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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Active-Controlled, 24-Week Study to Evaluate the Efficacy and Safety of Daily Oral TAK-875 50 mg Compared With Sitagliptin 100 mg When Used in Combination With Metformin in Subjects With Type 2 Diabetes

    Summary
    EudraCT number
    		 2013-000542-19
    Trial protocol
    		 HU   HR  
    Global end of trial date
    05 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-875_310
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01834274
    WHO universal trial number (UTN)
    		 U1111-1139-0467
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    One Takeda Parkway, Deerfield, IL, United States, 60015
    Public contact
    Medical Director, Clinical Science, Takeda , +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Takeda , +1 877-825-3327, trialdisclosures@takeda.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
    23 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Mar 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of TAK-875 plus metformin compared with sitagliptin plus metformin on glycemic control as measured by change from Baseline in glycosylated hemoglobin (HbA1c) over a 24-week Treatment Period.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2013
    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: 1
    Country: Number of subjects enrolled
    United States: 95
    Worldwide total number of subjects
    96
    EEA total number of subjects
    0
    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)
    82
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 25 sites in the United States and 1 site in Canada from 18 May 2013 (first patient to sign informed consent) to 05 March 2014.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of Type 2 Diabetes Mellitis were enrolled equally in 1 of 2 treatment groups, once a day fasiglifam 50 mg or Sitagliptin 100 mg in combination with metformin.

    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, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fasiglifam 50 mg
    Arm description
    		 TAK-875 50 mg tablets, orally, once daily, sitagliptin placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum-tolerated dose), tablets, orally, daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fasiglifam
    Investigational medicinal product code
    Other name
    TAK-875
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fasiglifam 50 mg tablets, orally, once daily, Sitagliptin placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum-tolerated dose), tablets, orally, daily for up to 24 weeks.

    Investigational medicinal product name
    Sitagliptin placebo-matching tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin placebo-matching tablets, orally, once daily.

    Arm title
    		 Sitagliptin 100 mg
    Arm description
    		 Sitagliptin 100 mg, tablets, once daily, fasiglifam placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum tolerated dose), tablets, orally, daily for up to 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin 100 mg, tablets, once daily, fasiglifam placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum tolerated dose), tablets, orally, daily for up to 24 weeks.

    Investigational medicinal product name
    Fasiglifam placebo-matching tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fasiglifam placebo-matching tablets, orally, once daily.

    Number of subjects in period 1
    		Fasiglifam 50 mg Sitagliptin 100 mg
    Started
    50
    46
    Completed
    3
    5
    Not completed
    47
    41
         Study Termination
    41
    38
         Unknown
    2
    1
         Withdrawal by Subject
    1
    1
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    		 TAK-875 50 mg tablets, orally, once daily, sitagliptin placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum-tolerated dose), tablets, orally, daily for up to 24 weeks.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    		 Sitagliptin 100 mg, tablets, once daily, fasiglifam placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum tolerated dose), tablets, orally, daily for up to 24 weeks.

    Reporting group values
    		 Fasiglifam 50 mg Sitagliptin 100 mg Total
    Number of subjects
    		 50 46 96
    Age categorical
    Units: Subjects
        < 65 years
    		 41 41 82
        ≥ 65 years
    		 9 5 14
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.6 ( 7.14 ) 55.1 ( 9.07 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 20 44
        Male
    		 26 26 52
    Race
    Units: Subjects
        Asian
    		 2 1 3
        Black or African American
    		 6 6 12
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        White
    		 42 37 79
        Multiracial
    		 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 34 31 65
        Non-Hispanic or Latino
    		 15 15 30
        Not Available
    		 1 0 1
    Baseline BMI Category
    Units: Subjects
        < 30 kg/m^2
    		 31 11 42
        ≥ 30 kg/m^2
    		 19 35 54
    Baseline Glycosylated Hemoglobin (HbA)1c Category
    Units: Subjects
        < 9%
    		 27 28 55
        ≥ 9 %
    		 23 18 41
    Smoking Classification
    Units: Subjects
        Never smoked
    		 38 29 67
        Current smoker
    		 7 9 16
        Ex-smoker
    		 5 8 13
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 168.7 ( 11.45 ) 169.9 ( 10.79 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 87.5 ( 18.769 ) 96.09 ( 19.295 ) -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 30.77 ( 6.112 ) 33.13 ( 4.787 ) -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 10.075 ( 6.53 ) 8.877 ( 5.942 ) -

    End points

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    End points reporting groups
    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    		 TAK-875 50 mg tablets, orally, once daily, sitagliptin placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum-tolerated dose), tablets, orally, daily for up to 24 weeks.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    		 Sitagliptin 100 mg, tablets, once daily, fasiglifam placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum tolerated dose), tablets, orally, daily for up to 24 weeks.

    Primary: Change from Baseline in Glycosylated Hemoglobin (HbA1c)

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    End point title
    		 Change from Baseline in Glycosylated Hemoglobin (HbA1c) [1]
    End point description
    The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 24 or final visit relative to Baseline. A negative change from Baseline indicated improvement.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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: Statistics is not reported for this endpoint.
    End point values
    		 Fasiglifam 50 mg Sitagliptin 100 mg
    Number of subjects analysed
    4 [2]
    3 [3]
    Units: percent
        arithmetic mean (standard deviation)
    -0.63 ( 0.34 )
    -0.43 ( 0.208 )
    Notes
    [2] - All randomized participants with data available for analysis.
    [3] - All randomized participants with data available for analysis.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with HbA1c <7% at Week 24

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    End point title
    		 Percentage of Participants with HbA1c <7% at Week 24
    End point description
    The percentage of participants with glycosylated hemoglobin less than 9% after 24 weeks of treatment. No summary is provided for the secondary efficacy endpoint incidence of HbA1c <7% at Week 24 due to the limited enrollment and study duration at the time of study termination.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Fasiglifam 50 mg Sitagliptin 100 mg
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: percentage of participants
        number (not applicable)
    Notes
    [4] - Analysis not done.
    [5] - Analysis not done.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG)

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG)
    End point description
    The change between FPG collected at week 24 or final visit relative to baseline. A negative change from Baseline indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Fasiglifam 50 mg Sitagliptin 100 mg
    Number of subjects analysed
    4 [6]
    3 [7]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.22 ( 1.971 )
    1.54 ( 5.087 )
    Notes
    [6] - All randomized participants with data available for analysis.
    [7] - All randomized participants with data available for analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 183
    Adverse event reporting additional description
    Safety population included all randomized participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Fasigliflam 50 mg
    Reporting group description
    		 TAK-875 50 mg tablets, orally, once daily, Sitagliptin placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum-tolerated dose), tablets, orally, daily for up to 24 weeks.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    		 Sitagliptin 100 mg, tablets, once daily, TAK-875 placebo-matching tablets, orally, once daily, and metformin stable dose ≥1500 mg (or maximum tolerated dose), tablets, orally, daily for up to 24 weeks.

    Serious adverse events
    		 Fasigliflam 50 mg Sitagliptin 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Fasigliflam 50 mg Sitagliptin 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 46 (10.87%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Diarrhoea
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 46 (2.17%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2013
    Protocol updates for amendment 1: • Number of Sites increased from 95 to 105. • Nonclinical and clinical data in the introduction were updated from the Investgator’s brochure. • Study drug would be taken after fasting blood samples were collected. • Added withdrawal criteria applied to adverse events involving liver function results. • Dosing recommendations for the rescue medication glimepiride. • Guidance on missed doses. • Guidance on the screening and fasting process. • Electrocardiograms (ECGs) were to be done before administration of study drug. • Euro Quality of Life5D (EQ-5D) and Diabetes-Management and Impact Questionnaire (D-MIQ) were to be administered before other study procedures, that subjects were required to complete the surveys independently.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Dec 2013
    Termination-due to concerns about potential liver safety.
    -

    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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