covariate in the ANCOVA model of US primary efficacy analysis to include both AM baseline and PM baseline pruritus scores, instead of the averaged value.
    29 Apr 2019
    Number of participants: 9. • The timing for rescreening was removed; participants could be rescreened at any time after failing eligibility criteria after consultation with the Medical Monitor. • Exclusion criterion 14 was revised to exclude participants with total bilirubin >10×upper limit of normal.
    24 Jun 2019
    Number of participants: 8. • The provision to allow participants experiencing intolerable symptoms of underlying disease to roll over to active treatment after completion of 12 weeks of the treatment period was removed.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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