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    Clinical Trial Results:
    Randomized, Double-blind, Placebo-Controlled Phase 2 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Subjects with Biliary Atresia after Hepatoportoenterostomy

    Summary
    EudraCT number
    		 2020-000974-22
    Trial protocol
    		 DE   FR   PL   GB   IT  
    Global end of trial date
    07 Feb 2024

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Nov 2024
    First version publication date
    23 Aug 2024
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    AE number correction

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MRX-701
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04524390
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mirum Pharmaceuticals Inc.
    Sponsor organisation address
    989 E Hillsdale Blvd. Suite 300 , Foster City, United States, 94404
    Public contact
    Chief Development Officer, Mirum Pharmaceuticals, Inc., 1 6506674085, medinfo@mirumpharma.com
    Scientific contact
    Chief Development Officer, 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-PIP04-20
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Feb 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of maralixibat on biliary drainage after hepatoportoenterostomy (HPE) in participants with BA.
    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
    15 Oct 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Viet Nam: 17
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    China: 36
    Worldwide total number of subjects
    75
    EEA total number of subjects
    3
    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)
    75
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    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 75 participants were enrolled at 19 sites across 8 countries (China, Germany, Poland, Singapore, Taiwan, United Kingdom, United States, and Vietnam).

    Pre-assignment
    Screening details
    		 The screening period starts when informed consent (by the legally authorized representative) is signed. The duration of the screening period is up to 3 weeks, during which all procedures listed for the screening visit in the schedule of assessment must be completed. A total of 77 patients were screened.

    Period 1
    Period 1 title
    Double Blind
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Participants who meet all eligibility criteria were randomized 1:1 at the baseline visit to receive maralixibat or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maralixibat
    Arm description
    		 The double-blind period comprised of 4-8 weeks of dose escalation followed by 18 - 22 weeks of stable dosing treatment. After 20 participants had completed dose escalation, a Data Monitoring Committee (DMC) review took place to analyze the potential to simplify dose escalation to a 2-step regimen.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maralixibat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in bottle
    Routes of administration
    Oral use
    Dosage and administration details
    Dose Escalation (4-8 Weeks) For participants ≥1 month of age assigned to maralixibat in the double-blind period, the dose-escalation treatment will consist of the following steps: • Dose level 1: 150 μg/kg maralixibat BID for 1–2 weeks • Dose level 2: 300 μg/kg maralixibat BID for 1–2 weeks • Dose level 3: 450 μg/kg maralixibat BID for 1–2 weeks • Dose level 4: 600 μg/kg maralixibat BID (or highest tolerated) for the remaining duration of the dosing period Following DMC recommendation the below simplified dose escalation was implemented: • Dose level 1: 300 μg/kg maralixibat BID for 1–2 weeks • Dose level 2: 600 μg/kg maralixibat BID (or highest tolerated) for the remaining duration of the dosing period For participants <1 month of age, doses of maralixibat 75 μg/kg QD should be given. Stable Dosing (18-22) During the stable dosing treatment, participants will continue treatment with the highest tolerated dose from the dose escalation period.

    Arm title
    		 Placebo
    Arm description
    		 The double-blind period comprised of 4-8 weeks of dose escalation followed by 18 - 22 weeks of stable dosing treatment. After 20 participants had completed dose escalation, a Data Monitoring Committee (DMC) review took place to analyze the potential to simplify dose escalation to a 2-step regimen.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in bottle
    Routes of administration
    Oral use
    Dosage and administration details
    Dose Escalation (4-8 weeks) For participants ≥1 month of age assigned to maralixibat in the double-blind period, the dose-escalation period (4–8 weeks) will consist of the following steps: • Dose level 1: 150 μg/kg Placebo BID for 1–2 weeks • Dose level 2: 300 μg/kg Placebo BID for 1–2 weeks • Dose level 3: 450 μg/kg Placebo BID for 1–2 weeks • Dose level 4: 600 μg/kg Placebo BID (or highest tolerated) for the remaining duration of the dosing period Following DMC recommendation the below simplified dose escalation was implemented: • Dose level 1: 300 μg/kg Placebo BID for 1–2 weeks • Dose level 2: 600 μg/kg Placebo BID (or highest tolerated) for the remaining duration of the dosing period less For participants <1 month of age, doses of Placebo 75 μg/kg QD should be given. Stable Dosing (18-22) During the stable dosing treatment, participants will continue treatment with the highest tolerated dose from the dose escalation period.

    Number of subjects in period 1
    		Maralixibat Placebo
    Started
    40
    35
    Completed
    28
    24
    Not completed
    12
    11
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    5
    3
         Liver Transplant
    5
    6
         Disease Progression
    -
    1
    Period 2
    Period 2 title
    Open-Label Extension
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    		 Open Label Extension
    Arm description
    		 The Open-Label period comprised of 4-8 weeks of dose escalation followed by 70 - 74 weeks of stable dosing treatment. After 20 participants had completed dose escalation during the Double-Blind Period, a Data Monitoring Committee (DMC) review took place to analyze the potential to simplify dose escalation to a 2-step regimen. During the OLE, all participants, regardless of treatment assignment in the double-blind period, received maralixibat.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maralixibat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in bottle
    Routes of administration
    Oral use
    Dosage and administration details
    Dose Escalation (4-8 Weeks) For participants ≥1 month of age assigned to maralixibat in the double-blind period, the dose-escalation treatment will consist of the following steps: • Dose level 1: 150 μg/kg maralixibat BID for 1–2 weeks • Dose level 2: 300 μg/kg maralixibat BID for 1–2 weeks • Dose level 3: 450 μg/kg maralixibat BID for 1–2 weeks • Dose level 4: 600 μg/kg maralixibat BID (or highest tolerated) for the remaining duration of the dosing period Following DMC recommendation the below simplified dose escalation was implemented: • Dose level 1: 300 μg/kg maralixibat BID for 1–2 weeks • Dose level 2: 600 μg/kg maralixibat BID (or highest tolerated) for the remaining duration of the dosing period Stable Dosing (70-74 weeks) During the stable dosing treatment, participants will continue treatment with the highest tolerated dose from the dose escalation period.

    Number of subjects in period 2
    		Open Label Extension
    Started
    52
    Completed
    1
    Not completed
    51
         Drug Interruption Criteria
    1
         Adverse event, non-fatal
    3
         Study Termination by sponsor
    45
         Liver Transplant
    1
         Disease Progression
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double Blind
    Reporting group description
    		 -

    Reporting group values
    		 Double Blind Total
    Number of subjects
    		 75 75
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 75 75
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: days
        median (standard deviation)
    		 76.1 ( 17.63 ) -
    Gender categorical
    Units: Subjects
        Female
    		 36 36
        Male
    		 39 39
    Subject analysis sets

    Subject analysis set title
    All participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants. Additional subgroups of the ITT population will be specified based on the presence/absence of post-baseline efficacy assessments for particular efficacy endpoints

    Subject analysis sets values
    		 All participants
    Number of subjects
    75
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    75
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: days
        median (standard deviation)
    76.1 ( 17.63 )
    Gender categorical
    Units: Subjects
        Female
    36
        Male
    39

    End points

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    End points reporting groups
    Reporting group title
    Maralixibat
    Reporting group description
    		 The double-blind period comprised of 4-8 weeks of dose escalation followed by 18 - 22 weeks of stable dosing treatment. After 20 participants had completed dose escalation, a Data Monitoring Committee (DMC) review took place to analyze the potential to simplify dose escalation to a 2-step regimen.

    Reporting group title
    Placebo
    Reporting group description
    		 The double-blind period comprised of 4-8 weeks of dose escalation followed by 18 - 22 weeks of stable dosing treatment. After 20 participants had completed dose escalation, a Data Monitoring Committee (DMC) review took place to analyze the potential to simplify dose escalation to a 2-step regimen.
    Reporting group title
    Open Label Extension
    Reporting group description
    		 The Open-Label period comprised of 4-8 weeks of dose escalation followed by 70 - 74 weeks of stable dosing treatment. After 20 participants had completed dose escalation during the Double-Blind Period, a Data Monitoring Committee (DMC) review took place to analyze the potential to simplify dose escalation to a 2-step regimen. During the OLE, all participants, regardless of treatment assignment in the double-blind period, received maralixibat.

    Subject analysis set title
    All participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants. Additional subgroups of the ITT population will be specified based on the presence/absence of post-baseline efficacy assessments for particular efficacy endpoints

    Primary: Mean change in Total Serum Bilirubin

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    End point title
    		 Mean change in Total Serum Bilirubin
    End point description
    End point type
    Primary
    End point timeframe
    Baseline through week 26
    End point values
    		 Maralixibat Placebo
    Number of subjects analysed
    40
    35
    Units: mg/dL
        least squares mean (standard error)
    -3.5 ( 0.853 )
    -3.11 ( 0.947 )
    Statistical analysis title
    		 Mean change in Total Serum Bilirubin
    Comparison groups
    Maralixibat v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7419
    Method
    		 MMRM
    Parameter type
    		 Least-Square mean
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.76
         upper limit
    		 1.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.182

    Secondary: Mean change in total Serum Bile Acids

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    End point title
    		 Mean change in total Serum Bile Acids
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline through week 26
    End point values
    		 Maralixibat Placebo
    Number of subjects analysed
    40
    35
    Units: umol/L
        least squares mean (standard error)
    -51.19 ( 25.436 )
    -5.29 ( 28.440 )
    Statistical analysis title
    		 Mean change in total Serum Bile Acids
    Comparison groups
    Maralixibat v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2002
    Method
    		 MMRM
    Parameter type
    		 Least-Square mean
    Point estimate
    -45.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -116.86
         upper limit
    		 25.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    35.398

    Secondary: Proportion of participants with mean TSB levels <2 mg/dL

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    End point title
    		 Proportion of participants with mean TSB levels <2 mg/dL
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 Maralixibat Placebo
    Number of subjects analysed
    40
    35
    Units: Number of participants
    24
    20
    Statistical analysis title
    		 MRX vs PCB
    Comparison groups
    Maralixibat v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8412
    Method
    		 Barnard's exact test
    Confidence interval

    Secondary: Proportion of participants observed to have a liver-related clinical event

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    End point title
    		 Proportion of participants observed to have a liver-related clinical event
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline Through Week 26
    End point values
    		 Maralixibat Placebo
    Number of subjects analysed
    40
    35
    Units: Number of Participants
    8
    7
    Statistical analysis title
    		 MRX vs PCB
    Comparison groups
    Placebo v Maralixibat
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.9999
    Method
    		 Barnard's exact test
    Confidence interval

    Secondary: Proportion of participants undergoing liver transplantation or death

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    End point title
    		 Proportion of participants undergoing liver transplantation or death
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline Through Week 26
    End point values
    		 Maralixibat Placebo
    Number of subjects analysed
    40
    35
    Units: Number of Participants
    5
    3
    Statistical analysis title
    		 MRX vs PCB
    Comparison groups
    Maralixibat v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6658
    Method
    		 Barnard's exact test
    Confidence interval

    Secondary: Proportion of participants observed to develop clinically evident portal hypertension

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    End point title
    		 Proportion of participants observed to develop clinically evident portal hypertension
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline through Week 26
    End point values
    		 Maralixibat Placebo
    Number of subjects analysed
    40
    35
    Units: Number of Participants
    3
    4
    Statistical analysis title
    		 MRX vs PCB
    Comparison groups
    Maralixibat v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6236
    Method
    		 Barnard's exact test
    Confidence interval

    Secondary: Proportion of participants with mean TSB levels ≤1.2 mg/dL

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    End point title
    		 Proportion of participants with mean TSB levels ≤1.2 mg/dL
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline through Week 26
    End point values
    		 Maralixibat Placebo
    Number of subjects analysed
    40
    35
    Units: Number of Participants
    23
    18
    Statistical analysis title
    		 MRX vs PCB
    Comparison groups
    Maralixibat v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6658
    Method
    		 Barnard's exact test
    Confidence interval

    Secondary: Proportion of participants with mean sBA levels ≤40 mmol/L

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    End point title
    		 Proportion of participants with mean sBA levels ≤40 mmol/L
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline through Week 26
    End point values
    		 Maralixibat Placebo
    Number of subjects analysed
    40
    35
    Units: Number of participants
    10
    7
    Statistical analysis title
    		 MRX vs PCB
    Comparison groups
    Maralixibat v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6659
    Method
    		 Barnard's exact test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to EOT
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Safety Population OLE Maralixibat
    Reporting group description
    		 All participants who receive at least 1 dose of study medication during the Open-Label Maralixibat Period.

    Reporting group title
    Safety Population Double Blinded Maralixibat
    Reporting group description
    		 All participants who receive at least 1 dose of study medication during the double-blinded Maralixibat Period.

    Reporting group title
    Safety Population Double Blinded Placebo
    Reporting group description
    		 All participants who receive at least 1 dose of study medication during the double-blinded Placebo Period.

    Serious adverse events
    		 Safety Population OLE Maralixibat Safety Population Double Blinded Maralixibat Safety Population Double Blinded Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 52 (40.38%)
    26 / 40 (65.00%)
    25 / 35 (71.43%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 40 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental exposure to product by child
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 40 (2.50%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 40 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    8 / 52 (15.38%)
    17 / 40 (42.50%)
    18 / 35 (51.43%)
         occurrences causally related to treatment / all
    0 / 10
    1 / 28
    0 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 40 (5.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    3 / 35 (8.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 40 (5.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 52 (3.85%)
    8 / 40 (20.00%)
    4 / 35 (11.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 13
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperinsulinism
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population OLE Maralixibat Safety Population Double Blinded Maralixibat Safety Population Double Blinded Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 52 (90.38%)
    38 / 40 (95.00%)
    33 / 35 (94.29%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 52 (7.69%)
    5 / 40 (12.50%)
    5 / 35 (14.29%)
         occurrences all number
    6
    5
    5
    Blood bilirubin increased
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 40 (2.50%)
    2 / 35 (5.71%)
         occurrences all number
    1
    3
    2
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 40 (7.50%)
    0 / 35 (0.00%)
         occurrences all number
    1
    3
    0
    Spleen palpable
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    2
    Vitamin A decreased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 40 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    2
    Injury, poisoning and procedural complications
    Scratch
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 40 (2.50%)
    3 / 35 (8.57%)
         occurrences all number
    3
    1
    5
    Coagulopathy
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 40 (5.00%)
    3 / 35 (8.57%)
         occurrences all number
    3
    3
    4
    Splenomegaly
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 40 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    2
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    12 / 52 (23.08%)
    14 / 40 (35.00%)
    8 / 35 (22.86%)
         occurrences all number
    18
    19
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 52 (25.00%)
    13 / 40 (32.50%)
    8 / 35 (22.86%)
         occurrences all number
    16
    19
    8
    Vomiting
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 40 (10.00%)
    6 / 35 (17.14%)
         occurrences all number
    2
    4
    8
    Dyspepsia
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 40 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    2
    0
    Haematochezia
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    4
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    3 / 52 (5.77%)
    6 / 40 (15.00%)
    6 / 35 (17.14%)
         occurrences all number
    3
    8
    6
    Hepatomegaly
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 40 (2.50%)
    2 / 35 (5.71%)
         occurrences all number
    0
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 52 (15.38%)
    8 / 40 (20.00%)
    5 / 35 (14.29%)
         occurrences all number
    9
    9
    6
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    5 / 52 (9.62%)
    3 / 40 (7.50%)
    0 / 35 (0.00%)
         occurrences all number
    8
    6
    0
    Eczema
         subjects affected / exposed
    1 / 52 (1.92%)
    6 / 40 (15.00%)
    4 / 35 (11.43%)
         occurrences all number
    1
    9
    4
    Rash
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 40 (7.50%)
    3 / 35 (8.57%)
         occurrences all number
    2
    3
    3
    Urticaria
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 40 (2.50%)
    0 / 35 (0.00%)
         occurrences all number
    4
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 40 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 40 (7.50%)
    3 / 35 (8.57%)
         occurrences all number
    5
    3
    3
    COVID-19
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 40 (7.50%)
    5 / 35 (14.29%)
         occurrences all number
    2
    3
    5
    Nasopharyngitis
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 40 (2.50%)
    1 / 35 (2.86%)
         occurrences all number
    7
    1
    1
    Otitis media
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 40 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    3
    0
    2
    Pharyngitis
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 40 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    2
    1
    Pneumonia
         subjects affected / exposed
    5 / 52 (9.62%)
    6 / 40 (15.00%)
    5 / 35 (14.29%)
         occurrences all number
    6
    8
    8
    Respiratory tract infection
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 40 (2.50%)
    2 / 35 (5.71%)
         occurrences all number
    2
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 52 (23.08%)
    7 / 40 (17.50%)
    3 / 35 (8.57%)
         occurrences all number
    23
    8
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 40 (2.50%)
    4 / 35 (11.43%)
         occurrences all number
    6
    1
    5
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 40 (5.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    2
    1
    Gastroenteritis
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    0
    Influenza
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 40 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 40 (5.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    2
    0
    Metabolism and nutrition disorders
    Vitamin A deficiency
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 40 (7.50%)
    7 / 35 (20.00%)
         occurrences all number
    3
    3
    7
    Vitamin D deficiency
         subjects affected / exposed
    8 / 52 (15.38%)
    7 / 40 (17.50%)
    9 / 35 (25.71%)
         occurrences all number
    8
    7
    9
    Vitamin E deficiency
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 40 (5.00%)
    4 / 35 (11.43%)
         occurrences all number
    4
    2
    4
    Zinc deficiency
         subjects affected / exposed
    2 / 52 (3.85%)
    5 / 40 (12.50%)
    5 / 35 (14.29%)
         occurrences all number
    2
    5
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2020
    Version 2 of the protocol implemented changes to the enhanced liver monitoring criteria following feedback from the FDA. The study duration was revised.
    03 Feb 2021
    Version 3 of the protocol included updates to the inclusion criteria, schedule of assessments, and exploratory endpoints. Additional information and guidance on maralixibat risk and benefits was included.
    06 May 2021
    Version 4 of the protocol decreased the number of clinic visits. Dose escalation was revised to a 2-step schedule, when prespecified criteria were met, upon recommendation by the DMC.
    25 Mar 2022
    Version 5 of the protocol updated blood sample order and priority. The schedule of assessments was updated.
    25 Apr 2023
    Version 6 of the protocol modified and reordered objectives to reflect the sponsor's planned analyses. Safety language was updated for consistency across sponsor protocols.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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