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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo- and Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-875 25 mg and 50 mg Compared to Placebo and Sitagliptin 100 mg When Used in Combination with Metformin in Subjects with Type 2 Diabetes

    Summary
    EudraCT number
    2011-001752-10
    Trial protocol
    HU   CZ   SK   BG   IT  
    Global end of trial date
    27 Mar 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-875_302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01549964
    WHO universal trial number (UTN)
    U1111-1124-2225
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    One Takeda Parkway, Deerfield, 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
    12 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Mar 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy of 2 doses of TAK-875 (25 mg and 50 mg), once daily (QD), plus metformin compared to placebo plus metformin and sitagliptin plus metformin on lowering blood sugar.
    Protection of trial subjects
    All participants were required to read and sign and Informed Consent Form. Rescue medications were available for participants with hypoglycemia or hyperglycemia.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Apr 2012
    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
    Slovakia: 231
    Country: Number of subjects enrolled
    Bulgaria: 24
    Country: Number of subjects enrolled
    Czech Republic: 51
    Country: Number of subjects enrolled
    Hungary: 206
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Croatia: 24
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Malaysia: 25
    Country: Number of subjects enrolled
    Thailand: 48
    Country: Number of subjects enrolled
    United States: 268
    Worldwide total number of subjects
    916
    EEA total number of subjects
    545
    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)
    757
    From 65 to 84 years
    159
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 168 investigative sites in Australia, Bulgaria, Croatia, Czech Republic, Hungary, Italy, Korea, Republic, Malaysia, Slovakia, Thailand and the United States from 05 April 2012 to 27 March 2014.

    Pre-assignment
    Screening details
    Participants with a diagnosis of Type 2 Diabetes Mellitus were randomly enrolled in 1 of 4 treatment groups in a 1:2:2:2 ratio, once a day placebo, 100 mg sitagliptin, 25 mg fasiglifam or 50 mg fasiglifam in combination with metformin.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    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 for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Arm title
    Sitagliptin 100 mg
    Arm description
    Sitagliptin 100 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    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, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Arm title
    Fasiglifam 25 mg
    Arm description
    Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Fasiglifam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Arm title
    Fasiglifam 50 mg
    Arm description
    Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Fasiglifam 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Number of subjects in period 1
    Placebo Sitagliptin 100 mg Fasiglifam 25 mg Fasiglifam 50 mg
    Started
    132
    260
    263
    261
    Safety Analysis Set=Received Treatment
    132
    260
    263
    260
    Completed
    71
    149
    147
    140
    Not completed
    61
    111
    116
    121
         Study Terminated by Sponsor
    50
    104
    104
    105
         Voluntary Withdrawal
    6
    3
    3
    8
         Other
    1
    -
    1
    -
         Completion Status Unknown
    1
    -
    1
    -
         Metformin/Sitagliptin Contraindication
    -
    -
    1
    -
         Lack of efficacy
    1
    -
    1
    1
         Randomized but Not Treated
    -
    -
    -
    1
         Lost to follow-up
    1
    -
    1
    2
         Pretreatment Event/Adverse Event
    1
    4
    4
    4
    Period 2
    Period 2 title
    80-Week Extension Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    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 for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Arm title
    Sitagliptin 100 mg
    Arm description
    Sitagliptin 100 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    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, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Arm title
    Fasiglifam 25 mg
    Arm description
    Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Fasiglifam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Arm title
    Fasiglifam 50 mg
    Arm description
    Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Fasiglifam 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Number of subjects in period 2 [1]
    Placebo Sitagliptin 100 mg Fasiglifam 25 mg Fasiglifam 50 mg
    Started
    66
    138
    140
    137
    Completed
    0
    0
    0
    0
    Not completed
    66
    138
    140
    137
         Study Terminated by Sponsor
    65
    137
    132
    132
         Voluntary Withdrawal
    -
    1
    4
    2
         Pregnancy
    -
    -
    1
    -
         Pretreatment Event/Adverse Event
    -
    -
    1
    2
         Lost to follow-up
    1
    -
    2
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 507 subjects who completed the 24-week Treatment Period, 481 entered the optional 80-week Extension Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    Sitagliptin 100 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Fasiglifam 25 mg
    Reporting group description
    Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group values
    Placebo Sitagliptin 100 mg Fasiglifam 25 mg Fasiglifam 50 mg Total
    Number of subjects
    132 260 263 261 916
    Age categorical
    Units: Subjects
        < 65 years
    107 214 216 220 757
        ≥ 65 years
    25 46 47 41 159
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.6 ± 9.72 55.8 ± 9.84 56.3 ± 9.58 56 ± 9.37 -
    Gender categorical
    Units: Subjects
        Female
    66 103 127 126 422
        Male
    66 157 136 135 494
    Race/Ethnicity, Customized
    [1] Race data is available for 260 participants in the fasiglifam 50 mg treatment arm.
    Units: Subjects
        American Indian or Alaska Native
    0 0 2 3 5
        Asian
    12 30 28 26 96
        Black or African American
    8 13 19 12 52
        Native Hawaiian or Other Pacific Islander
    0 0 0 2 2
        White
    112 216 214 217 759
        Multiracial
    0 1 0 0 1
        Data Not Available
    0 0 0 1 1
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    13 29 28 28 98
        Non-Hispanic or Latino
    28 59 53 55 195
        Not Collected
    91 172 182 178 623
    Region of Enrollment
    Units: Subjects
        Australia
    3 5 5 5 18
        Bulgaria
    3 7 7 7 24
        Croatia
    4 6 8 6 24
        Czech Republic
    8 15 14 14 51
        Hungary
    29 56 61 60 206
        Italy
    1 3 3 2 9
        Korea, Republic of
    2 4 4 2 12
        Malaysia
    2 8 7 8 25
        Slovakia
    34 66 65 66 231
        Thailand
    7 14 13 14 48
        United States
    39 76 76 77 268
    BMI Category
    BMI data is available for 262 and 260 participants in the fasiglifam 25 mg and fasiglifam 50 mg treatment arms, respectively.
    Units: Subjects
        < 30 kg/m^2
    53 106 92 101 352
        ≥ 30 kg/m^2
    79 154 170 159 562
        Data Not Available
    0 0 1 1 2
    HbA1c Category
    HbA1c data is available for 260 participants in the fasiglifam 50 mg treatment arm.
    Units: Subjects
        < 8.5%
    80 156 154 148 538
        ≥ 8.5%
    52 104 109 112 377
        Data Not Available
    0 0 0 1 1
    Weight
    Weight data is available for 260 participants in the fasiglifam 50 mg treatment arm.
    Units: kg
        arithmetic mean (standard deviation)
    91.15 ± 18.988 91.41 ± 19.664 91.44 ± 17.859 91.53 ± 18.772 -
    Height
    Height data is available for 262 and 260 participants in the fasiglifam 25 mg and fasiglifam 50 mg treatment arms, respectively.
    Units: cm
        arithmetic mean (standard deviation)
    168.2 ± 10.08 169.4 ± 10.74 168.5 ± 10.53 168.4 ± 9.85 -
    Body Mss Index (BMI)
    BMI data is available for 262 and 260 participants in the fasiglifam 25 mg and fasiglifam 50 mg treatment arms, respectively.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    32.06 ± 5.07 31.68 ± 5.282 32.11 ± 5.126 32.16 ± 5.651 -
    Glycosylated Hemoglobin (HbA1c)
    HbA1c data is available for 258 and 260 participants in the sitagliptin 100 mg and fasiglifam 50 mg treatment arms, respectively.
    Units: percent
        arithmetic mean (standard deviation)
    8.34 ± 0.739 8.35 ± 0.694 8.41 ± 0.712 8.43 ± 0.765 -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    6.655 ± 6.262 5.94 ± 4.942 6.726 ± 4.615 6.375 ± 5.214 -
    Fasting Plasma Glucose
    Data is only available for 258 and 259 participants in the sitagliptin 100 mg and fasiglifam 50 mg treatment arms, respectively.
    Units: ng/dL
        arithmetic mean (standard deviation)
    178.4 ± 36.94 175.6 ± 37.67 179 ± 33.52 180 ± 37.98 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    Sitagliptin 100 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Fasiglifam 25 mg
    Reporting group description
    Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.
    Reporting group title
    Placebo
    Reporting group description
    Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    Sitagliptin 100 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Fasiglifam 25 mg
    Reporting group description
    Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Primary: Change From Baseline in Glycosylated Hemoglobin (HbA1c)

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    End point title
    Change From Baseline in Glycosylated Hemoglobin (HbA1c)
    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 relative to Baseline. A Mixed Model Repeated Measures (MMRM) model was used for analysis with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with Baseline value and Baseline value by visit interaction as covariates with an unstructured covariance structure.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Sitagliptin 100 mg Fasiglifam 25 mg Fasiglifam 50 mg
    Number of subjects analysed
    67
    145
    144
    138
    Units: percent
        least squares mean (standard error)
    -0.19 ± 0.098
    -1.07 ± 0.074
    -0.75 ± 0.073
    -1.01 ± 0.074
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Fasiglifam 25 mg
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.77
         upper limit
    -0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.108
    Notes
    [1] - MMRM model with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates with an unstructured covariance structure.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Sitagliptin 100 mg v Fasiglifam 25 mg
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [2]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.15
         upper limit
    0.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.087
    Notes
    [2] - MMRM model with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates with an unstructured covariance structure.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v Fasiglifam 50 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [3]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.03
         upper limit
    -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.109
    Notes
    [3] - MMRM model with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates with an unstructured covariance structure.
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Sitagliptin 100 mg v Fasiglifam 50 mg
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.524 [4]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.087
    Notes
    [4] - MMRM model with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates with an unstructured covariance structure.

    Secondary: Incidence of HbA1c <7%

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    End point title
    Incidence of HbA1c <7%
    End point description
    Incidence (percentage) of participants with glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than 7% at Week 24.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    Placebo Sitagliptin 100 mg Fasiglifam 25 mg Fasiglifam 50 mg
    Number of subjects analysed
    67
    145
    144
    138
    Units: percentage of participants
        number (not applicable)
    14.9
    42.8
    24.3
    37
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Fasiglifam 25 mg
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05 [5]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    5.08
    Notes
    [5] - P-Value was obtained from a logistic model with treatment, schedule, baseline HbA1c as explanatory variables.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Sitagliptin 100 mg v Fasiglifam 25 mg
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.67
    Notes
    [6] - P-Value was obtained from a logistic model with treatment, schedule, baseline HbA1c as explanatory variables.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v Fasiglifam 50 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [7]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    5.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.24
         upper limit
    11.42
    Notes
    [7] - P-Value was obtained from a logistic model with treatment, schedule, baseline HbA1c as explanatory variables.
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Sitagliptin 100 mg v Fasiglifam 50 mg
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.493 [8]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    1.39
    Notes
    [8] - P-Value was obtained from a logistic model with treatment, schedule, baseline HbA1c as explanatory variables.

    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 relative to Baseline. A MMRM model was used for analysis with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with Baseline value and Baseline value by visit interaction as covariates with an unstructured covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Sitagliptin 100 mg Fasiglifam 25 mg Fasiglifam 50 mg
    Number of subjects analysed
    67
    145
    142
    135
    Units: mg/dL
        least squares mean (standard error)
    -1.6 ± 4.07
    -21.7 ± 3.13
    -26.9 ± 3.13
    -32.9 ± 3.18
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Fasiglifam 25 mg
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [9]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -25.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.8
         upper limit
    -16.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.36
    Notes
    [9] - MMRM model with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates with an unstructured covariance structure.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Sitagliptin 100 mg v Fasiglifam 25 mg
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.142 [10]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12
         upper limit
    1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.49
    Notes
    [10] - MMRM model with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates with an unstructured covariance structure.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v Fasiglifam 50 mg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [11]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -31.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.9
         upper limit
    -22.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.4
    Notes
    [11] - MMRM model with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates with an unstructured covariance structure.
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Sitagliptin 100 mg v Fasiglifam 50 mg
    Number of subjects included in analysis
    280
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [12]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -11.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.1
         upper limit
    -4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.53
    Notes
    [12] - MMRM model with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates with an unstructured covariance structure.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study medication to 30 day past last dose of study medication (Up to 637 days)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    Sitagliptin 100 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Fasiglifam placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Fasiglifam 25 mg
    Reporting group description
    Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.

    Serious adverse events
    Placebo Sitagliptin 100 mg Fasiglifam 25 mg Fasiglifam 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 132 (1.52%)
    10 / 260 (3.85%)
    14 / 263 (5.32%)
    4 / 260 (1.54%)
         number of deaths (all causes)
    1
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    0 / 263 (0.00%)
    1 / 260 (0.38%)
         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
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    0 / 263 (0.00%)
    1 / 260 (0.38%)
         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
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer female
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
    0 / 263 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Tumour of ampulla of Vater
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Carotid bruit
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Liver function test abnormal
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Cardiac failure
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 260 (0.00%)
    0 / 263 (0.00%)
    0 / 260 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    0 / 263 (0.00%)
    1 / 260 (0.38%)
         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
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Cholecystitis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 260 (0.38%)
    0 / 263 (0.00%)
    0 / 260 (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
    Pneumonia
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 260 (0.00%)
    0 / 263 (0.00%)
    1 / 260 (0.38%)
         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
    Sepsis
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 260 (0.77%)
    0 / 263 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Sitagliptin 100 mg Fasiglifam 25 mg Fasiglifam 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 132 (12.88%)
    16 / 260 (6.15%)
    18 / 263 (6.84%)
    20 / 260 (7.69%)
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    14 / 132 (10.61%)
    9 / 260 (3.46%)
    11 / 263 (4.18%)
    7 / 260 (2.69%)
         occurrences all number
    16
    11
    11
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 132 (2.27%)
    8 / 260 (3.08%)
    7 / 263 (2.66%)
    14 / 260 (5.38%)
         occurrences all number
    3
    11
    8
    15

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2012
    • Clarification that 80-week Extension Period was optional • lower limit for BMI changed • exclusion of participants with a history of pancreatitis • telephone follow-up call added for participants who prematurely discontinued • male subjects were not required to use contraception • exclusion of participants with uncontrolled thyroid disease • insulin could be used as rescue medication during the study • hypoglycemic rescue medication complied with local guidelines and clinical practices • clarification of management of hypoglycemic events.
    08 Apr 2013
    • Duration of previous stable metformin use that was required before Screening (ie, 8 weeks) • exclusion if laboratory or ECG abnormalities detected at Screening were clinically significant • clarification of the definition of probable symptomatic hypoglycemia • timing of in-clinic study drug administration and provided guidance on missed doses • glimepiride rescue medication dosing recommendations • clearer guidance on the screening and fasting process.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Dec 2013
    Termination of the compound development program by the sponsor.
    -

    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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