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    Clinical Trial Results:
    A Phase 2 Double-blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerability and Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH)

    Summary
    EudraCT number
    		 2016-000203-82
    Trial protocol
    		 GB  
    Global end of trial date
    27 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Feb 2019
    First version publication date
    24 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SHP626-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02787304
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to evaluate the effect of volixibat compared to placebo (PBO) on liver histology.
    Protection of trial subjects
    This study was conducted in accordance with current applicable regulations, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Europen Union (EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements.
    Background therapy
    		 None
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    24 Oct 2016
    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
    Canada: 15
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    United States: 158
    Worldwide total number of subjects
    197
    EEA total number of subjects
    24
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    152
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 68 centers in the United States of America, Canada, and the United Kingdom between 24 October 2016 (first subject first visit) and 27 July 2018 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 585 subjects were screened to randomize 197 subjects, of which 196 subjects were analyzed for safety; 1 subject was randomized but was lost to follow-up after the baseline visit.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The IP was supplied as double-blind blister packs. The actual double-blind treatment given to individual subjects was determined by a randomization schedule which was automatically assigned by the interactive response technology (IRT). Placebo capsules, which exactly matched the IP, were used in the blister packs to provide the same number and size capsules for each of the doses within the treatment groups.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SHP626 5 mg
    Arm description
    		 Subjects received 5 milligrams (mg) of SHP626 (Volixibat potassium) capsule once daily (QD) by mouth (PO) for ≥24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Volixibat potassium
    Investigational medicinal product code
    SHP626
    Other name
    Volixibat
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 5/10/20 mg of SHP626 capsule orally QD for ≥24 weeks.

    Arm title
    		 SHP626 10 mg
    Arm description
    		 Subjects received 10 mg of SHP626 capsule QD PO for ≥24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Volixibat potassium
    Investigational medicinal product code
    SHP626
    Other name
    Volixibat
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 5/10/20 mg of SHP626 capsule orally QD for ≥24 weeks.

    Arm title
    		 SHP626 20 mg
    Arm description
    		 Subjects received 20 mg of SHP626 capsule QD PO for ≥24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Volixibat potassium
    Investigational medicinal product code
    SHP626
    Other name
    Volixibat
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 5/10/20 mg of SHP626 capsule orally QD for ≥24 weeks.

    Arm title
    		 Placebo (PBO)
    Arm description
    		 Subjects received placebo matched to SHP626 capsule QD PO for ≥24 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to SHP626 capsule orally QD for ≥24 weeks.

    Number of subjects in period 1 [1]
    		SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Started
    49
    49
    49
    49
    Completed
    13
    12
    8
    15
    Not completed
    36
    37
    41
    34
         Physician decision
    -
    -
    1
    -
         Study terminated by sponsor
    25
    31
    31
    32
         Adverse event
    9
    3
    8
    1
         Non-compliance with study drug
    -
    -
    1
    -
         Lost to follow-up
    1
    -
    -
    1
         Withdrawal by subject
    1
    3
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: All enrolled subjects were not treated with study drug. As baseline included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SHP626 5 mg
    Reporting group description
    		 Subjects received 5 milligrams (mg) of SHP626 (Volixibat potassium) capsule once daily (QD) by mouth (PO) for ≥24 weeks.

    Reporting group title
    SHP626 10 mg
    Reporting group description
    		 Subjects received 10 mg of SHP626 capsule QD PO for ≥24 weeks.

    Reporting group title
    SHP626 20 mg
    Reporting group description
    		 Subjects received 20 mg of SHP626 capsule QD PO for ≥24 weeks.

    Reporting group title
    Placebo (PBO)
    Reporting group description
    		 Subjects received placebo matched to SHP626 capsule QD PO for ≥24 weeks

    Reporting group values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO) Total
    Number of subjects
    		 49 49 49 49
    Age categorical
    Units: Subjects
    Age continuous
    Safety analysis set (SAS) consisted of all subjects who took at least 1 dose of randomized investigational product (IP), and had at least 1 postbaseline safety assessment.
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 14.13 ) 53.0 ( 11.84 ) 53.2 ( 13.61 ) 53.4 ( 11.75 ) -
    Gender categorical
    SAS consisted of all subjects who took at least 1 dose of randomized IP, and had at least 1 postbaseline safety assessment.
    Units:
        Male
    		 22 15 24 17 78
        Female
    		 27 34 25 32 118

    End points

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    End points reporting groups
    Reporting group title
    SHP626 5 mg
    Reporting group description
    		 Subjects received 5 milligrams (mg) of SHP626 (Volixibat potassium) capsule once daily (QD) by mouth (PO) for ≥24 weeks.

    Reporting group title
    SHP626 10 mg
    Reporting group description
    		 Subjects received 10 mg of SHP626 capsule QD PO for ≥24 weeks.

    Reporting group title
    SHP626 20 mg
    Reporting group description
    		 Subjects received 20 mg of SHP626 capsule QD PO for ≥24 weeks.

    Reporting group title
    Placebo (PBO)
    Reporting group description
    		 Subjects received placebo matched to SHP626 capsule QD PO for ≥24 weeks

    Primary: Number of Subjects Achieving Binary Response at Week 48

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    End point title
    		 Number of Subjects Achieving Binary Response at Week 48 [1]
    End point description
    Binary response indicating (yes/no) whether a subject responded at week 48 with a reduction of at least 2 points, without worsening of fibrosis, from baseline nonalcoholic fatty Liver disease (NAFLD) activity Score (NAS). The NAS grades NAFLD on liver biopsy based on the individual scoring of steatosis, inflammation and ballooning. The NAS is assessed on a scale of 0 to 8 with higher scores indicating more severe disease and lower scores indicating less severe disease. NAS is obtained by adding steatosis(assessed on a scale of 0 to 3), inflammation (assessed on a scale of 0 to 3) and ballooning (assessed on a scale of 0 to 2). Full analysis set (FAS) consisted of all subjects in the SAS who had at least 1 post-baseline efficacy assessment. Here number of subjects analyzed refer to subjects with liver biopsy at both Baseline and Week 48. Subjects who achieved the response "Yes" were reported.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics was done, No inferential statistics was performed.
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    11
    11
    8
    13
    Units: Subjects
    4
    2
    3
    5
    No statistical analyses for this end point

    Secondary: Number of Subjects With a Change from Baseline to Week 48 in Liver Histology NAS Score

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    End point title
    		 Number of Subjects With a Change from Baseline to Week 48 in Liver Histology NAS Score
    End point description
    Change in liver histology was measured by the individual NAS components (ballooning, inflammation, steatosis). The NAS grades NAFLD on liver biopsy based on the individual scoring of steatosis, inflammation and ballooning. The NAS is assessed on a scale of 0 to 8 with higher scores indicating more severe disease and lower scores indicating less severe disease. NAS is obtained by adding steatosis (assessed on a scale of 0 to 3), inflammation (assessed on a scale of 0 to 3) and ballooning (assessed on a scale of 0 to 2). FAS consisted of all subjects in the SAS who had at least 1 postbaseline efficacy assessment. Here number of subjects analyzed refer to subjects with liver biopsy at both Baseline and Week 48.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    11
    11
    8
    13
    Units: Subjects
        Increase in Score >=1
    2
    1
    2
    1
        Stable in Score
    2
    3
    2
    1
        Decrease in Score by 1
    2
    4
    0
    4
        Decrease in Score >= 2
    5
    3
    4
    7
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 on Hepatic Steatosis as Measured by Magnetic Resonance Imaging-proton Density Fat-fraction (MRI-PDFF)

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    End point title
    		 Change from Baseline to Week 24 on Hepatic Steatosis as Measured by Magnetic Resonance Imaging-proton Density Fat-fraction (MRI-PDFF)
    End point description
    Hepatic steatosis was evaluated by measuring the reduction of liver fat with MRI-PDFF. Interim Analysis Set (IAS) consisted of all subjects in the SAS (subjects who had taken at least 1 dose of randomized IP, and had at least 1 post-baseline safety assessment) who have both baseline and scheduled Week 24 efficacy assessment (MRI and ALT biochemistry measurement) at the data cut time of the interim analysis (IA).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    21
    20
    18
    21
    Units: Percentage of liver fat
        arithmetic mean (standard deviation)
    -0.35 ( 5.731 )
    -0.23 ( 7.914 )
    -1.29 ( 4.846 )
    0.15 ( 5.106 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With a Change from Baseline to Week 48 on Liver Histology as Measured by Fibrosis Stage (NASH)

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    End point title
    		 Number of Subjects With a Change from Baseline to Week 48 on Liver Histology as Measured by Fibrosis Stage (NASH)
    End point description
    Fibrosis stage was assessed on a scale of 0-4 with higher scores indicating more severe disease and lower scores indicating less severe disease (F0= no fibrosis, F4=cirrhosis). FAS consisted of all subjects in the SAS (subjects who had taken at least 1 dose of randomized IP, and had at least 1 postbaseline safety assessment) who had at least 1 postbaseline efficacy assessment. Here number of subjects analyzed refer to subjects with liver biopsy at both Baseline and Week 48.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    11
    11
    8
    13
    Units: Subjects
    number (not applicable)
        Subjects with Increased score
    2
    4
    4
    4
        Subjects with Stable score
    4
    5
    3
    4
        Subjects with Decreased score
    5
    2
    1
    5
    No statistical analyses for this end point

    Secondary: Number of Subjects With Resolution of NASH at Week 48

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    End point title
    		 Number of Subjects With Resolution of NASH at Week 48
    End point description
    Resolution of NASH was defined as total absence of ballooning [score =0], absent or mild inflammation [score 0-1], steatosis can be present [score 0-3]) without worsening of fibrosis as assessed by liver histology.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    11
    11
    8
    13
    Units: Subjects
    2
    2
    2
    4
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 48 on Serum Liver-related Biochemistry

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    End point title
    		 Change from Baseline to Week 48 on Serum Liver-related Biochemistry
    End point description
    Serum liver-related biochemistry analysed by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) was reported. SAS consisted of all subjects who took at least 1 dose of randomized IP, and had at least 1 postbaseline safety assessment. Here number of subjects analyzed refer to subjects evaluable for this outcome at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    49
    49
    49
    49
    Units: Units per liter (U/L)
    arithmetic mean (standard deviation)
        ALT (n=18,16,15,20)
    1.2 ( 25.83 )
    4.2 ( 33.65 )
    -6.9 ( 37.91 )
    -0.2 ( 24.93 )
        AST (n=18,16,14,20)
    7.6 ( 16.57 )
    10.6 ( 31.23 )
    -7.2 ( 27.08 )
    -0.8 ( 14.45 )
        ALP (n=18,16,15,20)
    5.3 ( 9.62 )
    -0.9 ( 27.37 )
    -0.1 ( 14.82 )
    -0.7 ( 10.66 )
        GGT (n=18,16,15,20)
    8.8 ( 46.24 )
    5.2 ( 47.24 )
    -8.8 ( 45.43 )
    -8.5 ( 41.11 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 48 on Serum Liver-related Biochemistry- Total Bilirubin (TB)

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    End point title
    		 Change from Baseline to Week 48 on Serum Liver-related Biochemistry- Total Bilirubin (TB)
    End point description
    Serum liver-related biochemistry analysed by measuring total bilirubin (TB) was reported. SAS consisted of all subjects who took at least 1 dose of randomized IP, and had at least 1 postbaseline safety assessment. Here number of subjects analyzed refer to subjects evaluable for this outcome at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    18
    16
    15
    20
    Units: Milligrams per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    0.019 ( 0.2198 )
    0.124 ( 0.2872 )
    0.060 ( 0.2730 )
    0.058 ( 0.1762 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 48 in Serum Glucose Level

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    End point title
    		 Change from Baseline to Week 48 in Serum Glucose Level
    End point description
    Change from baseline to Week 48 in serum glucose level was reported. SAS consisted of all subjects who took at least 1 dose of randomized IP, and had at least 1 postbaseline safety assessment. Here number of subjects analyzed refer to subjects evaluable for this outcome at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    18
    16
    15
    20
    Units: Milligrams per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    3.5 ( 40.07 )
    -5.0 ( 23.11 )
    1.6 ( 21.31 )
    15.6 ( 45.84 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 48 in Hemoglobin A1C (HbA1c)

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    End point title
    		 Change from Baseline to Week 48 in Hemoglobin A1C (HbA1c)
    End point description
    Change from baseline to Week 48 in HbA1c was reported. SAS consisted of all subjects who took at least 1 dose of randomized IP, and had at least 1 postbaseline safety assessment. Here number of subjects analyzed refer to subjects evaluable for this outcome at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    18
    16
    15
    20
    Units: Fraction of 1
        arithmetic mean (standard deviation)
    -0.0003 ( 0.00559 )
    -0.0008 ( 0.00552 )
    -0.0020 ( 0.00426 )
    0.0033 ( 0.00701 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 48 in Serum Lipids

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    End point title
    		 Change from Baseline to Week 48 in Serum Lipids
    End point description
    Serum lipids level was measured by assessing cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglycerides. SAS consisted of all subjects who took at least 1 dose of randomized IP, and had at least 1 postbaseline safety assessment. Here number of subjects analyzed refer to subjects evaluable for this outcome at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 SHP626 5 mg SHP626 10 mg SHP626 20 mg Placebo (PBO)
    Number of subjects analysed
    18
    16
    15
    20
    Units: Milligrams per deciliter (mg/dL)
    arithmetic mean (standard deviation)
        Cholesterol
    -13.4 ( 32.06 )
    -19.1 ( 38.26 )
    -7.6 ( 26.94 )
    4.7 ( 30.38 )
        HDL-C
    1.8 ( 6.72 )
    2.2 ( 10.36 )
    2.7 ( 6.56 )
    0.0 ( 6.74 )
        LDL-C
    -13.4 ( 27.38 )
    -19.5 ( 31.78 )
    -9.0 ( 22.37 )
    -0.8 ( 26.12 )
        Triglycerides
    -9.5 ( 37.05 )
    -0.2 ( 92.34 )
    -7.2 ( 71.62 )
    28.7 ( 52.48 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment up to follow-up (Week 52)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    SHP626 5 Milligram (mg)
    Reporting group description
    		 Subject administered 5 mg SHP626 capsule by orally once daily in a double-blinded fashion

    Reporting group title
    SHP626 10 Milligram (mg)
    Reporting group description
    		 Subject administered 10 mg SHP626 capsule by orally once daily in a double-blinded fashion

    Reporting group title
    SHP626 20 Milligram (mg)
    Reporting group description
    		 Subject administered 20 mg SHP626 capsule by orally once daily in a double-blinded fashion

    Reporting group title
    Placebo (PBO)
    Reporting group description
    		 Subject administered SHP626 matching PBO capsule by orally once daily in a double-blinded fashion

    Serious adverse events
    		 SHP626 5 Milligram (mg) SHP626 10 Milligram (mg) SHP626 20 Milligram (mg) Placebo (PBO)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SHP626 5 Milligram (mg) SHP626 10 Milligram (mg) SHP626 20 Milligram (mg) Placebo (PBO)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 49 (85.71%)
    42 / 49 (85.71%)
    40 / 49 (81.63%)
    24 / 49 (48.98%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    0
    1
    0
    3
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    4 / 49 (8.16%)
         occurrences all number
    1
    3
    0
    4
    Vitamin d decreased
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
         occurrences all number
    1
    1
    4
    2
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    2
    0
    5
    0
    Headache
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    4 / 49 (8.16%)
    3 / 49 (6.12%)
         occurrences all number
    1
    0
    4
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 49 (6.12%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
         occurrences all number
    4
    3
    3
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences all number
    1
    1
    1
    3
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
         occurrences all number
    1
    3
    1
    1
    Abdominal distension
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    3
    1
    0
    2
    Abdominal pain
         subjects affected / exposed
    10 / 49 (20.41%)
    9 / 49 (18.37%)
    6 / 49 (12.24%)
    3 / 49 (6.12%)
         occurrences all number
    11
    10
    6
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
         occurrences all number
    0
    3
    4
    0
    Constipation
         subjects affected / exposed
    2 / 49 (4.08%)
    4 / 49 (8.16%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences all number
    2
    4
    1
    3
    Diarrhoea
         subjects affected / exposed
    38 / 49 (77.55%)
    35 / 49 (71.43%)
    35 / 49 (71.43%)
    10 / 49 (20.41%)
         occurrences all number
    43
    46
    47
    11
    Frequent bowel movements
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    4
    1
    0
    1
    Nausea
         subjects affected / exposed
    5 / 49 (10.20%)
    4 / 49 (8.16%)
    7 / 49 (14.29%)
    2 / 49 (4.08%)
         occurrences all number
    6
    6
    7
    2
    Vomiting
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    4 / 49 (8.16%)
    3 / 49 (6.12%)
         occurrences all number
    1
    4
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences all number
    3
    3
    1
    4
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    3
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
         occurrences all number
    0
    3
    1
    1
    Rash
         subjects affected / exposed
    0 / 49 (0.00%)
    4 / 49 (8.16%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences all number
    0
    4
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 49 (4.08%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Back pain
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
         occurrences all number
    0
    0
    3
    3
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    3
    2
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
         occurrences all number
    1
    1
    3
    5
    Sinusitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
         occurrences all number
    1
    0
    3
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 49 (8.16%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences all number
    1
    4
    1
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 49 (2.04%)
    6 / 49 (12.24%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
         occurrences all number
    2
    7
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2016
    Amendment 1 • Requirement for meal fat content of 10-20 grams before daily dose of investigational product added • Planned duration of screening period increased from 42 to 56 days • Acceptable methods of contraception were modified to delete the use of double-barrier methods and clarify barrier methods, add male sterilization, add and define abstinence • Clarified that the Week 24 and Week 48 MRIs will be conducted for subjects in the IA set only
    19 Jul 2016
    Amendment 2 • Alcohol Test revised from Serum to Blood, Vitamins A and E were • Added to the schedule of assessments, MRI time points were clarified, and window for Visit 10 was added. • Exclusion criterion #24 regarding pregnant women, women who plan to become pregnant, or men who plan to father a child during the study, was added. • The list of acceptable methods of contraception was revised. • Clarified that abnormal screening labs may be repeated before determining screen failure.
    22 Mar 2017
    Amendment 3 • Extended planned study period from July 2019 to July 2020. • Revised 1) Eligibility criteria; 2) sample size description; and 3) definition of secondary endpoint • “Resolution of NASH” • Added mention that the number of F0 subjects will be capped at 81 if 1 dose is dropped after the interim analysis and at 62 if 2 doses are dropped. • Criterion #6 was revised to allow for F0 (fibrosis score), in addition to F1-F3. • Revised criteria #11 and #12 to allow for enrollment of subjects with elevation in AST (#11) and ALT (#12) up to 7 times the ULN (instead of 5 times the ULN). • Revised criterion #30 to remove exclusion of subjects who previously failed screening. • Increased approximate number of subjects screened from 334 to 677 subjects. • The definition of “Resolution of NASH” was revised.
    25 Aug 2017
    Amendment 4 • Reduced planned study period from July 2020 to January 2020. • The “Methodology” section was updated to reflect new numbers following elimination of the previously planned enrollment pause. • Lengthened screening window from 8 weeks (56 days) to 10 weeks (70 days). • Revised the capping number for F0 subjects; this will be capped at 88 if 1 dose is dropped after the interim analysis and at 78 if 2 doses are dropped (% remains the same at 30%) following elimination of the previously planned enrollment pause.

    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.
    Based on predefined IA criteria at Week 24, an external independent DMC & an internal unblinded recommendation review team recommended study termination as no dose of Volixibat was effective, based on reduction of steatosis on MRIPDFF & ALT reduction
    For support, Contact us.
    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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