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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, and Efficacy of the Addition of MK-3102 to Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin Therapy

    Summary
    EudraCT number
    		 2012-003670-11
    Trial protocol
    		 HU   SK   ES   BG   PL   RO  
    Global end of trial date
    16 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2017
    First version publication date
    23 Feb 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-3102-024
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01755156
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    16 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the safety and efficacy of omarigliptin compared to placebo in participants with inadequate glycemic control on metformin monotherapy. The primary hypothesis is that after 24 weeks, the addition of treatment with omarigliptin provides greater reduction in hemoglobin A1c (A1C) than placebo.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measure defined for this individual study was in place for the protection of trial subjects: Rescue therapy (open-label glimepiride during Phase A or insulin glargine during Phase B) was initiated in participants who did not meet pre-specified glycemic goals after Day 1.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jan 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
    Bulgaria: 29
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Romania: 48
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Slovakia: 56
    Country: Number of subjects enrolled
    South Africa: 34
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United States: 149
    Worldwide total number of subjects
    402
    EEA total number of subjects
    189
    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)
    325
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Eligible participants had type 2 diabetes mellitus and were on a stable dose of metformin monotherapy (>=1500 mg per day) for at least 12 weeks prior to study participation.

    Pre-assignment
    Screening details
    		 All eligible participants were randomly allocated to trial treatment and received a randomization number.

    Period 1
    Period 1 title
    Phase A (Weeks 0-24)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B)
    Arm description
    		 Phase A: Omarigliptin 25 mg capsule administered orally once weekly for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omarigliptin
    Investigational medicinal product code
    Other name
    MK-3102
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Omarigliptin 25 mg capsule administered orally once weekly (preferably on the same day of each week).

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Amaryl®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Phase A rescue therapy: open-label glimepiride 1 or 2 mg tablet/capsule administered orally once daily and uptitrated to a maximum dose of 6 mg daily.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Fortamet® Glucophage® Glucophage® XR Glumetza® Riomet® Metgluco® Glycoran®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants continue stable pre-study dose of metformin tablet(s) administered orally (>= 1500 mg daily) throughout the study.

    Arm title
    		 Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Arm description
    		 Phase A: matching placebo to omarigliptin orally once a week for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo to omarigliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to omarigliptin capsule administered orally once weekly (preferably on the same day of each week).

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Amaryl®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Phase A rescue therapy: open-label glimepiride 1 or 2 mg tablet/capsule administered orally once daily and up-titrated to a maximum dose of 6 mg daily.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Fortamet® Glucophage® Glucophage® XR Glumetza® Riomet® Metgluco® Glycoran®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants continue stable pre-study dose of metformin tablet(s) administered orally (>= 1500 mg daily) throughout the study.

    Number of subjects in period 1
    		Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Started
    201
    201
    Completed
    184
    177
    Not completed
    17
    24
         Consent withdrawn by subject
    6
    13
         Physician decision
    -
    1
         Creatinine or eGFR Discontinuation Criteria
    -
    2
         Adverse event, non-fatal
    2
    3
         Non-compliance with study drug
    1
    -
         Lost to follow-up
    5
    3
         Need for Excluded Med. Discontinuation Criteria
    1
    1
         Lack of efficacy
    1
    -
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    Phase B (Weeks 24-104)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B)
    Arm description
    		 Phase B: Omarigliptin 25 mg capsule administered orally once weekly and matching placebo to glimepiride tablet/capsule administered orally once daily for 80 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omarigliptin
    Investigational medicinal product code
    Other name
    MK-3102
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Omarigliptin 25 mg capsule administered orally once weekly (preferably on the same day of each week).

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Fortamet® Glucophage® Glucophage® XR Glumetza® Riomet® Metgluco® Glycoran®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants continue stable pre-study dose of metformin tablet(s) administered orally (>= 1500 mg daily) throughout the study.

    Investigational medicinal product name
    Matching placebo to glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to glimepiride tablet/capsule administered orally once daily and up-titrated to a mock maximum dose of 6 mg daily. Participants rescued with open-label glimepiride during Phase A will not receive glimepiride or matching placebo to glimepiride during Phase B.

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Lantus®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During Phase B of the study, participants who received a maximum up-titration of open-label glimepiride or blinded glimepiride/matching placebo to glimepiride, may be rescued with open-label insulin glargine.

    Arm title
    		 Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Arm description
    		 Phase B: Matching placebo to omarigliptin capsule administered orally once weekly and glimepiride 1 or 2 mg tablet/capsule administered orally once daily (titrated up to 6 mg daily) for 80 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Matching placebo to omarigliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to omarigliptin capsule administered orally once weekly (preferably on the same day of each week).

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Amaryl®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride 1 or 2 mg tablet/capsule administered orally once daily and up-titrated to a maximum dose of 6 mg daily.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Fortamet® Glucophage® Glucophage® XR Glumetza® Riomet® Metgluco® Glycoran®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants continue stable pre-study dose of metformin tablet(s) administered orally (>= 1500 mg daily) throughout the study.

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Lantus®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During Phase B of the study, participants who received a maximum up-titration of open-label glimepiride or blinded glimepiride/matching placebo to glimepiride, may be rescued with open-label insulin glargine.

    Number of subjects in period 2 [1]
    		Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Started
    183
    177
    Completed
    144
    141
    Not completed
    39
    36
         Consent withdrawn by subject
    27
    31
         Lost to follow-up
    12
    5
    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: One omarigliptin participant completed Phase A but did not continue to Phase B.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Omarigliptin (Phase A) → Omarigliptin (Phase B)
    Reporting group description
    		 Phase A: Omarigliptin 25 mg capsule administered orally once weekly for 24 weeks.

    Reporting group title
    Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Reporting group description
    		 Phase A: matching placebo to omarigliptin orally once a week for 24 weeks.

    Reporting group values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B) Total
    Number of subjects
    		 201 201
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 57.5 ( 8.1 ) 56.8 ( 9.1 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 100 99 199
        Male
    		 101 102 203
    Study Specific Characteristic | Hemoglobin A1C (A1C)
    Units: Percent
        arithmetic mean (standard deviation)
    		 8.06 ( 0.87 ) 8.02 ( 0.89 ) -
    Study Specific Characteristic | 2-hour post-meal glucose (2-hr PMG)
    Omarigliptin (Phase A), n=192; Placebo to omarigliptin (Phase A), n=193; Total, n=385
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 240.2 ( 60.5 ) 236 ( 59.9 ) -
    Study Specific Characteristic | Fasting plasma glucose (FPG)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 168.8 ( 37.6 ) 168.6 ( 37.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Omarigliptin (Phase A) → Omarigliptin (Phase B)
    Reporting group description
    		 Phase A: Omarigliptin 25 mg capsule administered orally once weekly for 24 weeks.

    Reporting group title
    Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Reporting group description
    		 Phase A: matching placebo to omarigliptin orally once a week for 24 weeks.
    Reporting group title
    Omarigliptin (Phase A) → Omarigliptin (Phase B)
    Reporting group description
    		 Phase B: Omarigliptin 25 mg capsule administered orally once weekly and matching placebo to glimepiride tablet/capsule administered orally once daily for 80 weeks.

    Reporting group title
    Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Reporting group description
    		 Phase B: Matching placebo to omarigliptin capsule administered orally once weekly and glimepiride 1 or 2 mg tablet/capsule administered orally once daily (titrated up to 6 mg daily) for 80 weeks.

    Subject analysis set title
    Omarigliptin (Phase A)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase A: Omarigliptin 25 mg capsule orally once a week for 24 weeks.

    Subject analysis set title
    Placebo to omarigliptin (Phase A)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase A: Matching placebo to omarigliptin capsule administered orally once weekly for 24 weeks

    Subject analysis set title
    Omarigliptin (Phase A) → Omarigliptin (Phase B)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase A: Omarigliptin 25 mg capsule administered orally once weekly for 24 weeks. Phase B: Omarigliptin 25 mg capsule administered orally once weekly and matching placebo to glimepiride tablet/capsule administered orally once daily for 80 weeks.

    Subject analysis set title
    Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase A: matching placebo to omarigliptin orally once a week for 24 weeks. Phase B: Matching placebo to omarigliptin capsule administered orally once weekly and glimepiride 1 or 2 mg tablet/capsule administered orally once daily (titrated up to 6 mg daily) for 80 weeks.

    Primary: Change from baseline in glycosylated hemoglobin (A1C) at Week 24 (Phase A)

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    End point title
    		 Change from baseline in glycosylated hemoglobin (A1C) at Week 24 (Phase A)
    End point description
    A1C is measured as a percent. Change from baseline in A1C at Week 24 was analyzed using constrained longitudinal data analysis (cLDA) method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    201
    201
    Units: Percent
        least squares mean (confidence interval 95%)
    -0.54 (-0.69 to -0.4)
    0 (-0.14 to 0.15)
    Statistical analysis title
    		 Pairwise comparison
    Comparison groups
    Omarigliptin (Phase A) v Placebo to omarigliptin (Phase A)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 cLDA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.75
         upper limit
    		 -0.34
    Notes
    [1] - Based on a cLDA method with a restriction of the same baseline mean.

    Primary: Percentage of participants who experienced at least one adverse event (Phase A+B)

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    End point title
    		 Percentage of participants who experienced at least one adverse event (Phase A+B)
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Presented data exclude data after glycemic rescue. All participants as treated population included all participants who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to 107 weeks
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (not applicable)
    65.7
    65.2
    Statistical analysis title
    		 Comparison between reporting groups
    Statistical analysis description
    Based on Miettinen & Nurminen method. The 95% CI was computed only for those endpoints with at least 4 participants having events in 1 or more treatment groups
    Comparison groups
    Omarigliptin (Phase A) → Omarigliptin (Phase B) v Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 9.8

    Primary: Percentage of participants who discontinued study drug due to an adverse event (Phase A+B)

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    End point title
    		 Percentage of participants who discontinued study drug due to an adverse event (Phase A+B)
    End point description
    An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Presented data exclude data after glycemic rescue. All participants as treated population included all participants who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to 104 weeks
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (not applicable)
    2
    4.5
    Statistical analysis title
    		 Comparison between reporting groups
    Statistical analysis description
    Based on Miettinen & Nurminen method. The 95% CI was computed only for those endpoints with at least 4 participants having events in 1 or more treatment groups.
    Comparison groups
    Omarigliptin (Phase A) → Omarigliptin (Phase B) v Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 1.1

    Primary: Percentage of participants who experienced an adverse event which were included under the System Order Class of Investigations (Phase A+B)

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    End point title
    		 Percentage of participants who experienced an adverse event which were included under the System Order Class of Investigations (Phase A+B)
    End point description
    The following laboratory parameters were included: blood chemistry, hematology, electrocardiograms, lipids, body weight, and vital signs. All participants as treated population included all participants who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to 104 weeks
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (not applicable)
    21.9
    17.4
    Statistical analysis title
    		 Comparison between reporting groups
    Statistical analysis description
    Based on Miettinen & Nurminen method. The 95% CI was computed only for those endpoints with at least 4 participants having events in 1 or more treatment groups
    Comparison groups
    Omarigliptin (Phase A) → Omarigliptin (Phase B) v Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 12.3

    Secondary: Change from baseline in 2-hour post-meal glucose (PMG) at Week 24 (Phase A)

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    End point title
    		 Change from baseline in 2-hour post-meal glucose (PMG) at Week 24 (Phase A)
    End point description
    Change from baseline in 2-hour PMG at Week 24 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    195
    199
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -26.8 (-34.8 to -18.7)
    -12.2 (-20.7 to -3.8)
    Statistical analysis title
    		 Pairwise comparison
    Comparison groups
    Omarigliptin (Phase A) v Placebo to omarigliptin (Phase A)
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [2]
    Method
    		 cLDA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -14.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.6
         upper limit
    		 -3.4
    Notes
    [2] - Based on a cLDA method with a restriction of the same baseline mean.

    Secondary: Change from baseline in fasting plasma glucose (FPG) at Week 24 (Phase A)

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    End point title
    		 Change from baseline in fasting plasma glucose (FPG) at Week 24 (Phase A)
    End point description
    Change from baseline in FPG at Week 24 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    201
    201
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -10.7 (-16 to -5.5)
    -1.2 (-6.6 to 4.1)
    Statistical analysis title
    		 Pairwise comparison
    Comparison groups
    Omarigliptin (Phase A) v Placebo to omarigliptin (Phase A)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [3]
    Method
    		 cLDA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -9.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.7
         upper limit
    		 -2.3
    Notes
    [3] - Based on a cLDA method with a restriction of the same baseline mean.

    Secondary: Change from baseline in A1C at Week 104 (Phase A+B)

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    End point title
    		 Change from baseline in A1C at Week 104 (Phase A+B)
    End point description
    A1C is measured as a percent. Change from baseline in A1C at Week 104 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: Percent
        least squares mean (confidence interval 95%)
    -0.42 (-0.59 to -0.25)
    -0.51 (-0.68 to -0.34)
    No statistical analyses for this end point

    Secondary: Change from baseline in FPG at Week 104 (Phase A+B)

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    End point title
    		 Change from baseline in FPG at Week 104 (Phase A+B)
    End point description
    Change from baseline in FPG at Week 104 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -7.8 (-14.4 to -1.3)
    -18.2 (-24.7 to -11.7)
    No statistical analyses for this end point

    Secondary: Percentage of participants attaining A1C glycemic goals of <7.0% after 24 weeks of treatment (Phase A)

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    End point title
    		 Percentage of participants attaining A1C glycemic goals of <7.0% after 24 weeks of treatment (Phase A)
    End point description
    Percentage of participants attaining A1C glycemic goals of <7.0% (53 mmol/mol) after 24 weeks of treatment estimated using standard multiple imputation techniques. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (confidence interval 95%)
    38 (31.3 to 45.1)
    18.8 (13.9 to 25)
    Statistical analysis title
    		 Pairwise comparison
    Comparison groups
    Omarigliptin (Phase A) v Placebo to omarigliptin (Phase A)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Between-group rate difference (%)
    Point estimate
    19.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.1
         upper limit
    		 28

    Secondary: Percentage of participants attaining A1C glycemic goals of <6.5% after 24 weeks of treatment (Phase A)

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    End point title
    		 Percentage of participants attaining A1C glycemic goals of <6.5% after 24 weeks of treatment (Phase A)
    End point description
    Percentage of participants attaining A1C glycemic goals of <6.5% (48 mmol/mol) after 24 weeks of treatment estimated using standard multiple imputation techniques. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (confidence interval 95%)
    10.6 (6.8 to 16.2)
    6.4 (3.6 to 11.2)
    Statistical analysis title
    		 Parirwise comparison
    Comparison groups
    Omarigliptin (Phase A) v Placebo to omarigliptin (Phase A)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.164
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Between-group rate difference (%)
    Point estimate
    4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 10.5

    Secondary: Percentage of participants attaining A1C glycemic goals of <7% after 104 weeks of treatment (Phase A+B)

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    End point title
    		 Percentage of participants attaining A1C glycemic goals of <7% after 104 weeks of treatment (Phase A+B)
    End point description
    Percentage of participants attaining A1C glycemic goals of <7.0% (53 mmol/mol) after 104 weeks of treatment estimated using standard multiple imputation techniques. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        least squares mean (confidence interval 95%)
    32.2 (25.7 to 39.5)
    39 (31.7 to 46.8)
    No statistical analyses for this end point

    Secondary: Percentage of participants attaining A1C glycemic goals of <6.5% after 104 weeks of treatment (Phase A+B)

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    End point title
    		 Percentage of participants attaining A1C glycemic goals of <6.5% after 104 weeks of treatment (Phase A+B)
    End point description
    Percentage of participants attaining A1C glycemic goals of <6.5% (48 mmol/mol) after 104 weeks of treatment estimated using standard multiple imputation techniques. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    104 weeks
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        least squares mean (confidence interval 95%)
    13.7 (9.4 to 19.6)
    17.9 (12.5 to 24.8)
    No statistical analyses for this end point

    Secondary: Change from baseline in PMG total area under the plasma concentration time curve (AUC) at Week 24 (Phase A)

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    End point title
    		 Change from baseline in PMG total area under the plasma concentration time curve (AUC) at Week 24 (Phase A)
    End point description
    Change from baseline in PMG total AUC at Week 24 based on a cLDA model including terms for treatment, time, and the interaction of time by treatment. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    195
    198
    Units: mg*h/dL
        least squares mean (confidence interval 95%)
    -46.4 (-58.7 to -34.1)
    -18.6 (-31.5 to -5.7)
    Statistical analysis title
    		 Pairwise comparison
    Comparison groups
    Omarigliptin (Phase A) v Placebo to omarigliptin (Phase A)
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001 [4]
    Method
    		 cLDA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -27.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.8
         upper limit
    		 -10.8
    Notes
    [4] - Based on a cLDA method with a restriction of the same baseline mean.

    Secondary: Change from baseline in fasting insulin at Week 24 (Phase A)

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    End point title
    		 Change from baseline in fasting insulin at Week 24 (Phase A)
    End point description
    Change from baseline in fasting insulin at Week 24 based on a cLDA model including terms for treatment, time, and the interaction of time by treatment. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    200
    200
    Units: micro International Unit (μIU)/mL
        least squares mean (confidence interval 95%)
    1.8 (-0.6 to 4.2)
    -1.9 (-4.3 to 0.5)
    Statistical analysis title
    		 Pairwise comparison
    Comparison groups
    Omarigliptin (Phase A) v Placebo to omarigliptin (Phase A)
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.025 [5]
    Method
    		 cLDA
    Parameter type
    		 Difference in least squares means
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 6.9
    Notes
    [5] - Based on a cLDA method with a restriction of the same baseline mean.

    Secondary: Change from baseline in fasting insulin at Week 104 (Phase A+B)

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    End point title
    		 Change from baseline in fasting insulin at Week 104 (Phase A+B)
    End point description
    Change from baseline in fasting insulin at Week 104 based on a cLDA model including terms for treatment, time, and the interaction of time by treatment. Full analysis set population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    200
    Units: μIU/mL
        least squares mean (confidence interval 95%)
    1.2 (-1.9 to 4.2)
    1.8 (-1.2 to 4.8)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier estimate of cumulative incidence of participants requiring glycemic rescue therapy by 24 weeks (Phase A)

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    End point title
    		 Kaplan-Meier estimate of cumulative incidence of participants requiring glycemic rescue therapy by 24 weeks (Phase A)
    End point description
    Participants who did not meet progressively stricter glycemic criteria in Phase A had rescue initiated with open-label glimepiride. All participants randomized population.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (confidence interval 95%)
    8.5 (5.3 to 13.6)
    9.7 (6.2 to 15)
    Statistical analysis title
    		 Pairwise comparison
    Comparison groups
    Omarigliptin (Phase A) v Placebo to omarigliptin (Phase A)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.654
    Method
    		 Logrank
    Parameter type
    		 Kaplan-Meier difference %
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 4.7

    Secondary: Kaplan-Meier estimate of cumulative incidence of participants requiring glycemic rescue therapy by 104 weeks (Phase A+B)

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    End point title
    		 Kaplan-Meier estimate of cumulative incidence of participants requiring glycemic rescue therapy by 104 weeks (Phase A+B)
    End point description
    Participants who did not meet progressively stricter glycemic criteria in Phase A had rescue initiated with open-label glimepiride. If during Phase B participants on open-label glimepiride or blinded glimepiride/glimepiride matching placebo needed rescue after maximum up-titration, then insulin glargine was initiated and the dose of open-label glimepiride or blinded glimepiride/glimepiride-matching placebo was discontinued. All participants randomized population.
    End point type
    Secondary
    End point timeframe
    Up to 104 weeks
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (confidence interval 95%)
    20.2 (14.9 to 27.1)
    16.2 (11.5 to 22.7)
    No statistical analyses for this end point

    Secondary: Percentage of participants requiring glycemic rescue therapy at or before Week 24 (Phase A)

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    End point title
    		 Percentage of participants requiring glycemic rescue therapy at or before Week 24 (Phase A)
    End point description
    Data presented are a cumulative incidence of participants with glycemic rescue by Week 24. All participants randomized population.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (not applicable)
    8
    9
    No statistical analyses for this end point

    Secondary: Percentage of participants requiring glycemic rescue therapy at or before Week 104 (Phase A+B)

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    End point title
    		 Percentage of participants requiring glycemic rescue therapy at or before Week 104 (Phase A+B)
    End point description
    Data presented are a cumulative incidence of participants with glycemic rescue by Week 104. All participants randomized population.
    End point type
    Secondary
    End point timeframe
    Up to 104 weeks
    End point values
    		 Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Number of subjects analysed
    201
    201
    Units: Percentage of participants
        number (not applicable)
    17.4
    13.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 107 weeks (treatment period + 21-day follow-up)
    Adverse event reporting additional description
    All randomized participants who took at least 1 dose of study drug. Serious AEs include data after glycemic rescue; non-serious AEs exclude data after glycemic rescue. The AEs reported in the (Phase A) → (Phase B) columns are a total of the AEs (SAEs) that occurred in Phases A and B.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1, 18.1
    Reporting groups
    Reporting group title
    Omarigliptin (Phase A)
    Reporting group description
    		 Phase A: Omarigliptin 25 mg capsule orally once a week for 24 weeks. MedDRA version 17.1

    Reporting group title
    Placebo to omarigliptin (Phase A)
    Reporting group description
    		 Phase A: Matching placebo to omarigliptin capsule administered orally once weekly for 24 weeks. MedDRA version 17.1

    Reporting group title
    Omarigliptin (Phase A) → Omarigliptin (Phase B)
    Reporting group description
    		 Phase A: Omarigliptin 25 mg capsule administered orally once weekly for 24 weeks. Phase B: Omarigliptin 25 mg capsule administered orally once weekly and matching placebo to glimepiride tablet/capsule administered orally once daily for 80 weeks. MedDRA version 18.1

    Reporting group title
    Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Reporting group description
    		 Phase A: matching placebo to omarigliptin orally once a week for 24 weeks. Phase B: Matching placebo to omarigliptin capsule administered orally once weekly and glimepiride 1 or 2 mg tablet/capsule administered orally once daily (titrated up to 6 mg daily) for 80 weeks. MedDRA version 18.1

    Serious adverse events
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A) Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 201 (2.49%)
    10 / 201 (4.98%)
    12 / 201 (5.97%)
    18 / 201 (8.96%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (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
    Breast cancer
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (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
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (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
    Seroma
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         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
    Coronary artery disease
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         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
    Myocardial ischaemia
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         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
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric polyps
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         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
    Pancreatitis
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 201 (0.50%)
    2 / 201 (1.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (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
    Osteochondrosis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         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
    Pneumonia
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
    0 / 201 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Omarigliptin (Phase A) Placebo to omarigliptin (Phase A) Omarigliptin (Phase A) → Omarigliptin (Phase B) Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 201 (13.43%)
    17 / 201 (8.46%)
    53 / 201 (26.37%)
    58 / 201 (28.86%)
    Investigations
    Blood glucose increased
         subjects affected / exposed
    9 / 201 (4.48%)
    7 / 201 (3.48%)
    14 / 201 (6.97%)
    10 / 201 (4.98%)
         occurrences all number
    9
    10
    16
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 201 (2.49%)
    5 / 201 (2.49%)
    8 / 201 (3.98%)
    11 / 201 (5.47%)
         occurrences all number
    5
    5
    8
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 201 (0.00%)
    11 / 201 (5.47%)
    8 / 201 (3.98%)
         occurrences all number
    3
    0
    12
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 201 (2.49%)
    1 / 201 (0.50%)
    11 / 201 (5.47%)
    7 / 201 (3.48%)
         occurrences all number
    5
    1
    12
    7
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    7 / 201 (3.48%)
    5 / 201 (2.49%)
    17 / 201 (8.46%)
    32 / 201 (15.92%)
         occurrences all number
    13
    8
    43
    112

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jan 2013
    Amendment 1: the primary reason for amendment was to add the age limit of 65 years of age for participants enrolled in India.
    05 Apr 2013
    Amendment 4: the primary reason for amendment was to add amylase and lipase to the chemistry panel.
    20 Feb 2014
    Amendment 5: the primary reasons for amendment were (1) to reduce the number of participants from 250 participants per treatment group (500 total) to 200 participants per treatment group (400 total), (2) to clarify glycemic rescue, meal tolerance test and discontinuation/withdrawal, and (3) to add and modify secondary objectives.
    10 Mar 2015
    Amendment 6: the primary reason for amendment was to add capsule as a dosage form for glimepiride.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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