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    Clinical Trial Results:
    A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety and efficacy of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA).

    Summary
    EudraCT number
    2018-001171-20
    Trial protocol
    GR   HU   DE   FR   AT   PL   NL   ES   BE   IT   RO  
    Global end of trial date
    16 Feb 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Apr 2021
    First version publication date
    04 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CB8025-31735
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03602560
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CymaBay Therapeutics, Inc.
    Sponsor organisation address
    7575 Gateway Blvd, Suite 110, Newark, United States, 94560
    Public contact
    Mary Standen, CymaBay Therapeutics, Inc., +1 5102938800, mstanden@cymabay.com
    Scientific contact
    Elaine Watkins, CymaBay Therapeutics, Inc., +1 5102938800, ewatkins@cymabay.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
    01 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluate the safety and effect on cholestasis of two seladelpar regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of treatment compared to placebo.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and its revisions and the International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP). The study was also in compliance with the applicable local regulatory requirements and laws of each country in which the study was conducted, as well as with any applicable guidelines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Sep 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    United States: 108
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Mexico: 9
    Worldwide total number of subjects
    265
    EEA total number of subjects
    55
    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)
    221
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 159 clinical sites in the Asia Pacific, Europe, Latin America, and North America regions between 01 October 2018 and 16 February 2020.

    Pre-assignment
    Screening details
    A total of 501 subjects were screened, and 265 subjects were randomized into the study. All 265 subjects received at least 1 randomized dose: 87 subjects received placebo, 89 subjects received seladelpar 5 mg, and 89 subjects received seladelpar 10 mg at Day 1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Seladelpar 5 mg (initial Dose)
    Arm description
    Subjects received seladelpar 5 milligram (mg) capsules orally once daily for the study duration
    Arm type
    Experimental

    Investigational medicinal product name
    Seladelpar
    Investigational medicinal product code
    MBX-8025
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received seladelpar 5 milligram (mg) capsules orally once daily for the treatment period

    Arm title
    Seladelpar 10 mg (initial dose)
    Arm description
    Subjects received seladelpar 10 mg capsules orally once daily for the study duration
    Arm type
    Experimental

    Investigational medicinal product name
    Seladelpar
    Investigational medicinal product code
    MBX-8025
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received seladelpar 10 milligram (mg) capsules orally once daily for the treatment period

    Arm title
    Placebo
    Arm description
    Subjects received matched placebo capsules orally once daily for the study duration
    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 matching placebo capsules orally once daily for the study duration

    Number of subjects in period 1
    Seladelpar 5 mg (initial Dose) Seladelpar 10 mg (initial dose) Placebo
    Started
    89
    89
    87
    Completed
    1
    1
    0
    Not completed
    88
    88
    87
         Consent withdrawn by subject
    2
    -
    -
         Other - early termination by sponsor
    84
    86
    86
         Adverse event, non-fatal
    -
    2
    -
         Lost to follow-up
    1
    -
    1
         Other than listed
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Seladelpar 5 mg (initial Dose)
    Reporting group description
    Subjects received seladelpar 5 milligram (mg) capsules orally once daily for the study duration

    Reporting group title
    Seladelpar 10 mg (initial dose)
    Reporting group description
    Subjects received seladelpar 10 mg capsules orally once daily for the study duration

    Reporting group title
    Placebo
    Reporting group description
    Subjects received matched placebo capsules orally once daily for the study duration

    Reporting group values
    Seladelpar 5 mg (initial Dose) Seladelpar 10 mg (initial dose) Placebo Total
    Number of subjects
    89 89 87 265
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    75 73 73 221
        From 65-84 years
    14 16 14 44
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.7 ( 9.70 ) 55.6 ( 9.12 ) 55.9 ( 8.17 ) -
    Gender categorical
    Units: Subjects
        Female
    82 83 85 250
        Male
    7 6 2 15
    Race
    Units: Subjects
        White
    83 77 80 240
        Black or African-American
    1 4 2 7
        Asian
    4 8 5 17
        American Indian or Alaska Native
    1 0 0 1
        Native Hawaiian or other Pacific Islander
    0 0 0 0
        Other
    0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Seladelpar 5 mg (initial Dose)
    Reporting group description
    Subjects received seladelpar 5 milligram (mg) capsules orally once daily for the study duration

    Reporting group title
    Seladelpar 10 mg (initial dose)
    Reporting group description
    Subjects received seladelpar 10 mg capsules orally once daily for the study duration

    Reporting group title
    Placebo
    Reporting group description
    Subjects received matched placebo capsules orally once daily for the study duration

    Primary: Percentage of Subjects with Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% reduction in ALP, and total bilirubin ≤ ULN) at Endpoint

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    End point title
    Percentage of Subjects with Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% reduction in ALP, and total bilirubin ≤ ULN) at Endpoint
    End point description
    Percentage of Subjects with Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% reduction in ALP, and total bilirubin ≤ ULN) at Month 3. The mITT analysis set included all randomized subjects who received at least one study drug dose. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Primary
    End point timeframe
    At Month 3 (Endpoint)
    End point values
    Seladelpar 5 mg (initial Dose) Seladelpar 10 mg (initial dose) Placebo
    Number of subjects analysed
    56
    55
    56
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Month 3 (n= 56, 55, 56)
    57.1 (43.2 to 70.3)
    78.2 (65.0 to 88.2)
    12.5 (5.2 to 24.1)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Seladelpar 10 mg vs Placebo
    Comparison groups
    Seladelpar 10 mg (initial dose) v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Cochran-Mantel-Haenszel (CMH) test adjusted for both randomization stratification variables (ALP level: < 350 U/L and ≥ 350 U/L; pruritus NRS: < 4 and ≥ 4) was used to test the association between treatment groups
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Seladelpar 5 mg vs Placebo
    Comparison groups
    Seladelpar 5 mg (initial Dose) v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of Subjects With Response Defined by Normalized Alkaline Phosphatase Levels at Endpoint

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    End point title
    Percentage of Subjects With Response Defined by Normalized Alkaline Phosphatase Levels at Endpoint
    End point description
    The response was defined by normalized ALP levels (ALP ≤1.0 × ULN) at endpoint. The mITT analysis set included all randomized subjects who received at least one study drug dose.
    End point type
    Secondary
    End point timeframe
    At Month 3 (Endpoint)
    End point values
    Seladelpar 5 mg (initial Dose) Seladelpar 10 mg (initial dose) Placebo
    Number of subjects analysed
    56
    55
    56
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Month 3 (n= 56, 55, 56)
    5.4 (1.1 to 14.9)
    27.3 (16.1 to 41.0)
    0 (0 to 6.4)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Cochran-Mantel-Haenszel (CMH) test adjusted for both randomization stratification variables (ALP level: < 350 U/L and ≥ 350 U/L; pruritus NRS: < 4 and ≥ 4) was used to test the association between treatment groups. Breslow-Day test is used to check the homogeneity of treatment effects across stratum.
    Comparison groups
    Seladelpar 10 mg (initial dose) v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Cochran-Mantel-Haenszel (CMH) test adjusted for both randomization stratification variables (ALP level: < 350 U/L and ≥ 350 U/L; pruritus NRS: < 4 and ≥ 4) was used to test the association between treatment groups. Breslow-Day test is used to check the homogeneity of treatment effects across stratum.
    Comparison groups
    Seladelpar 5 mg (initial Dose) v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0839
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Change From Baseline in Pruritus as Assessed by Numerical Rating Scale (NRS) for Subjects with Baseline NRS ≥4

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    End point title
    Change From Baseline in Pruritus as Assessed by Numerical Rating Scale (NRS) for Subjects with Baseline NRS ≥4
    End point description
    Pruritus NRS at Month 3 is the key secondary efficacy endpoint. The weekly pruritus score was calculated by recording the daily pruritus score each day for seven days and later taking the mean value of the seven days’ daily recorded data. If any data was available for a given week, the available NRS results was used for the calculation of the weekly mean. If no NRS results was available in a given week, the mean of the prior week was used to impute those missing results using the LOCF method. Only assessments before or within 2 days after the last dose was used in determining weekly means. Baseline pruritus NRS is defined as the mean of the all daily recorded scores during run-in. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3 (Endpoint)
    End point values
    Seladelpar 5 mg (initial Dose) Seladelpar 10 mg (initial dose) Placebo
    Number of subjects analysed
    17
    18
    18
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 3 (n=17, 18, 18)
    -1.95 ( 2.226 )
    -3.01 ( 1.952 )
    -1.44 ( 1.831 )
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Seladelpar 10 mg (initial dose) v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0164
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.87
         upper limit
    -0.3
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Seladelpar 5 mg (initial Dose) v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4781
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.77
         upper limit
    0.84

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to week 56
    Adverse event reporting additional description
    Adverse events
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Seladelpar 5 mg (initial Dose)
    Reporting group description
    Subjects received seladelpar 5 milligram (mg) capsules orally once daily for the study duration

    Reporting group title
    Seladelpar 10 mg (initial dose)
    Reporting group description
    Subjects received seladelpar 10 mg capsules orally once daily for the study duration

    Reporting group title
    Placebo
    Reporting group description
    Subjects received matched placebo capsules orally once daily for the study duration

    Serious adverse events
    Seladelpar 5 mg (initial Dose) Seladelpar 10 mg (initial dose) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 89 (1.12%)
    3 / 87 (3.45%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoid cystic carcinoma
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 89 (0.00%)
    0 / 87 (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
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 89 (0.00%)
    0 / 87 (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
    Partial seizures
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 89 (0.00%)
    0 / 87 (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
    Rectal polyp
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         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: 3%
    Non-serious adverse events
    Seladelpar 5 mg (initial Dose) Seladelpar 10 mg (initial dose) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 89 (61.80%)
    58 / 89 (65.17%)
    62 / 87 (71.26%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 89 (5.62%)
    7 / 89 (7.87%)
    1 / 87 (1.15%)
         occurrences all number
    5
    8
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 89 (2.25%)
    4 / 89 (4.49%)
    8 / 87 (9.20%)
         occurrences all number
    2
    4
    8
    Asthenia
         subjects affected / exposed
    0 / 89 (0.00%)
    3 / 89 (3.37%)
    0 / 87 (0.00%)
         occurrences all number
    0
    3
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 89 (3.37%)
    3 / 89 (3.37%)
    2 / 87 (2.30%)
         occurrences all number
    3
    3
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    8 / 89 (8.99%)
    6 / 89 (6.74%)
    3 / 87 (3.45%)
         occurrences all number
    9
    6
    3
    Nausea
         subjects affected / exposed
    5 / 89 (5.62%)
    7 / 89 (7.87%)
    4 / 87 (4.60%)
         occurrences all number
    6
    8
    5
    Diarrhoea
         subjects affected / exposed
    4 / 89 (4.49%)
    4 / 89 (4.49%)
    4 / 87 (4.60%)
         occurrences all number
    4
    6
    5
    Constipation
         subjects affected / exposed
    5 / 89 (5.62%)
    3 / 89 (3.37%)
    2 / 87 (2.30%)
         occurrences all number
    5
    3
    2
    Dyspepsia
         subjects affected / exposed
    3 / 89 (3.37%)
    4 / 89 (4.49%)
    3 / 87 (3.45%)
         occurrences all number
    3
    4
    3
    Abdominal distension
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 89 (3.37%)
    3 / 87 (3.45%)
         occurrences all number
    1
    4
    3
    Dry mouth
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 89 (1.12%)
    0 / 87 (0.00%)
         occurrences all number
    5
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 89 (0.00%)
    3 / 89 (3.37%)
    3 / 87 (3.45%)
         occurrences all number
    0
    3
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 89 (3.37%)
    0 / 87 (0.00%)
         occurrences all number
    1
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 89 (4.49%)
    2 / 89 (2.25%)
    4 / 87 (4.60%)
         occurrences all number
    4
    2
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 89 (3.37%)
    10 / 89 (11.24%)
    11 / 87 (12.64%)
         occurrences all number
    4
    11
    16
    Pruritus generalised
         subjects affected / exposed
    3 / 89 (3.37%)
    3 / 89 (3.37%)
    3 / 87 (3.45%)
         occurrences all number
    3
    3
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 89 (1.12%)
    4 / 89 (4.49%)
    0 / 87 (0.00%)
         occurrences all number
    1
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 89 (4.49%)
    5 / 87 (5.75%)
         occurrences all number
    5
    4
    5
    Back pain
         subjects affected / exposed
    2 / 89 (2.25%)
    4 / 89 (4.49%)
    3 / 87 (3.45%)
         occurrences all number
    2
    5
    3
    Muscle spasms
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 89 (3.37%)
    1 / 87 (1.15%)
         occurrences all number
    2
    3
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 89 (0.00%)
    3 / 89 (3.37%)
    0 / 87 (0.00%)
         occurrences all number
    0
    3
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 89 (6.74%)
    4 / 89 (4.49%)
    2 / 87 (2.30%)
         occurrences all number
    7
    4
    2
    Sinusitis
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 89 (1.12%)
    5 / 87 (5.75%)
         occurrences all number
    2
    1
    5
    Nasopharyngitis
         subjects affected / exposed
    3 / 89 (3.37%)
    2 / 89 (2.25%)
    2 / 87 (2.30%)
         occurrences all number
    3
    2
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 89 (2.25%)
    5 / 89 (5.62%)
    0 / 87 (0.00%)
         occurrences all number
    2
    5
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2018
    Protocol amendment (version 1.1) for sites outside of US •Clarified that an abdominal ultrasound was to be performed, and liver elastography was to be performed at selected sites. •Added the requirement that subjects perform a urine pregnancy test monthly (every 30±3 days) through the duration of treatment. •Clarified that platelet counts were to be measured by local laboratories, if deemed necessary by the investigator. •Cystatin C was added as an analyte.
    29 Nov 2018
    Protocol amendment (version 1.1ES) for Spain •Clarified that the subject population included only those subjects with an inadequate response to UDCA; subjects with UDCA intolerance were excluded. •Clarified that the assessment of TEAEs was based on CTCAE Version 5.0.
    18 Jan 2019
    Protocol amendment (version 1.1RU) for Russia •Changes were made to the protocol to address comments received by the Ministry of Health of the Russian Federation: An update on the CB8025-21629 study was provided, efficacy and safety data were updated with a July 2018 cut-off. •Clarified that Version 5.0 rather than Version 4.0 of the CTCAE was to be used for this study. •Included the window for obtaining the pre-dose liver elastography which could have been performed from the Run-in Visit (Week -2) to study drug dosing at Day 1.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    25 Nov 2019
    On 25 November 2019, as a precautionary measure until the NASH study (CB8025-21730) histology findings could be understood, Study CB8025-31735 was put on hold and subjects stopped treatment with study drug. At that time, the study was fully enrolled and subjects had a broad range of study drug treatment durations. Based on the receipt of information requests from the United States Food and Drug Administration (FDA) for the Phase 2 NASH study and the PBC studies, it was concluded that it would not be reasonable to maintain the PBC studies on hold given the time it would take to resolve the FDA requests. On 20 December 2019 the sites were informed of the ENHANCE study termination and requested to perform necessary safety evaluations on all active subjects.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    As a result of early termination of study while the study was still blinded the primary endpoint and key secondary endpoints were revised to be assessed at Month 3 instead of Month 12 based on the number of subjects who reached 3 months of treatment.
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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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