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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Study To Evaluate The Safety And Efficacy Of Lum001, An Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), In The Treatment Of Cholestatic Liver Disease In Paediatric Patients With Alagille Syndrome

    Summary
    EudraCT number
    		 2012-005346-38
    Trial protocol
    		 GB  
    Global end of trial date
    23 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Mar 2016
    First version publication date
    30 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LUM001-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01903460
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 SHP625-302: Shire Development LLC, IMAGO: Shire Trial Acronym
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard, Wayne, United States, 19087
    Public contact
    Study Physician, Shire Development LLC, +1 8668425335,
    Scientific contact
    Study Physician, Shire Development LLC, +1 8668425335,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of LUM001 in paediatric subjects with Alagille Syndrome (ALGS), to evaluate the effect of LUM001 versus placebo on serum bile acids associated with ALGS, to evaluate the effect of LUM001 versus placebo on liver enzymes associated with ALGS, to evaluate the effect of LUM001 versus placebo on pruritus associated with ALGS, and to explore the effect of LUM001 versus placebo on other biochemical markers associated with ALGS.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and its revisions as well as with the valid national law(s) of the participating country/ies, with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP) (E6) issued in July 1996, and with the Commission Directives 1991/507/EEC, 2001/20/EC, 2005/28/EC and 2001/83/EC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    3
    Children (2-11 years)
    13
    Adolescents (12-17 years)
    4
    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
    		 Subjects were recruited to participate at three sites in the United Kingdom.

    Pre-assignment
    Screening details
    		 Subjects were screened over a period of 28 days.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Matching placebo contains the diluent with no active ingredient.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LUM001 140ug/kg/day
    Arm description
    		 Subjects received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 140ug/kg/day, then received 8 to 10 weeks of treatment at either 140ug/kg/day or the highest tolerated dose below 140ug/kg/day. Subjects were then followed for 4 weeks after treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LUM001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Dose (14 to 140ug/kg/day) was administered orally as a 1.0mL solution (for subjects who weighed 10kg or more), or as a 0.5mL solution (for subjects who weighed less than 10kg) containing study drug (LUM001) using the syringe provided. Study drug was to be taken at least 30 minutes prior to the first meal of the day (every morning, before food) and should have been administered approximately at the same time each day for the duration of the treatment period.

    Arm title
    		 LUM001 280ug/kg/day
    Arm description
    		 Subjects received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 280ug/kg/day, then received 8 to 10 weeks of treatment at either 280ug/kg/day or the highest tolerated dose below 280ug/kg/day. Subjects were then followed for 4 weeks after treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LUM001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Dose (14 to 280ug/kg/day) was administered orally as a 1.0mL solution (for subjects who weighed 10kg or more), as a 0.5mL solution (for subjects who weighed less than 10kg) containing study drug (LUM001) using the syringe provided. Study drug was to be taken at least 30 minutes prior to the first meal of the day (every morning, before food) and should have been administered approximately at the same time each day for the duration of the treatment period.

    Arm title
    		 Placebo Cohort A
    Arm description
    		 Subjects received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Matching diluent placebo was administered orally using the syringe provided. Placebo was to be taken at least 30 minutes prior to the first meal of the day (every morning, before food) and should have been administered approximately at the same time each day for the duration of the treatment period.

    Arm title
    		 Placebo Cohort B
    Arm description
    		 Subjects received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Matching diluent placebo was administered orally using the syringe provided. Placebo was to be taken at least 30 minutes prior to the first meal of the day (every morning, before food) and should have been administered approximately at the same time each day for the duration of the treatment period.

    Number of subjects in period 1
    		LUM001 140ug/kg/day LUM001 280ug/kg/day Placebo Cohort A Placebo Cohort B
    Started
    6
    8
    3
    3
    Completed
    6
    8
    3
    2
    Not completed
    0
    0
    0
    1
         Adverse event
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LUM001 140ug/kg/day
    Reporting group description
    		 Subjects received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 140ug/kg/day, then received 8 to 10 weeks of treatment at either 140ug/kg/day or the highest tolerated dose below 140ug/kg/day. Subjects were then followed for 4 weeks after treatment.

    Reporting group title
    LUM001 280ug/kg/day
    Reporting group description
    		 Subjects received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 280ug/kg/day, then received 8 to 10 weeks of treatment at either 280ug/kg/day or the highest tolerated dose below 280ug/kg/day. Subjects were then followed for 4 weeks after treatment.

    Reporting group title
    Placebo Cohort A
    Reporting group description
    		 Subjects received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment.

    Reporting group title
    Placebo Cohort B
    Reporting group description
    		 Subjects received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment.

    Reporting group values
    		 LUM001 140ug/kg/day LUM001 280ug/kg/day Placebo Cohort A Placebo Cohort B Total
    Number of subjects
    		 6 8 3 3 20
    Age categorical
    Units: Subjects
        <2 years
    		 0 3 0 0 3
        2 to 4 years
    		 3 1 1 2 7
        5 to 8 years
    		 1 1 2 1 5
        9 to 12 years
    		 2 0 0 0 2
        13 to 18 years
    		 0 3 0 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.8 ( 4.49 ) 6.8 ( 6.73 ) 5 ( 2 ) 4.3 ( 3.21 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 3 3 2 10
        Male
    		 4 5 0 1 10
    Region of enrollment
    Units: Subjects
        United Kingdom
    		 6 8 3 3 20

    End points

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    End points reporting groups
    Reporting group title
    LUM001 140ug/kg/day
    Reporting group description
    		 Subjects received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 140ug/kg/day, then received 8 to 10 weeks of treatment at either 140ug/kg/day or the highest tolerated dose below 140ug/kg/day. Subjects were then followed for 4 weeks after treatment.

    Reporting group title
    LUM001 280ug/kg/day
    Reporting group description
    		 Subjects received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 280ug/kg/day, then received 8 to 10 weeks of treatment at either 280ug/kg/day or the highest tolerated dose below 280ug/kg/day. Subjects were then followed for 4 weeks after treatment.

    Reporting group title
    Placebo Cohort A
    Reporting group description
    		 Subjects received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment.

    Reporting group title
    Placebo Cohort B
    Reporting group description
    		 Subjects received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment.

    Subject analysis set title
    LUM001 Overall
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects received either dose of LUM001 for up to 10 or 13 weeks, then were followed for 4 weeks after treatment.

    Subject analysis set title
    Placebo Overall
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment.

    Primary: Change From Baseline to Week 13 (End of Treatment) in Fasting Serum Bile Acid Level

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    End point title
    		 Change From Baseline to Week 13 (End of Treatment) in Fasting Serum Bile Acid Level [1]
    End point description
    Subjects were required to fast for at least 4 hours; only water was permitted prior to collection. A negative change from baseline indicates that the level of bile acid decreased. This endpoint is analyzed for the modified Intent-to-Treat (mITT) population, defined as all subjects in the Safety population who had at least 1 post-baseline efficacy assessment. The Safety population was defined as all subjects randomly assigned to study treatment who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to 13 weeks or end of treatment
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Active treatment groups (combined and individual) were tested against the combined placebo group, so data for the individual placebo cohorts are not reported.
    End point values
    		 LUM001 140ug/kg/day LUM001 280ug/kg/day LUM001 Overall Placebo Overall
    Number of subjects analysed
    6
    8
    14
    6
    Units: umol/L
        least squares mean (standard error)
    -82.864 ( 50.1513 )
    -49.388 ( 43.4732 )
    -66.126 ( 33.1208 )
    -42.157 ( 50.0903 )
    Statistical analysis title
    		 Analysis of LUM001 140ug/kg/day
    Comparison groups
    LUM001 140ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.574
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    -40.707
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -191.679
         upper limit
    		 110.265
    Statistical analysis title
    		 Analysis of LUM001 280ug/kg/day
    Comparison groups
    LUM001 280ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9147
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    -7.231
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -148.726
         upper limit
    		 134.264
    Statistical analysis title
    		 Analysis of all doses of LUM001
    Comparison groups
    Placebo Overall v LUM001 Overall
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6954
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    -23.969
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -151.969
         upper limit
    		 104.031

    Secondary: Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes

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    End point title
    		 Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes [2]
    End point description
    Analysis of liver enzymes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). A negative change from baseline indicates that the level of that enzyme decreased. This endpoint is analyzed for the mITT population, defined as all subjects in the Safety population who had at least 1 post-baseline efficacy assessment. The Safety population was defined as all subjects randomly assigned to study treatment who received any amount of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to 13 weeks or end of treatment
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Active treatment groups (combined and individual) were tested against the combined placebo group, so data for the individual placebo cohorts are not reported.
    End point values
    		 LUM001 140ug/kg/day LUM001 280ug/kg/day LUM001 Overall Placebo Overall
    Number of subjects analysed
    6
    8
    14
    6
    Units: U/L
    least squares mean (standard error)
        ALT
    59.3 ( 20.99 )
    10.5 ( 18.06 )
    34.9 ( 13.86 )
    2.7 ( 21.06 )
        AST
    37.2 ( 13.64 )
    -2.7 ( 11.7 )
    17.3 ( 8.98 )
    13.2 ( 13.63 )
        ALP
    71.4 ( 53.35 )
    31.6 ( 43.59 )
    51.5 ( 36.13 )
    19.7 ( 60.76 )
    Statistical analysis title
    		 Analysis of LUM001 140ug/kg/day for ALT
    Comparison groups
    LUM001 140ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0783
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    56.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 120.6
    Statistical analysis title
    		 Analysis of LUM001 280ug/kg/day for ALT
    Comparison groups
    LUM001 280ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7827
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    7.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.4
         upper limit
    		 67
    Statistical analysis title
    		 Analysis of all doses of LUM001 for ALT
    Comparison groups
    Placebo Overall v LUM001 Overall
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2235
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    32.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.9
         upper limit
    		 86.3
    Statistical analysis title
    		 Analysis of LUM001 140ug/kg/day for AST
    Comparison groups
    LUM001 140ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2372
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.5
         upper limit
    		 65.5
    Statistical analysis title
    		 Analysis of LUM001 280ug/kg/day for AST
    Comparison groups
    LUM001 280ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3914
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    -15.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.1
         upper limit
    		 22.4
    Statistical analysis title
    		 Analysis of all doses of LUM001 for AST
    Comparison groups
    Placebo Overall v LUM001 Overall
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8081
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31
         upper limit
    		 39.1
    Statistical analysis title
    		 Analysis of LUM001 140ug/kg/day for ALP
    Comparison groups
    LUM001 140ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5748
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    51.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -140.3
         upper limit
    		 243.7
    Statistical analysis title
    		 Analysis of LUM001 280ug/kg/day for ALP
    Comparison groups
    LUM001 280ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8835
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    11.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -158.4
         upper limit
    		 182.2
    Statistical analysis title
    		 Analysis of all doses of LUM001 for ALP
    Comparison groups
    Placebo Overall v LUM001 Overall
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6917
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    31.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -135.8
         upper limit
    		 199.4

    Secondary: Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores

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    End point title
    		 Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores [3]
    End point description
    The ItchRO was administered as a twice daily electronic diary (eDiary). Children ≥9 years of age completed the patient ItchRO; those between 5 and 8 years completed the patient ItchRO with a caregiver's assistance. There was no patient report for subjects under the age of 5. ItchRO scores range from 0 to 4, with higher scores indicating increasing itch severity. ItchRO average daily scores were calculated as the sum of daily scores (ie, the maximum of morning and evening scores) divided by the number of days. The average daily score was calculated by using the 7 days pre-treatment for baseline, and the last 7 days of treatment for Week 13. A negative change from Baseline indicates that itch severity decreased. This endpoint is analyzed for the mITT population, defined as all subjects in the Safety population who had at least 1 post-baseline efficacy assessment. The Safety population was defined as all subjects randomly assigned to study treatment who received any amount of study drug
    End point type
    Secondary
    End point timeframe
    Baseline to 13 weeks or end of treatment
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Active treatment groups (combined and individual) were tested against the combined placebo group, so data for the individual placebo cohorts are not reported.
    End point values
    		 LUM001 140ug/kg/day LUM001 280ug/kg/day LUM001 Overall Placebo Overall
    Number of subjects analysed
    6
    8
    14
    6
    Units: scores on a scale
    least squares mean (standard error)
        Patient ItchRO
    -1.159 ( 0.5396 )
    -0.608 ( 0.4399 )
    -0.883 ( 0.3484 )
    -0.811 ( 0.5684 )
        Observer ItchRO
    -0.802 ( 0.2732 )
    -0.419 ( 0.2318 )
    -0.61 ( 0.1776 )
    -0.592 ( 0.269 )
    Statistical analysis title
    		 Analysis of LUM001 140ug/kg/day Patient ItchRO
    Comparison groups
    LUM001 140ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6907
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    -0.348
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.468
         upper limit
    		 1.772
    Statistical analysis title
    		 Analysis of LUM001 280ug/kg/day Patient ItchRO
    Comparison groups
    LUM001 280ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7897
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    0.202
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.647
         upper limit
    		 2.052
    Statistical analysis title
    		 Analysis of all doses LUM001 Patient ItchRO
    Comparison groups
    Placebo Overall v LUM001 Overall
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9203
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    -0.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.85
         upper limit
    		 1.705
    Statistical analysis title
    		 Analysis of LUM001 140ug/kg/day Observer ItchRO
    Comparison groups
    LUM001 140ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5966
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.038
         upper limit
    		 0.618
    Statistical analysis title
    		 Analysis of LUM001 280ug/kg/day Observer ItchRO
    Comparison groups
    LUM001 280ug/kg/day v Placebo Overall
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.632
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    0.173
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 0.926
    Statistical analysis title
    		 Analysis of all doses of LUM001 Observer ItchRO
    Comparison groups
    Placebo Overall v LUM001 Overall
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9547
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference from placebo
    Point estimate
    -0.019
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 0.673

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 19 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    LUM001 140ug/kg/day
    Reporting group description
    		 Subjects received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 140ug/kg/day, then received 8 to 10 weeks of treatment at either 140ug/kg/day or the highest tolerated dose below 140ug/kg/day. Subjects were then followed for 4 weeks after treatment.

    Reporting group title
    LUM001 280ug/kg/day
    Reporting group description
    		 Subjects received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 280ug/kg/day, then received 8 to 10 weeks of treatment at either 280ug/kg/day or the highest tolerated dose below 280ug/kg/day. Subjects were then followed for 4 weeks after treatment.

    Reporting group title
    Placebo Overall
    Reporting group description
    		 Subjects received LUM001- matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment.

    Serious adverse events
    		 LUM001 140ug/kg/day LUM001 280ug/kg/day Placebo Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LUM001 140ug/kg/day LUM001 280ug/kg/day Placebo Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    7 / 8 (87.50%)
    4 / 6 (66.67%)
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Feeling abnormal
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Anal injury
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Contusion
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Excoriation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Ear pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Middle ear inflammation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    0
    1
    Diarrhoea
         subjects affected / exposed
    4 / 6 (66.67%)
    5 / 8 (62.50%)
    2 / 6 (33.33%)
         occurrences all number
    5
    9
    3
    Frequent bowel movements
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    5 / 8 (62.50%)
    1 / 6 (16.67%)
         occurrences all number
    1
    8
    5
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Rash generalised
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 8 (12.50%)
    3 / 6 (50.00%)
         occurrences all number
    5
    2
    6
    Viral rash
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Vitamin E deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2013
    Substantive changes to the protocol: 1. Clarified Inclusion Criterion 8B to define effective barrier method of contraception as condom and diaphragm plus a spermicide. 2. Provided instructions in Section 6.4 for unblinding treatment assignment.
    03 Jul 2013
    Substantive changes to the protocol: 1. Clarified the following: ItchRO (observer [obs]) and ItchRO (patient [pt]) were analyzed separately; subjects 5 to 8 years of age completed the eDiary with caretaker assistance; no ItchRO (pt) was to be completed for subjects less than 5 years. 2. Removed the following exploratory endpoints: Change from baseline in pruritus as measured by the average daily ItchRO (Observer ItchRO/patient ItchRO) (patient ItchRO/Observer ItchRO) at Weeks 5, 9, and 13. 3. Change from baseline in pruritus as measured by the weekly sum and the average daily and the weekly sum ItchRO for the observer and patient and observer scores separately at Weeks 5, 9, and 13. 4. Updates made to missing data strategy for ItchRO on how compliance was measured. 5. Clarifications made to subject screening and randomization number assignment process. 6. Clarification made regarding the replacement of randomized subjects who were not dosed due to their no longer meeting eligibility criteria. 7. Modification to provide further details regarding eDiary completion and subject/caregiver expectations. 8. Modifications made to the Schedule of Events concerning the visit window for Study Week 7, total serum bile acid during screening if none serum bile acid test was available within the past 3 months, and clarification regarding dose escalation. 9. Patient Global Therapeutic Benefit (PGTB) removed.
    25 Sep 2013
    Substantive changes to the protocol: 1. Clarified subject eligibility for the open label study based on completion of the present study. 2. Corrected statement in section discussing previous clinical experience concerning the occurrence of a related SAE.
    25 Feb 2014
    Substantive changes to the protocol: 1. Lowered eligibility age from 2 years of age to 12 months of age 2. Subjects who weigh 10 kg or more at screening received a 10 mL solution of LUM001 or placebo; subjects who weigh less than 10 kg at screening received a 0.5 mL solution of LUM001 or placebo. 3. Tabular summaries of the composition of the LUM001 0.5 mL solution and the 0.5 mL placebo solution have been included; a correction was made to the maximum LUM001 dose. 4. Clarified that dosing errors are documented in the eCRF and in paper-dosing diaries. 5. Added PedQL for infants 6. Visit window for Study Week 17 has a ± 5-day window rather than the 7 day window previously noted

    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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