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    Clinical Trial Results:
    A 12-week, double-blind, randomized, placebo-controlled, Phase 2 study to evaluate the effects of two doses of MBX-8025 in subjects with Primary Biliary Cirrhosis (PBC) and an inadequate response to ursodeoxycholic acid (UDCA).

    Summary
    EudraCT number
    		 2015-002698-39
    Trial protocol
    		 GB   DE   PL  
    Global end of trial date
    01 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jul 2017
    First version publication date
    26 Jul 2017
    Other versions
    Summary report(s)
    		 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    CB8025-21528
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02609048
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CymaBay Therapeutics, Inc.
    Sponsor organisation address
    7999 Gateway Blvd, Suite 130, Newark, United States, CA94560
    Public contact
    Karen Benson, CymaBay Therapeutics, Inc. , Kbenson@cymabay.com
    Scientific contact
    Pol Boudes, CymaBay Therapeutics, Inc. , Pboudes@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 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the effect of seladelpar on alkaline phosphatase (AP) levels.
    Protection of trial subjects
    Participation in the study is voluntary. Subjects can refuse to participate or stop at any time without stating a reason. Withdrawal will not affect access to other medical care to which the subject would otherwise be entitled.
    Background therapy
    		 Ursodeoxycholic acid (UDCA) was continued to be taken by subjects in all treatment arms at the same dose during the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Nov 2015
    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: 4
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Germany: 8
    Worldwide total number of subjects
    41
    EEA total number of subjects
    17
    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)
    35
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrollment period began in November 2015. On 26-May-16, the sponsor decided to terminate the study for safety and efficacy reasons.

    Pre-assignment
    Screening details
    		 Subjects are male or female with diagnosed PBC by at least two of the following criteria: History of AP above ULN for at least 6 months; Positive AMA titers or positive PBC-specific antinuclear antibodies; documented liver biopsy result consistent with PBC. Subjects are on a stable and recommended dose of UDCA for 12 months and have AP ≥ 1.67 ×ULN.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline / seladelpar 50 mg
    Arm description
    		 4 weeks Baseline Period / seladelpar 50 mg
    Arm type
    		 Baseline evaluations

    Investigational medicinal product name
    Seladelpar 50 mg
    Investigational medicinal product code
    MBX-8025 50 mg
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Not applicable

    Arm title
    		 Baseline / seladelpar 200 mg
    Arm description
    		 4 weeks Baseline Period / seladelpar 200 mg
    Arm type
    		 Baseline evaluations

    Investigational medicinal product name
    Seladelpar 200 mg
    Investigational medicinal product code
    MBX-8025 200 mg
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Not applicable

    Arm title
    		 Baseline / placebo
    Arm description
    		 4 weeks Baseline Period / placebo
    Arm type
    		 Baseline evaluations

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Not applicable

    Number of subjects in period 1
    		Baseline / seladelpar 50 mg Baseline / seladelpar 200 mg Baseline / placebo
    Started
    14
    13
    14
    Completed
    13
    12
    13
    Not completed
    1
    1
    1
         Adverse event, non-fatal
    -
    1
    -
         Administrative decision by investigator/sponsor
    1
    -
    1
    Period 2
    Period 2 title
    Double blind treatment and follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 50 mg
    Arm description
    		 12-weeks treatment period with seladelpar 50 mg daily, followed by 2 week follow-up period
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seladelpar 50 mg
    Investigational medicinal product code
    MBX-8025 50 mg
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Seladelpar 50 mg taken orally once a day

    Arm title
    		 200 mg
    Arm description
    		 12-weeks treatment period with seladelpar 200 mg daily, followed by 2 week follow-up period
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seladelpar 200 mg
    Investigational medicinal product code
    MBX-8025 200 mg
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Seladelpar 200 mg taken orally once a day

    Arm title
    		 placebo
    Arm description
    		 12-weeks treatment period with placebo daily, followed by 2 week follow-up period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo taken orally once a day

    Number of subjects in period 2
    		50 mg 200 mg placebo
    Started
    13
    12
    13
    Completed
    4
    2
    4
    Not completed
    9
    10
    9
         Consent withdrawn by subject
    -
    1
    -
         Adverse event, non-fatal
    -
    3
    -
         Early termination of the study
    9
    6
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    		 -

    Reporting group values
    		 Baseline period Total
    Number of subjects
    		 41 41
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 35 35
        From 65-84 years
    		 6 6
    Gender categorical
    Units: Subjects
        Female
    		 39 39
        Male
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    Baseline / seladelpar 50 mg
    Reporting group description
    		 4 weeks Baseline Period / seladelpar 50 mg

    Reporting group title
    Baseline / seladelpar 200 mg
    Reporting group description
    		 4 weeks Baseline Period / seladelpar 200 mg

    Reporting group title
    Baseline / placebo
    Reporting group description
    		 4 weeks Baseline Period / placebo
    Reporting group title
    50 mg
    Reporting group description
    		 12-weeks treatment period with seladelpar 50 mg daily, followed by 2 week follow-up period

    Reporting group title
    200 mg
    Reporting group description
    		 12-weeks treatment period with seladelpar 200 mg daily, followed by 2 week follow-up period

    Reporting group title
    placebo
    Reporting group description
    		 12-weeks treatment period with placebo daily, followed by 2 week follow-up period

    Primary: To evaluate the effect of seladelpar on AP levels

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    End point title
    		 To evaluate the effect of seladelpar on AP levels
    End point description
    End point type
    Primary
    End point timeframe
    End of treatment - Week 12
    End point values
    		 50 mg 200 mg placebo
    Number of subjects analysed
    13
    10
    12
    Units: LS mean percentage change from Baseline
        number (not applicable)
    -53.21
    -62.83
    -1.84
    Statistical analysis title
    		 effect of seladelpar on AP levels
    Statistical analysis description
    ANCOVA model
    Comparison groups
    placebo v 50 mg v 200 mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - LS mean difference 50 mg vs. placebo: P < 0.0001. LS mean difference 200 mg vs. placebo: P < 0.0001. LS mean difference 50 mg vs. 200 mg: P = 0.1167.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    An AE will be recorded any time after the time of signed ICF and captured until the end-of-study visit.
    Adverse event reporting additional description
    Please see attached synopsis
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Justification: Please see attached synopsis

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2015
    The protocol was amended on 4 September 2015 to create Version 3.0. The main changes to the protocol were as follows: - Tightened the requirements for contraceptive use during the study, including requiring the use of contraception for 90 days after the last dose of study medication because the effect of MBX‑8025 on pregnant women and fetuses has not been characterized. - Introduced stratification by geographic region in the efficacy analyses.
    12 Oct 2015
    The protocol was amended on 12 October 2015 to create Version 4.0. The main changes to the protocol were as follows: - Reporting of the severity of AEs was updated to reflect the use of NCI CTCAE Version 4. - Serum creatinine above the ULN was added to the study exclusion criteria because the target population for this study is early-stage PBC subjects. In early stages of PBC, patients have normal serum creatinine levels. - The current use of fibrates, including fenofibrates or simvastatin was added to the study exclusion criteria because of their potential to confound the primary efficacy analysis. - ECGs were moved to be performed 60-90 minutes after dosing to coincide with the time of the maximum plasma MBX-8025 concentration. Changes specific to the UK were made to Protocol Version 4.0 on 22 October 2015 to create Version 4.1 per the request of regulatory authorities. The main UK-specific changes to the protocol were as follows: - Added serum pregnancy tests for women of childbearing potential during the baseline period (within 2 weeks of Visit 2) and at each visit during the double-blind treatment period. - Specified that female subjects who became pregnant during the study were to be discontinued from the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 May 2016
    On 23 May 2016, a total of 3 subjects had experienced Grade 3 alanine aminotransferase (ALT) elevations. The study drug was unblinded for these cases and all 3 subjects were receiving seladelpar(1 receiving 50 mg and 2 receiving 200 mg). At the same time, based on concomitant decreases in GGT and 5’nucleotidase observed in the study overall (AP values were blinded during study), the proof-of-concept efficacy was demonstrated. As such, the Sponsor determined that there was no justification for continuing to expose subjects to seladelpar, and stopped and unblinded the study. An ad hoc DSMB meeting was held on 26-May-2016, at which the Sponsor informed the DSMB that the study had been stopped. On 27-May-2016, all active subjects were instructed to continue treatment with study medication until their next planned study visit. The last dose of study drug would be the day prior to this visit, and this visit was considered the end of treatment visit. Subjects were then to proceed, as planned in the original protocol, to a follow-up (off treatment) end of study visit, 2 weeks later.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Because the study was discontinued before its completion, the interpretation of the results is limited by the small sample size and some imbalance in baseline characteristics.
    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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