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    Clinical Trial Results:
    Long-Term, Open-Label Study with a Double-Blind, Placebo-Controlled, Randomized Drug Withdrawal Period of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Patients with Alagille Syndrome

    Summary
    EudraCT number
    		 2013-005373-43
    Trial protocol
    		 ES   PL   BE   GB   FR  
    Global end of trial date
    28 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Dec 2020
    First version publication date
    20 Dec 2020
    Other versions
    Summary report(s)
    		 Final Clinical Study Report Overall Conclusions
    Interim Clinical Study Report Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    LUM001-304
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02160782
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mirum Pharmaceuticals, Inc
    Sponsor organisation address
    950 Tower Lane, Suite 1050, Foster City, United States, CA 94404
    Public contact
    Medical Information Mirum, Mirum Pharmaceuticals, Inc., +1 6506674085, medinfo@mirumpharma.com
    Scientific contact
    Medical Information Mirum, Mirum Pharmaceuticals, Inc., +1 6506674085, medinfo@mirumpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001475-PIP03-17
    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
    21 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study (up to and including Week 48) were: - To evaluate the long-term safety and tolerability of maralixibat (MRX) - To evaluate the effect of MRX on serum bile acid (sBA) levels - To evaluate the effect of MRX on biochemical markers of cholestasis and liver disease - To evaluate the effect of MRX on pruritus - To evaluate the long-term effect of MRX during 48 weeks of treatment in children with Alagille Syndrome (ALGS) The objectives of the optional long-term extension period (after Week 48) were: - To offer eligible participants continued study treatment after Week 48 - To explore a twice daily (BID) dosing regimen and higher daily dosing of MRX - To obtain safety and efficacy data in participants treated long-term with MRX, including genotyping characteristics - To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma - To assess palatability of the maralixibat formulation
    Protection of trial subjects
    All study participants (caregivers as applicable) were required to read and sign an Informed Consent Form (ICF). Participants were re-consented to the most current version of the ICF(s) during their participation in the study
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Australia: 9
    Worldwide total number of subjects
    31
    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)
    6
    Children (2-11 years)
    20
    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
    		 A total of 31 participants were enrolled at 9 sites in 6 countries (Australia, UK, France, Poland, Spain and Belgium). Participants included 12 females (38.7%) and 19 males (61.3%), with a mean (SD) age of 5.4 (4.25) years (range: 1 to 15 years).

    Pre-assignment
    Screening details
    		 A total of 36 patients were screened for the study. Five of these patients were screen failures.

    Period 1
    Period 1 title
    Open-label period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-label period: MRX
    Arm description
    		 All participants received MRX at doses of up to 400 μg/kg once daily (QD) during a 6-week open-label dose-escalation period, followed by a 12-week open-label stable-dosing period. All participants reached 400 μg/kg QD for this period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maralixibat chloride
    Investigational medicinal product code
    Other name
    LUM001
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    During a 6-week dose escalation period, all participants received MRX at doses of up to 400 μg/kg QD. This was followed by a 12-week stable-dosing period, using the dose administered at Week 6, which may have been 400 μg/kg QD or the highest tolerated dose below 400 μg/kg QD.

    Number of subjects in period 1
    		Open-label period: MRX
    Started
    31
    Completed
    29
    Not completed
    2
         Adverse event, non-fatal
    2
    Period 2
    Period 2 title
    Randomized withdrawal period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Participants were randomized 1:1 to continue to receive MRX or placebo for 4 weeks between the start of Week 19 and the end of Week 22 (the double-blind, placebo-controlled study drug withdrawal period). All participants, monitors, and study center personnel related to the study, except for the central pharmacist who prepared the study drug, were blinded to study treatment and to the participants' study drug withdrawal period treatment assignment during the randomized withdrawal (RWD) period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RWD period: MRX
    Arm description
    		 Participants continued to receive MRX at 400 μg/kg QD during the RWD period
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maralixibat chloride
    Investigational medicinal product code
    Other name
    LUM001
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants continued to receive MRX at the dose administered at Week 18.

    Arm title
    		 RWD period: placebo
    Arm description
    		 Participants received a corresponding placebo during the RWD period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a corresponding placebo.

    Number of subjects in period 2
    		RWD period: MRX RWD period: placebo
    Started
    13
    16
    Completed
    13
    16
    Period 3
    Period 3 title
    After randomized withdrawal period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 After RWD period: MRX
    Arm description
    		 Participants who received placebo during the RWD period returned to the MRX dose received during the initial escalation in a 26-week long-term exposure period to complete 48 weeks of treatment. Participants who received MRX during the RWD period continued in a 26-week long-term exposure period to complete 48 weeks of treatment. Participants remained blinded to their assigned arm during the RWD period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maralixibat chloride
    Investigational medicinal product code
    Other name
    LUM001
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who received placebo in the RWD period received MRX dosed according to the dose escalation schedule that mirrored the initial escalation, i.e., the MRX dose was increased weekly over a 6-week period to the maximum tolerated dose (MTD) up to 400 μg/kg QD, or the highest tolerated dose below the 400 μg/kg QD dose. Participants who received MRX during the RWD period continued to receive the same dose of MRX and, following Week 22, a simulated dose escalation occurred to maintain the blind in the RWD period. Dosing with MRX continued in a 26-week long-term exposure period to complete 48 weeks of treatment.

    Number of subjects in period 3
    		After RWD period: MRX
    Started
    29
    Completed
    23
    Not completed
    6
         Adverse event, non-fatal
    1
         Did not consent to protocol amendment for period 4
    5
    Period 4
    Period 4 title
    Long-term extension period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Long-term extension period: MRX
    Arm description
    		 The long-term extension (LTE) period consisted of 2 phases: (1) a 52-week optional follow-up treatment period (Weeks 49-100), during which participants received up to 400 μg/kg QD MRX. This was followed by: (2) a long-term optional follow-up treatment period (>Week 100) during which participants received up to 400 μg/kg BID doses of MRX.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maralixibat chloride
    Investigational medicinal product code
    Other name
    LUM001
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants continuing into the LTE period were maintained at the same dose level of MRX that they had been taking at Week 48 during the 52-week optional follow-up treatment period (Weeks 49-100). After Week 100, during the long-term optional follow-up treatment period, participants received the same dose level of MRX, or, if they were eligible, started BID dosing up to their MTD or a maximum daily dose of 400 μg/kg BID.

    Number of subjects in period 4
    		Long-term extension period: MRX
    Started
    23
    Completed
    14
    Not completed
    9
         Physician decision
    1
         Withdrawal by caregiver
    1
         Adverse event, non-fatal
    3
         Did not consent to protocol amendment
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label period: MRX
    Reporting group description
    		 All participants received MRX at doses of up to 400 μg/kg once daily (QD) during a 6-week open-label dose-escalation period, followed by a 12-week open-label stable-dosing period. All participants reached 400 μg/kg QD for this period.

    Reporting group values
    		 Open-label period: MRX Total
    Number of subjects
    		 31 31
    Age categorical
    The mean (SD) age in the overall study population was 5.4 (4.25) years (range: 1 to 15 years) at baseline. Mean age was similar between the MRX and placebo groups in the different periods of the study.
    Units: Subjects
        <2 years
    		 6 6
        2 to 4 years
    		 9 9
        5 to 8 years
    		 9 9
        9 to 12 years
    		 4 4
        13 to 18 years
    		 3 3
    Gender categorical
    In the overall study population (N = 31), there were more males (61.3%) than females (38.7%) at baseline.
    Units: Subjects
        Female
    		 12 12
        Male
    		 19 19
    Country
    The majority of the participants were from Australia and France (each 29.0% of the overall study population).
    Units: Subjects
        Australia
    		 9 9
        Belgium
    		 5 5
        France
    		 9 9
        Poland
    		 3 3
        Spain
    		 2 2
        United Kingdom
    		 3 3
    Height z-score
    Units: z-score
        arithmetic mean (standard deviation)
    		 -1.668 ± 1.3413 -
    Weight z-score
    Units: Z-score
        arithmetic mean (standard deviation)
    		 -1.700 ± 1.1840 -

    End points

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    End points reporting groups
    Reporting group title
    Open-label period: MRX
    Reporting group description
    		 All participants received MRX at doses of up to 400 μg/kg once daily (QD) during a 6-week open-label dose-escalation period, followed by a 12-week open-label stable-dosing period. All participants reached 400 μg/kg QD for this period.
    Reporting group title
    RWD period: MRX
    Reporting group description
    		 Participants continued to receive MRX at 400 μg/kg QD during the RWD period

    Reporting group title
    RWD period: placebo
    Reporting group description
    		 Participants received a corresponding placebo during the RWD period
    Reporting group title
    After RWD period: MRX
    Reporting group description
    		 Participants who received placebo during the RWD period returned to the MRX dose received during the initial escalation in a 26-week long-term exposure period to complete 48 weeks of treatment. Participants who received MRX during the RWD period continued in a 26-week long-term exposure period to complete 48 weeks of treatment. Participants remained blinded to their assigned arm during the RWD period.
    Reporting group title
    Long-term extension period: MRX
    Reporting group description
    		 The long-term extension (LTE) period consisted of 2 phases: (1) a 52-week optional follow-up treatment period (Weeks 49-100), during which participants received up to 400 μg/kg QD MRX. This was followed by: (2) a long-term optional follow-up treatment period (>Week 100) during which participants received up to 400 μg/kg BID doses of MRX.

    Subject analysis set title
    Open-label period: MRX baseline
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    These are the baseline values for participants in the open-label period

    Subject analysis set title
    Open-label period: MRX Week 18
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    These are the Week 18 values for participants in the open-label period. These participants are also represented in the Open-label Period: MRX baseline group; the analyses look at the change from baseline to Week 18 in the same participants.

    Primary: Change from Week 18 to Week 22 in fasting sBA levels in participants who had a reduction in sBA ≥50% from baseline to Week 12 or Week 18

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    End point title
    		 Change from Week 18 to Week 22 in fasting sBA levels in participants who had a reduction in sBA ≥50% from baseline to Week 12 or Week 18
    End point description
    The primary efficacy endpoint of this study was the mean change from Week 18 to Week 22 (the RWD period) of fasting sBA levels in participants who previously responded to MRX treatment, as defined by a reduction in sBA ≥50% from baseline to Week 12 or Week 18 (Modified Intent-to-Treat [MITT] Population). Five participants in the MRX group and 10 participants in the placebo group met the prespecified sBA reduction criteria. The difference of 5 versus 10 participants in the MRX and placebo groups, respectively, was a result of the randomization schedule which used a central by-block randomization process (within IRT), with entire blocks assigned by study site. The randomization allocation method resulted in more participants in the placebo group from those participants with a ≥50% reduction in sBA at Week 12.
    End point type
    Primary
    End point timeframe
    Week 18 to Week 22
    End point values
    		 RWD period: MRX RWD period: placebo
    Number of subjects analysed
    5
    10
    Units: μmol/L
        least squares mean (standard error)
    -21.73 ± 43.125
    95.55 ± 30.488
    Statistical analysis title
    		 Change from Week 18 to Week 22 in sBA levels
    Statistical analysis description
    The difference between treatment groups in change from Week 18 to Week 22 in fasting sBA levels was evaluated using an analysis of covariance (ANCOVA) model with treatment group as a factor, and Week 18 sBA as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the MITT population, which included all participants who were enrolled, received study drug through Week 18, and had a reduction from baseline in sBA of ≥50% at the Week 12 or Week 18 measurement.
    Comparison groups
    RWD period: placebo v RWD period: MRX
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.0464 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -117.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -232.38
         upper limit
    		 -2.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    52.828
    Notes
    [1] - The P-value for testing if the treatment group least squares (LS) means were equal was calculated to determine if the change in sBA levels between the treatment groups was statistically significant.
    [2] - P-value for change from Week 18 to Week 22 in the MRX group = 0.6234; P-value for change from Week 18 to Week 22 in the placebo group = 0.0086.

    Secondary: Change from Week 18 to Week 22 in alkaline phosphatase

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    End point title
    		 Change from Week 18 to Week 22 in alkaline phosphatase
    End point description
    This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in ALP
    End point type
    Secondary
    End point timeframe
    Week 18 to Week 22
    End point values
    		 RWD period: MRX RWD period: placebo
    Number of subjects analysed
    13
    16
    Units: U/L
        least squares mean (standard error)
    2.8 ± 22.55
    -7.2 ± 20.31
    Statistical analysis title
    		 Change from Week 18 to Week 22 in ALP
    Statistical analysis description
    The difference between treatment groups in change from Week 18 to Week 22 in ALP levels was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ALP as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.
    Comparison groups
    RWD period: MRX v RWD period: placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.7455 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.6
         upper limit
    		 72.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    30.44
    Notes
    [3] - The P-value for testing if the treatment group LS means were equal was calculated to determine if the change in ALP levels between the treatment groups was statistically significant.
    [4] - P-value for change from Week 18 to Week 22 in the MRX group = 0.9026; P-value for change from Week 18 to Week 22 in the placebo group = 0.7258.

    Secondary: Change from Week 18 to Week 22 in alanine aminotransferase

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    End point title
    		 Change from Week 18 to Week 22 in alanine aminotransferase
    End point description
    This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in alanine aminotransferase (ALT)
    End point type
    Secondary
    End point timeframe
    Week 18 to Week 22
    End point values
    		 RWD period: MRX RWD period: placebo
    Number of subjects analysed
    13
    16
    Units: U/L
        least squares mean (standard error)
    34.5 ± 14.04
    19.4 ± 12.56
    Statistical analysis title
    		 Change from Week 18 to Week 22 in ALT
    Statistical analysis description
    The difference between treatment groups in change from Week 18 to Week 22 in ALT levels was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ALT as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.
    Comparison groups
    RWD period: MRX v RWD period: placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 = 0.4472 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    15.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.1
         upper limit
    		 55.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.53
    Notes
    [5] - The P-value for testing if the treatment group LS means were equal was calculated to determine if the change in ALT levels between the treatment groups was statistically significant.
    [6] - P-value for change from Week 18 to Week 22 in the MRX group = 0.0211; P-value for change from Week 18 to Week 22 in the placebo group = 0.1343.

    Secondary: Change from Week 18 to Week 22 in total bilirubin

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    End point title
    		 Change from Week 18 to Week 22 in total bilirubin
    End point description
    This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in total bilirubin
    End point type
    Secondary
    End point timeframe
    Week 18 to Week 22
    End point values
    		 RWD period: MRX RWD period: placebo
    Number of subjects analysed
    13
    16
    Units: mg/dL
        least squares mean (standard error)
    0.32 ± 0.265
    0.46 ± 0.238
    Statistical analysis title
    		 Change from Week 18 to Week 22 in total bilirubin
    Statistical analysis description
    The difference between treatment groups in change from Week 18 to Week 22 in total bilirubin was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 total bilirubin as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.
    Comparison groups
    RWD period: MRX v RWD period: placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    P-value
    		 = 0.7 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.361
    Notes
    [7] - The P-value for testing if the treatment group LS means were equal was calculated to determine if the change in total bilirubin between the treatment groups was statistically significant.
    [8] - P-value for change from Week 18 to Week 22 in the MRX group = 0.2447; P-value for change from Week 18 to Week 22 in the placebo group = 0.0665.

    Secondary: Change from Week 18 to Week 22 in direct bilirubin

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    End point title
    		 Change from Week 18 to Week 22 in direct bilirubin
    End point description
    This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in direct bilirubin
    End point type
    Secondary
    End point timeframe
    Week 18 to Week 22
    End point values
    		 RWD period: MRX RWD period: placebo
    Number of subjects analysed
    12
    15
    Units: mg/dL
        least squares mean (standard error)
    0.13 ± 0.195
    0.14 ± 0.174
    Statistical analysis title
    		 Change from Week 18 to Week 22 in direct bilirubin
    Statistical analysis description
    The difference between treatment groups in change from Week 18 to Week 22 in ALP levels was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 direct bilirubin as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.
    Comparison groups
    RWD period: MRX v RWD period: placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    P-value
    		 = 0.9517 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 0.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.265
    Notes
    [9] - The P-value for testing if the treatment group LS means were equal was calculated to determine if the change in direct bilirubin between the treatment groups was statistically significant.
    [10] - P-value for change from Week 18 to Week 22 in the MRX group = 0.5183; P-value for change from Week 18 to Week 22 in the placebo group = 0.4159.

    Secondary: Change from Week 18 to Week 22 in pruritus as measured by ItchRO

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    End point title
    		 Change from Week 18 to Week 22 in pruritus as measured by ItchRO
    End point description
    This secondary efficacy endpoint is the change from Week 18 to Week 22 in pruritus as measured by ItchRO(Obs) weekly average morning score and ItchRO(Pt) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe).
    End point type
    Secondary
    End point timeframe
    Week 18 to Week 22
    End point values
    		 RWD period: MRX RWD period: placebo
    Number of subjects analysed
    12 [11]
    16 [12]
    Units: Points (0-4)
    least squares mean (standard error)
        ItchRO(Obs) weekly average morning score
    0.217 ± 0.2345
    1.700 ± 0.2031
        ItchRO(Pt) weekly average morning score
    -0.149 ± 0.3719
    1.839 ± 0.2771
    Notes
    [11] - n=12 for ItchRO(Obs) weekly average morning score; n=5 for ItchRO(Pt) weekly average morning score.
    [12] - n=16 for ItchRO(Obs) weekly average morning score; n=9 for ItchRO(Pt) weekly average morning score.
    Statistical analysis title
    		 Change from Week 18 to Week 22 in ItchRO(Obs)
    Statistical analysis description
    The difference between treatment groups in change from Week 18 to Week 22 in ItchRO(Obs) was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ItchRO(Obs) as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.
    Comparison groups
    RWD period: MRX v RWD period: placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.483
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.122
         upper limit
    		 -0.844
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3103
    Notes
    [13] - The P-value for testing if the treatment group LS means were equal was calculated to determine if the change in ItchRO(Obs) between the treatment groups was statistically significant.
    [14] - P-value for change from Week 18 to Week 22 in the MRX group = 0.3639; P-value for change from Week 18 to Week 22 in the placebo group <0.0001.
    Statistical analysis title
    		 Change from Week 18 to Week 22 in ItchRO(Pt)
    Statistical analysis description
    The difference between treatment groups in change from Week 18 to Week 22 in ItchRO (Pt) was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ItchRO(Pt) as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.
    Comparison groups
    RWD period: MRX v RWD period: placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [15]
    P-value
    		 = 0.0013 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.988
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.009
         upper limit
    		 -0.967
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4641
    Notes
    [15] - The P-value for testing if the treatment group LS means were equal was calculated to determine if the change in ItchRO(Pt) between the treatment groups was statistically significant. While the number of participants included in analysis for the end point indicates 28, there were only 14; n = 5 for ItchRO(Pt): MRX and n = 9 for ItchRO(Pt): placebo.
    [16] - P-value for change in ItchRO(Pt) from Week 18 to Week 22 in the MRX group = 0.6956; P-value for change in ItchRO(Pt) from Week 18 to Week 22 in the placebo group <0.0001.

    Secondary: Change from baseline to Week 18 in fasting sBA levels

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    End point title
    		 Change from baseline to Week 18 in fasting sBA levels
    End point description
    This secondary efficacy endpoint is the mean change from baseline to Week 18 in fasting sBA levels
    End point type
    Secondary
    End point timeframe
    Baseline to Week 18
    End point values
    		 Open-label period: MRX baseline Open-label period: MRX Week 18
    Number of subjects analysed
    31 [17]
    29 [18]
    Units: μmol/L
        arithmetic mean (standard deviation)
    283.43 ± 210.569
    192.50 ± 161.278
    Notes
    [17] - Values were collected from 31 participants at baseline.
    [18] - Values were collected at Week 18 from 29 of the 31 participants who contributed values at baseline.
    Statistical analysis title
    		 Change from baseline to Week 18 in sBA levels
    Statistical analysis description
    This analysis investigated whether a statistically significant change in sBA levels was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population.
    Comparison groups
    Open-label period: MRX Week 18 v Open-label period: MRX baseline
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [19]
    P-value
    		 = 0.0005 [20]
    Method
    		 Student's t-test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -87.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -133.37
         upper limit
    		 -42.09
    Variability estimate
    Standard deviation
    Dispersion value
    119.979
    Notes
    [19] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in sBA levels between baseline and Week 18 (the open-label period) was statistically significant.
    [20] - Data for this analysis were obtained from 31 participants at baseline; 29 of those participants contributed Week 18 data.

    Secondary: Change from baseline to Week 18 in alkaline phosphatase

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    End point title
    		 Change from baseline to Week 18 in alkaline phosphatase
    End point description
    This secondary efficacy endpoint is the mean change from baseline to Week 18 in ALP
    End point type
    Secondary
    End point timeframe
    Baseline to Week 18
    End point values
    		 Open-label period: MRX baseline Open-label period: MRX Week 18
    Number of subjects analysed
    31 [21]
    29 [22]
    Units: U/L
        arithmetic mean (standard deviation)
    601.3 ± 274.77
    580.8 ± 215.50
    Notes
    [21] - Values were collected from 31 participants at baseline.
    [22] - Values were collected at Week 18 from 29 of the 31 participants who contributed values at baseline.
    Statistical analysis title
    		 Change from baseline to Week 18 in ALP
    Statistical analysis description
    This analysis investigated whether a statistically significant change in ALP levels was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population.
    Comparison groups
    Open-label period: MRX baseline v Open-label period: MRX Week 18
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [23]
    P-value
    		 = 0.2163 [24]
    Method
    		 Student's t-test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -27.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -72.8
         upper limit
    		 17.2
    Variability estimate
    Standard deviation
    Dispersion value
    118.33
    Notes
    [23] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ALP levels between baseline and Week 18 (the open-label period) was statistically significant.
    [24] - Data for this analysis were obtained from 31 participants at baseline; 29 of those participants contributed Week 18 data.

    Secondary: Change from baseline to Week 18 in alanine aminotransferase

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    End point title
    		 Change from baseline to Week 18 in alanine aminotransferase
    End point description
    This secondary efficacy endpoint is the mean change from baseline to Week 18 in ALT
    End point type
    Secondary
    End point timeframe
    Baseline to Week 18
    End point values
    		 Open-label period: MRX baseline Open-label period: MRX Week 18
    Number of subjects analysed
    31 [25]
    29 [26]
    Units: U/L
        arithmetic mean (standard deviation)
    181.0 ± 108.56
    177.4 ± 92.08
    Notes
    [25] - Values were collected from 31 participants at baseline.
    [26] - Values were collected at Week 18 from 29 of the 31 participants who contributed values at baseline.
    Statistical analysis title
    		 Change from baseline to Week 18 in ALT
    Statistical analysis description
    This analysis investigated whether a statistically significant change in ALT levels was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population.
    Comparison groups
    Open-label period: MRX baseline v Open-label period: MRX Week 18
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [27]
    P-value
    		 = 0.9358 [28]
    Method
    		 Student's t-test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.4
         upper limit
    		 30.9
    Variability estimate
    Standard deviation
    Dispersion value
    84.54
    Notes
    [27] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ALT levels between baseline and Week 18 (the open-label period) was statistically significant.
    [28] - Data for this analysis were obtained from 31 participants at baseline; 29 of those participants contributed Week 18 data.

    Secondary: Change from baseline to Week 18 in total bilirubin

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    End point title
    		 Change from baseline to Week 18 in total bilirubin
    End point description
    This secondary efficacy endpoint is the mean change from baseline to Week 18 in total bilirubin
    End point type
    Secondary
    End point timeframe
    Baseline to Week 18
    End point values
    		 Open-label period: MRX baseline Open-label period: MRX Week 18
    Number of subjects analysed
    31 [29]
    29 [30]
    Units: mg/dL
        arithmetic mean (standard deviation)
    6.09 ± 5.781
    5.12 ± 5.337
    Notes
    [29] - Values were collected from 31 participants at baseline.
    [30] - Values were collected at Week 18 from 29 of the 31 participants who contributed values at baseline.
    Statistical analysis title
    		 Change from baseline to Week 18 in total bilirubin
    Statistical analysis description
    This analysis investigated whether a statistically significant change in total bilirubin levels was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population.
    Comparison groups
    Open-label period: MRX baseline v Open-label period: MRX Week 18
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [31]
    P-value
    		 = 0.0893 [32]
    Method
    		 Student's t-test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 0.08
    Variability estimate
    Standard deviation
    Dispersion value
    1.424
    Notes
    [31] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in total bilirubin levels between baseline and Week 18 (the open-label period) was statistically significant.
    [32] - Data for this analysis were obtained from 31 participants at baseline; 29 of those participants contributed Week 18 data.

    Secondary: Change from baseline to Week 18 in direct bilirubin

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    End point title
    		 Change from baseline to Week 18 in direct bilirubin
    End point description
    This secondary efficacy endpoint is the mean change from baseline to Week 18 in total bilirubin
    End point type
    Secondary
    End point timeframe
    Baseline to Week 18
    End point values
    		 Open-label period: MRX baseline Open-label period: MRX Week 18
    Number of subjects analysed
    31 [33]
    28 [34]
    Units: mg/dL
        arithmetic mean (standard deviation)
    4.57 ± 3.666
    3.98 ± 3.369
    Notes
    [33] - Values were collected from 31 participants at baseline.
    [34] - Values were collected at Week 18 from 28 of the 31 participants who contributed values at baseline.
    Statistical analysis title
    		 Change from baseline to Week18 in direct bilirubin
    Statistical analysis description
    This analysis investigated whether a statistically significant change in direct bilirubin levels was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population.
    Comparison groups
    Open-label period: MRX baseline v Open-label period: MRX Week 18
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [35]
    P-value
    		 = 0.0139 [36]
    Method
    		 Student's t-test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.11
    Variability estimate
    Standard deviation
    Dispersion value
    1.012
    Notes
    [35] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in direct bilirubin levels between baseline and Week 18 (the open-label period) was statistically significant.
    [36] - Data for this analysis were obtained from 31 participants at baseline; 28 of those participants contributed Week 18 data.

    Secondary: Change from baseline to Week 18 in pruritus as measured by ItchRO

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    End point title
    		 Change from baseline to Week 18 in pruritus as measured by ItchRO
    End point description
    This secondary efficacy endpoint is the change from baseline to Week 18 in pruritus as measured by ItchRO(Obs) weekly average morning score and ItchRO(Pt) weekly average morning score
    End point type
    Secondary
    End point timeframe
    Baseline to Week 18
    End point values
    		 Open-label period: MRX baseline Open-label period: MRX Week 18
    Number of subjects analysed
    31 [37]
    29 [38]
    Units: Points (0-4)
    arithmetic mean (standard deviation)
        ItchRO(Obs) weekly average morning score
    2.909 ± 0.5480
    1.203 ± 0.8446
        ItchRO(Pt) weekly average morning score
    2.903 ± 0.6616
    0.831 ± 0.8122
    Notes
    [37] - Values collected at baseline from 31 and 14 participants, respectively, for ItchRO(Obs) and (Pt).
    [38] - Values were collected at Week 18 from 29 and 14 participants, respectively, for ItchRO(Obs) and (Pt)
    Statistical analysis title
    		 Change from baseline to Week 18 in ItchRO(Obs)
    Statistical analysis description
    This analysis investigated whether a statistically significant change in ItchRO(Obs) score was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity.
    Comparison groups
    Open-label period: MRX baseline v Open-label period: MRX Week 18
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [39]
    P-value
    		 < 0.0001 [40]
    Method
    		 Student's t-test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.704
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.051
         upper limit
    		 -1.357
    Variability estimate
    Standard deviation
    Dispersion value
    0.9114
    Notes
    [39] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ItchRO(Obs) scores between baseline and Week 18 (the open-label period) was statistically significant.
    [40] - Data for this analysis were obtained from 31 participants at baseline; 29 of those participants contributed Week 18 data.
    Statistical analysis title
    		 Change from baseline to Week 18 in ItchRO(Pt)
    Statistical analysis description
    This analysis investigated whether a statistically significant change in ItchRO(Pt) score was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity.
    Comparison groups
    Open-label period: MRX baseline v Open-label period: MRX Week 18
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [41]
    P-value
    		 < 0.0001 [42]
    Method
    		 Student's t-test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.072
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.645
         upper limit
    		 -1.498
    Variability estimate
    Standard deviation
    Dispersion value
    0.9931
    Notes
    [41] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ItchRO(Pt) scores between baseline and Week 18 (the open-label period) was statistically significant.
    [42] - Data for this analysis were obtained from 14 participants at baseline; 14 of those participants contributed Week 18 data.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to EOT
    Adverse event reporting additional description
    All treatment-emergent AEs, whether observed by the Investigator, reported by the participant, the participant’s caregiver, from laboratory findings, or other means, were recorded on the AE eCRF and medical record. 'Occurrences' relates to the number of events; 'subjects affected' relates to the number of participants who experienced the AE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Open-label period
    Reporting group description
    		 Open-label period: 18-week OL run-in period (Day 1 to Week 18). All participants received MRX.

    Reporting group title
    Randomized withdrawal period: MRX
    Reporting group description
    		 Randomized withdrawal [RWD] period: MRX 4-week randomized, double-blind, placebo-controlled drug-withdrawal period (Weeks 19 to 22) with participants randomized to receive MRX

    Reporting group title
    Randomized withdrawal period: Placebo
    Reporting group description
    		 Randomized withdrawal [RWD] period: Placebo 4-week randomized, double-blind, placebo-controlled drug-withdrawal period (Weeks 19 to 22) with participants randomized to receive placebo

    Reporting group title
    After randomized withdrawal period
    Reporting group description
    		 After randomized withdrawal (ARW) period 26-week stable-dosing period (Weeks >22 - 48): all participants received MRX

    Reporting group title
    Long-term extension period
    Reporting group description
    		 Long-term Extension (LTE) period Optional long-term treatment period (> Weeks 48) during which all participants received MRX.

    Reporting group title
    Safety population
    Reporting group description
    		 The safety population was defined as all participants who were assigned and received at least one dose of the study drug.

    Serious adverse events
    		 Open-label period Randomized withdrawal period: MRX Randomized withdrawal period: Placebo After randomized withdrawal period Long-term extension period Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 13 (7.69%)
    1 / 16 (6.25%)
    5 / 29 (17.24%)
    6 / 23 (26.09%)
    13 / 31 (41.94%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Marrow hyperplasia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Extradural haematoma
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac dysfunction
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Aplasia pure red cell
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Open-label period Randomized withdrawal period: MRX Randomized withdrawal period: Placebo After randomized withdrawal period Long-term extension period Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 31 (96.77%)
    7 / 13 (53.85%)
    12 / 16 (75.00%)
    25 / 29 (86.21%)
    23 / 23 (100.00%)
    31 / 31 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm skin
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    Subclavian artery stenosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Surgical and medical procedures
    Gastrostomy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Condition aggravated
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Face oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    0
    1
    2
    4
    Influenza like illness
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    2 / 29 (6.90%)
    2 / 23 (8.70%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    0
    2
    2
    4
    Pyrexia
         subjects affected / exposed
    6 / 31 (19.35%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    7 / 29 (24.14%)
    10 / 23 (43.48%)
    17 / 31 (54.84%)
         occurrences all number
    12
    0
    1
    12
    27
    52
    Immune system disorders
    Allergy to animal
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    3 / 29 (10.34%)
    8 / 23 (34.78%)
    13 / 31 (41.94%)
         occurrences all number
    3
    0
    0
    3
    12
    18
    Dysphonia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    2 / 31 (6.45%)
         occurrences all number
    3
    0
    0
    0
    2
    5
    Oropharyngeal pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    3 / 29 (10.34%)
    3 / 23 (13.04%)
    7 / 31 (22.58%)
         occurrences all number
    1
    0
    0
    3
    5
    9
    Rhinorrhoea
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    4 / 31 (12.90%)
         occurrences all number
    2
    0
    0
    1
    1
    4
    Sneezing
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Psychiatric disorders
    Breath holding
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Enuresis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Hallucination, visual
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    0
    2
    3
    Intentional self-injury
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Psychological trauma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Product issues
    Skin papilloma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    4 / 23 (17.39%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    0
    0
    5
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    International normalised ratio increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Vitamin A increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Vitamin D decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Bite
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Contusion
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    3 / 23 (13.04%)
    4 / 31 (12.90%)
         occurrences all number
    1
    0
    0
    0
    3
    4
    Face injury
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    4 / 31 (12.90%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    3 / 29 (10.34%)
    0 / 23 (0.00%)
    6 / 31 (19.35%)
         occurrences all number
    7
    0
    0
    5
    0
    12
    Head injury
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    3 / 31 (9.68%)
         occurrences all number
    3
    0
    0
    1
    1
    5
    Ligament sprain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Lip injury
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Muscle strain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    2 / 23 (8.70%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    0
    1
    2
    4
    Nasal injury
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    2 / 29 (6.90%)
    1 / 23 (4.35%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    0
    2
    1
    3
    Overdose
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Procedural pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Skin abrasion
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    3 / 31 (9.68%)
         occurrences all number
    2
    0
    0
    5
    1
    8
    Skin laceration
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    2 / 29 (6.90%)
    1 / 23 (4.35%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    0
    3
    1
    5
    Thermal burn
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Tooth avulsion
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Traumatic haematoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Vaccination complication
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nervous system disorders
    Arachnoid cyst
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Headache
         subjects affected / exposed
    5 / 31 (16.13%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    2 / 29 (6.90%)
    4 / 23 (17.39%)
    9 / 31 (29.03%)
         occurrences all number
    5
    0
    0
    4
    10
    19
    Hyperaesthesia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Lethargy
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    Poor quality sleep
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Coagulopathy
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    1
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Ear and labyrinth disorders
    Conductive deafness
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Deafness neurosensory
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Ear pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    3 / 29 (10.34%)
    1 / 23 (4.35%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    0
    3
    2
    6
    Excessive cerumen production
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Middle ear effusion
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Eye disorders
    Hypermetropia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Abdominal pain
         subjects affected / exposed
    12 / 31 (38.71%)
    1 / 13 (7.69%)
    1 / 16 (6.25%)
    6 / 29 (20.69%)
    12 / 23 (52.17%)
    18 / 31 (58.06%)
         occurrences all number
    22
    1
    1
    12
    31
    67
    Abdominal pain upper
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Constipation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    0
    1
    1
    3
    Dental caries
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Diarrhoea
         subjects affected / exposed
    13 / 31 (41.94%)
    1 / 13 (7.69%)
    1 / 16 (6.25%)
    5 / 29 (17.24%)
    7 / 23 (30.43%)
    18 / 31 (58.06%)
         occurrences all number
    18
    1
    1
    10
    18
    48
    Faeces pale
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    2 / 23 (8.70%)
    3 / 31 (9.68%)
         occurrences all number
    2
    0
    0
    1
    2
    5
    Gastritis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    0
    0
    2
    3
    Haematochezia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Lip discolouration
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Lip swelling
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    2 / 23 (8.70%)
    2 / 31 (6.45%)
         occurrences all number
    4
    1
    0
    1
    2
    8
    Proctalgia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Tongue discolouration
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Toothache
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Vomiting
         subjects affected / exposed
    11 / 31 (35.48%)
    1 / 13 (7.69%)
    1 / 16 (6.25%)
    2 / 29 (6.90%)
    8 / 23 (34.78%)
    16 / 31 (51.61%)
         occurrences all number
    15
    1
    2
    3
    13
    34
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Jaundice
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Erythema
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    Pruritus
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 13 (7.69%)
    5 / 16 (31.25%)
    2 / 29 (6.90%)
    0 / 23 (0.00%)
    9 / 31 (29.03%)
         occurrences all number
    4
    1
    5
    3
    0
    13
    Rash
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Urticaria
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    Dysuria
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Glomerulonephropathy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Renal tubular acidosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    2
    1
    5
    Back pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Bone cyst
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Flank pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Growth retardation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Joint swelling
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Ligamentitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    4 / 23 (17.39%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    0
    0
    5
    5
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    2 / 23 (8.70%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    0
    1
    6
    7
    Croup infectious
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Dermatitis infected
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Ear infection
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    4 / 29 (13.79%)
    5 / 23 (21.74%)
    8 / 31 (25.81%)
         occurrences all number
    4
    0
    0
    4
    6
    14
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    Fungal skin infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Gastritis viral
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    1 / 29 (3.45%)
    5 / 23 (21.74%)
    7 / 31 (22.58%)
         occurrences all number
    0
    0
    1
    1
    7
    9
    Infected bite
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Influenza
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 13 (7.69%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    2 / 23 (8.70%)
    5 / 31 (16.13%)
         occurrences all number
    2
    1
    0
    1
    2
    6
    Laryngitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Localised infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Molluscum contagiosum
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 13 (7.69%)
    1 / 16 (6.25%)
    8 / 29 (27.59%)
    9 / 23 (39.13%)
    13 / 31 (41.94%)
         occurrences all number
    4
    1
    1
    21
    46
    73
    Oral herpes
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Otitis media
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    2 / 23 (8.70%)
    4 / 31 (12.90%)
         occurrences all number
    2
    0
    0
    0
    2
    4
    Otitis media acute
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Pharyngitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    3 / 23 (13.04%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    1
    0
    3
    4
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Pneumonia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 16 (6.25%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    1
    0
    0
    3
    Rhinitis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    3 / 31 (9.68%)
         occurrences all number
    1
    1
    0
    0
    1
    3
    Rotavirus infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Skin infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    1
    0
    2
    Staphylococcal infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    1 / 23 (4.35%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 31 (19.35%)
    2 / 13 (15.38%)
    0 / 16 (0.00%)
    3 / 29 (10.34%)
    4 / 23 (17.39%)
    9 / 31 (29.03%)
         occurrences all number
    16
    3
    0
    3
    6
    28
    Urinary tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Varicella
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    5 / 23 (21.74%)
    8 / 31 (25.81%)
         occurrences all number
    1
    1
    0
    1
    5
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    3
    0
    0
    0
    0
    3
    Dehydration
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    Malnutrition
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    1 / 29 (3.45%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Vitamin A deficiency
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    0 / 23 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Vitamin C deficiency
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Weight gain poor
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 16 (0.00%)
    0 / 29 (0.00%)
    1 / 23 (4.35%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2015
    Substantial changes made to the protocol were to add additional exclusion criteria of history or presence of gallstones or kidney stones, and known hypersensitivity to MRX or any of its components.
    08 May 2015
    Substantial changes made to the protocol were to add exclusion of participants weighing over 50 kg at screening, sBA definition for randomization corrected to Week 12, and language added to address the randomization and statistical management of data generated from siblings enrolled in the study and to describe a planned extension study.
    13 Nov 2015
    Substantial changes made to the protocol were to add an optional follow-up treatment period (after Week 48) that allowed eligible participants treated in Study LUM001-304 to continue on treatment after Week 48 until the first of the following occurred: (1) up to 52 weeks of additional treatment (Week 100), or (2) in the event that a new study opened to enrollment; add an objective to obtain safety and efficacy data in participants treated long term on maralixibat, including genotyping characteristics; add NOTCH2 to list of laboratory analytes.
    28 Mar 2017
    Substantial changes made to the protocol were to allow continued participation in the optional follow-up treatment period, beyond what had been described in Protocol Amendment 3; and describe objectives and assessments of the optional follow-up treatment period; and update the contraceptive requirements to align with the Heads of Medicine Clinical Trials Facilitation Group Recommendations Related to Contraception and Pregnancy Testing. During the optional follow-up treatment period, participants must have met ongoing efficacy (sBA level and ItchRO score) and safety criteria to be eligible to undergo BID dosing with MRX. Only participants with sBA levels above normal and/or ItchRO score ≥1.5 were eligible to start BID dosing. The maximum daily dose was 400 μg/kg BID, that is, 800 μg/kg daily. If a participant experienced intolerance (e.g., GI symptoms such as diarrhea, abdominal pain, cramping) at any time during the study, the investigator, in consultation with the medical monitor, was allowed to lower the dose for the remainder of the study.
    06 Nov 2017
    Substantial changes made to the protocol were to change the study design going forward to an OL study beyond what had been described in Protocol Amendment 4; to add details regarding interim analyses up to Week 48 and unblinding of the study; and to add clinician xanthoma scale to the Schedule of Procedures.
    08 Feb 2019
    Substantial changes made to the protocol were to reflect the change of sponsorship from Lumena Pharmaceuticals LLC to Mirum Pharmaceuticals, Inc., and to document the change in medical monitor.

    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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