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    Clinical Trial Results:
    A Pooled Analysis of the Safety and Efficacy of MK-0431A and MK-0431A XR in Pediatric Patients with Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Therapy (Alone or in Combination with Insulin).

    Summary
    EudraCT number
    2014-003583-20
    Trial protocol
    DE   GB  
    Global end of trial date
    17 Sep 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Mar 2020
    First version publication date
    25 Mar 2020
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    0431A-170 and 0431A-289
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01472367
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    EudraCT Number: 2012-004035-23, NCT Number: NCT01760447, EudraCT Number: 2011-002529-23
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Sep 2019
    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 effect of the addition of sitagliptin (administered as MK-0431A or MK-0431A XR) relative to the addition of placebo on glycated hemoglobin (A1C), and the safety and tolerability of the addition of sitagliptin, in pediatric participants (ages 10-17 years) with type 2 diabetes mellitus with inadequate glycemic control on metformin therapy (alone or in combination with insulin).
    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: Insulin as glycemic rescue therapy. In protocol MK-0431A-170, the type of insulin used as glycemic rescue therapy was at the investigator's discretion during Weeks 0-20, but only insulin glargine was used as glycemic rescue therapy during Weeks 20-54. In protocol MK-0431A-289, only insulin glargine was used as glycemic rescue therapy throughout Weeks 0-54.
    Background therapy
    Participants who were on insulin at screening continued receiving insulin during the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Dec 2011
    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
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Costa Rica: 4
    Country: Number of subjects enrolled
    Dominican Republic: 10
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Guatemala: 8
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Malaysia: 22
    Country: Number of subjects enrolled
    Mauritius: 6
    Country: Number of subjects enrolled
    Mexico: 30
    Country: Number of subjects enrolled
    Philippines: 4
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Saudi Arabia: 6
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    Sri Lanka: 23
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    United Arab Emirates: 4
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    223
    EEA total number of subjects
    16
    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)
    21
    Adolescents (12-17 years)
    202
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study recruited participants in clinics/clinical offices in 28 countries.

    Pre-assignment
    Screening details
    The Pre-Assignment Period included a one-week single-blind placebo run-in prior to randomization during which participants received metformin with sitagliptin/metformin placebo or metformin XR with sitagliptin/metformin XR placebo each day.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sitagliptin/Metformin
    Arm description
    Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.
    Arm type
    Experimental

    Investigational medicinal product name
    Sitagliptin plus metformin
    Investigational medicinal product code
    Other name
    MK-0431A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 100 mg of sitagliptin and 1000mg, 1700mg or 2000 mg of metformin. Dosage of metformin was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Placebo to metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to metformin.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Arm title
    Metformin
    Arm description
    Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.
    Arm type
    Placebo

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 1000 mg, 1700 mg or 2000 mg of metformin. Dosage was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Placebo to sitagliptin plus metformin
    Investigational medicinal product code
    Other name
    Placebo to MK-0431A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to sitagliptin plus metformin.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Arm title
    Sitagliptin/Metformin XR
    Arm description
    Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.
    Arm type
    Experimental

    Investigational medicinal product name
    Sitagliptin plus metformin XR
    Investigational medicinal product code
    Other name
    MK-0431A XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 100 mg of sitagliptin and 1000mg, 1500mg or 2000 mg of metformin. Dosage of metformin XR was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Placebo to metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to metformin XR.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin glargine as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Arm title
    Metformin XR
    Arm description
    Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo to sitagliptin plus metformin XR
    Investigational medicinal product code
    Other name
    Placebo to MK-0431A XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to sitagliptin plus metformin XR.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin glargine as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Investigational medicinal product name
    Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 1000 mg, 1500 mg or 2000 mg of metformin XR. Dosage was based on each participant's daily metformin dose prior to enrollment.

    Number of subjects in period 1
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR
    Started
    63
    62
    47
    51
    Completed
    62
    62
    45
    51
    Not completed
    1
    0
    2
    0
         Randomized but not treated
    1
    -
    2
    -
    Period 2
    Period 2 title
    Weeks 0-20
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sitagliptin/Metformin
    Arm description
    Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.
    Arm type
    Experimental

    Investigational medicinal product name
    Sitagliptin plus metformin
    Investigational medicinal product code
    Other name
    MK-0431A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 100 mg of sitagliptin and 1000mg, 1700mg or 2000 mg of metformin. Dosage of metformin was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Placebo to metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to metformin.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Arm title
    Metformin
    Arm description
    Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.
    Arm type
    Placebo

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 1000 mg, 1700 mg or 2000 mg of metformin. Dosage was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Placebo to sitagliptin plus metformin
    Investigational medicinal product code
    Other name
    Placebo to MK-0431A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to sitagliptin plus metformin.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Arm title
    Sitagliptin/Metformin XR
    Arm description
    Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.
    Arm type
    Experimental

    Investigational medicinal product name
    Sitagliptin plus metformin XR
    Investigational medicinal product code
    Other name
    MK-0431A XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 100 mg of sitagliptin and 1000mg, 1500mg or 2000 mg of metformin. Dosage of metformin XR was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin glargine as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Investigational medicinal product name
    Placebo to metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to metformin XR.

    Arm title
    Metformin XR
    Arm description
    Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo to sitagliptin plus metformin XR
    Investigational medicinal product code
    Other name
    Placebo to MK-0431A XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to sitagliptin plus metformin XR.

    Investigational medicinal product name
    Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 1000 mg, 1500 mg or 2000 mg of metformin XR. Dosage was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin glargine as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 includes all participants randomized. Period 2 includes all participants who were both randomized and treated with study medication, which is the population used for baseline characteristics.
    Number of subjects in period 2 [2]
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR
    Started
    62
    62
    45
    51
    Treated
    62
    62
    45
    51
    Completed
    59
    62
    42
    47
    Not completed
    3
    0
    3
    4
         Consent withdrawn by Parent/Guardian
    -
    -
    1
    3
         Consent withdrawn by subject
    2
    -
    1
    -
         Lost to follow-up
    1
    -
    1
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The baseline period used all participants both randomized and treated with study medication rather than all participants randomized, which was used as the worldwide total.
    Period 3
    Period 3 title
    Weeks 20-54
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sitagliptin/Metformin
    Arm description
    Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, during Weeks 20-54. Participants in this arm were enrolled in protocol MK-0431A-170.
    Arm type
    Experimental

    Investigational medicinal product name
    Sitagliptin plus metformin
    Investigational medicinal product code
    Other name
    MK-0431A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 100 mg of sitagliptin and 1000mg, 1700mg or 2000 mg of metformin. Dosage of metformin was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Placebo to metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to metformin.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin glargine as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Arm title
    Metformin
    Arm description
    Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, during Weeks 20-54. Participants in this arm were enrolled in protocol MK-0431A-170.
    Arm type
    Placebo

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 1000 mg, 1700 mg or 2000 mg of metformin. Dosage was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin glargine as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Investigational medicinal product name
    Placebo to sitagliptin plus metformin
    Investigational medicinal product code
    Other name
    Placebo to MK-0431A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to sitagliptin plus metformin.

    Arm title
    Sitagliptin/Metformin XR
    Arm description
    Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, during Weeks 20-54. Participants in this arm were enrolled in protocol MK-0431A-289.
    Arm type
    Experimental

    Investigational medicinal product name
    Sitagliptin plus metformin XR
    Investigational medicinal product code
    Other name
    MK-0431A XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 100 mg of sitagliptin and 1000mg, 1500mg or 2000 mg of metformin. Dosage of metformin XR was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin glargine as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Investigational medicinal product name
    Placebo to metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to metformin XR.

    Arm title
    Metformin XR
    Arm description
    Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, during Weeks 20-54. Participants in this arm were enrolled in protocol MK-0431A-289.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo to sitagliptin plus metformin XR
    Investigational medicinal product code
    Other name
    Placebo to MK-0431A XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to sitagliptin plus metformin XR.

    Investigational medicinal product name
    Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 1000 mg, 1500 mg or 2000 mg of metformin XR. Dosage was based on each participant's daily metformin dose prior to enrollment.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who met protocol-specific glycemic rescue criteria received insulin glargine as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue.

    Number of subjects in period 3 [3]
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR
    Started
    28
    30
    42
    47
    Completed
    25
    28
    39
    43
    Not completed
    3
    2
    3
    4
         Consent withdrawn by Parent/Guardian
    1
    1
    1
    -
         Consent withdrawn by subject
    2
    1
    1
    2
         Lost to follow-up
    -
    -
    1
    2
    Notes
    [3] - 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: Not all participants who completed the Weeks 0-20 Period continued in the Weeks 20-54 Period. In protocol MK-0431A-170, participants were required to re-consent to enter the Weeks 20-54 period, and many did not do so.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin/Metformin
    Reporting group description
    Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.

    Reporting group title
    Metformin
    Reporting group description
    Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.

    Reporting group title
    Sitagliptin/Metformin XR
    Reporting group description
    Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.

    Reporting group title
    Metformin XR
    Reporting group description
    Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.

    Reporting group values
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR Total
    Number of subjects
    62 62 45 51 220
    Age Categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    10 7 3 1 21
        Adolescents (12-17 years)
    52 55 42 50 199
        Adults (18-64 years)
    0 0 0 0 0
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    14.4 ± 2.2 13.9 ± 1.8 14.8 ± 1.9 14.9 ± 1.6 -
    Gender Categorical
    Units: Subjects
        Female
    41 40 32 32 145
        Male
    21 22 13 19 75
    Race
    Units: Subjects
        American Indian Or Alaska Native
    0 1 3 9 13
        Asian
    21 22 15 6 64
        Native Hawaiian or Other Pacific Islander
    1 1 0 0 2
        Black or African American
    2 2 2 4 10
        White
    24 23 22 27 96
        More than one race
    14 13 3 5 35
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    23 23 11 20 77
        Not Hispanic or Latino
    35 36 29 28 128
        Unknown or Not Reported
    4 3 5 3 15
    Glycated Hemoglobin (A1C)
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. The analysis population includes all randomized participants who received ≥1 dose of study medication and had a baseline measurement of A1C.
    Units: Percentage
        arithmetic mean (standard deviation)
    8.02 ± 1.22 8.13 ± 1.08 7.87 ± 0.94 7.97 ± 1.05 -
    Subject analysis sets

    Subject analysis set title
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This analysis set contains the pooled population of treated participants from the experimental-drug groups "Sitagliptin/Metformin" (from protocol MK-0431A-170) and "Sitagliptin/Metformin XR" (from protocol MK-0431A-289).

    Subject analysis set title
    Metformin and Metformin XR Pooled
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This analysis set contains the pooled population of treated participants from the placebo groups "Metformin" (from protocol MK-0431A-170) and "Metformin XR" (from protocol MK-0431A-289).

    Subject analysis sets values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects
    107
    113
    Age Categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    13
    8
        Adolescents (12-17 years)
    94
    105
        Adults (18-64 years)
    0
    0
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    14.5 ± 2.1
    14.4 ± 1.8
    Gender Categorical
    Units: Subjects
        Female
    73
    72
        Male
    34
    41
    Race
    Units: Subjects
        American Indian Or Alaska Native
    3
    10
        Asian
    36
    28
        Native Hawaiian or Other Pacific Islander
    1
    1
        Black or African American
    4
    6
        White
    46
    50
        More than one race
    17
    18
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    34
    43
        Not Hispanic or Latino
    64
    64
        Unknown or Not Reported
    9
    6
    Glycated Hemoglobin (A1C)
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. The analysis population includes all randomized participants who received ≥1 dose of study medication and had a baseline measurement of A1C.
    Units: Percentage
        arithmetic mean (standard deviation)
    7.96 ± 1.11
    8.06 ± 1.07

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin/Metformin
    Reporting group description
    Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.

    Reporting group title
    Metformin
    Reporting group description
    Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.

    Reporting group title
    Sitagliptin/Metformin XR
    Reporting group description
    Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.

    Reporting group title
    Metformin XR
    Reporting group description
    Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.
    Reporting group title
    Sitagliptin/Metformin
    Reporting group description
    Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.

    Reporting group title
    Metformin
    Reporting group description
    Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-170.

    Reporting group title
    Sitagliptin/Metformin XR
    Reporting group description
    Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.

    Reporting group title
    Metformin XR
    Reporting group description
    Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, during Weeks 0-20. Participants in this arm were enrolled in protocol MK-0431A-289.
    Reporting group title
    Sitagliptin/Metformin
    Reporting group description
    Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, during Weeks 20-54. Participants in this arm were enrolled in protocol MK-0431A-170.

    Reporting group title
    Metformin
    Reporting group description
    Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, during Weeks 20-54. Participants in this arm were enrolled in protocol MK-0431A-170.

    Reporting group title
    Sitagliptin/Metformin XR
    Reporting group description
    Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, during Weeks 20-54. Participants in this arm were enrolled in protocol MK-0431A-289.

    Reporting group title
    Metformin XR
    Reporting group description
    Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, during Weeks 20-54. Participants in this arm were enrolled in protocol MK-0431A-289.

    Subject analysis set title
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This analysis set contains the pooled population of treated participants from the experimental-drug groups "Sitagliptin/Metformin" (from protocol MK-0431A-170) and "Sitagliptin/Metformin XR" (from protocol MK-0431A-289).

    Subject analysis set title
    Metformin and Metformin XR Pooled
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This analysis set contains the pooled population of treated participants from the placebo groups "Metformin" (from protocol MK-0431A-170) and "Metformin XR" (from protocol MK-0431A-289).

    Primary: Change from Baseline in A1C at Week 20

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    End point title
    Change from Baseline in A1C at Week 20
    End point description
    Glycated hemoglobin (A1C) is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Mean change from baseline at Week 20 was estimated from a longitudinal data analysis model. The analysis population includes all randomized participants who received ≥1 dose of study medication and who had at least 1 measurement of A1C. Per protocol, only the pooled analysis groups were analyzed for this primary endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 20
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    107
    113
    Units: Percentage
    least squares mean (confidence interval 95%)
        Change from Baseline at Week 20
    -0.58 (-0.94 to -0.22)
    -0.09 (-0.43 to 0.26)
    Statistical analysis title
    Difference in Change from Baseline
    Statistical analysis description
    The Least Squares (LS) Mean for the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled."
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.018
    Method
    Mixed models analysis
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    -0.09

    Primary: Number of participants who experienced ≥1 Adverse Event During Weeks 0-20

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    End point title
    Number of participants who experienced ≥1 Adverse Event During Weeks 0-20
    End point description
    The number of participants experiencing ≥1 adverse event during Weeks 0-20 was reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The analysis population includes all randomized participants who received ≥1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to Week 20
    End point values
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    62
    62
    45
    51
    107
    113
    Units: Participants
    42
    46
    29
    30
    71
    76
    Statistical analysis title
    Difference in Percentage
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.9
         upper limit
    11.3
    Notes
    [1] - The percentage of participants who experienced ≥1 adverse event for the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled."

    Primary: Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-20

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    End point title
    Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-20
    End point description
    The number of participants who discontinued from study drug due to an adverse event during Weeks 0-20 was reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The analysis population includes all randomized participants who received ≥1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to Week 20
    End point values
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    62
    62
    45
    51
    107
    113
    Units: Participants
    1
    2
    2
    2
    3
    4
    Statistical analysis title
    Difference in Percentage
    Statistical analysis description
    The percentage of participants who discontinued study drug due to experiencing an adverse event for the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled."
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.2
         upper limit
    5

    Primary: Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-56

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    End point title
    Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-56
    End point description
    The number of participants experiencing ≥1 adverse event during Weeks 0-56 were reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The analysis population includes all randomized participants who received ≥1 dose of study medication and continued in the study beyond Week 20.
    End point type
    Primary
    End point timeframe
    Up to approximately Week 56
    End point values
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    28
    30
    42
    47
    70
    77
    Units: Participants
    26
    27
    36
    39
    62
    66
    Statistical analysis title
    Difference in Percentage
    Statistical analysis description
    The percentage of participants who experienced ≥1 adverse event for the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled."
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.9
         upper limit
    14.4

    Primary: Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-54

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    End point title
    Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-54
    End point description
    The number of participants who discontinued from study drug due to an adverse event during Weeks 0-54 was reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The analysis population includes all randomized participants who received ≥1 dose of study medication and continued in the study beyond Week 20.
    End point type
    Primary
    End point timeframe
    Up to Week 54
    End point values
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    28
    30
    42
    47
    70
    77
    Units: Participants
    1
    1
    1
    3
    2
    4
    Statistical analysis title
    Difference in Percentage
    Statistical analysis description
    The percentage of participants who discontinued study drug due to experiencing an adverse event for the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled."
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    -2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.1
         upper limit
    5.8

    Secondary: Change from baseline in A1C at Week 54

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    End point title
    Change from baseline in A1C at Week 54
    End point description
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Mean change from baseline at Week 54 was estimated from a longitudinal data analysis model. The analysis population includes all randomized participants who received ≥1 dose of study medication, had at least 1 measurement of A1C, and continued in the study beyond Week 20. Per protocol, only the pooled analysis groups were analyzed for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 54
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    70
    77
    Units: Percentage
        least squares mean (confidence interval 95%)
    0.35 (-0.48 to 1.19)
    0.73 (-0.08 to 1.54)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG) at Week 20

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    End point title
    Change from Baseline in Fasting Plasma Glucose (FPG) at Week 20
    End point description
    Blood glucose was measured on a fasting basis. Mean change from baseline at Week 20 was estimated from a longitudinal data analysis model. The analysis population includes all randomized participants who received ≥1 dose of study medication, and who had at least 1 measurement of FPG. Per protocol, only the pooled analysis groups were analyzed for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 20
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    107
    113
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -2.5 (-16.7 to 11.7)
    8.3 (-5.0 to 21.6)
    Statistical analysis title
    Difference in Change from Baseline
    Statistical analysis description
    The Least Squares (LS) Mean for the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled."
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.159
    Method
    Mixed models analysis
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -10.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.9
         upper limit
    4.3

    Secondary: Change from Baseline in FPG at Week 54

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    End point title
    Change from Baseline in FPG at Week 54
    End point description
    Blood glucose was measured on a fasting basis. Mean change from baseline at Week 54 was estimated from a longitudinal data analysis model. The analysis population includes all randomized participants who received ≥1 dose of study medication, had at least 1 measurement of FPG, and continued in the study beyond Week 20. Per protocol, only the pooled analysis groups were analyzed for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 54
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    70
    77
    Units: mg/dL
        least squares mean (confidence interval 95%)
    16.8 (-8.4 to 42.0)
    16.9 (-7.0 to 40.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with A1C at Goal (<7.0%) at Week 20

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    End point title
    Percentage of Participants with A1C at Goal (<7.0%) at Week 20
    End point description
    Percentage of participants with A1C at goal (<7.0%) at Week 20 was presented. The analysis population includes all randomized participants who received ≥1 dose of study medication. Per protocol, only the pooled analysis groups were analyzed for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Week 20
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    107
    113
    Units: Percentage
        number (not applicable)
    43.0
    31.0
    Statistical analysis title
    Difference in Percentage
    Statistical analysis description
    The percentage of participants with A1C at the A1C goal (<7.0%) in the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled." For estimating the treatment difference, when the A1C result for a participant at Week 20 was not available, a multiple imputation method was used to impute whether the participant had met the goal.
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.017
    Method
    Miettinen and Nurminen
    Parameter type
    Difference in Percentage
    Point estimate
    16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.9
         upper limit
    28.9

    Secondary: Percentage of Participants with A1C at Goal (<6.5%) at Week 20

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    End point title
    Percentage of Participants with A1C at Goal (<6.5%) at Week 20
    End point description
    Percentage of participants with A1C at goal (<6.5%) at Week 20 was presented. The analysis population includes all randomized participants who received ≥1 dose of study medication. Per protocol, only the pooled analysis groups were analyzed for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Week 20
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    107
    113
    Units: Percentage
        number (not applicable)
    29.0
    20.4
    Statistical analysis title
    Difference in Percentage
    Statistical analysis description
    The percentage of participants with A1C at the A1C goal (<6.5%) in the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled." For estimating the treatment difference, when the A1C result for a participant at Week 20 was not available, a multiple imputation method was used to impute whether the participant had met the goal.
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.049
    Method
    Miettinen and Nurminen
    Parameter type
    Difference in Percentage
    Point estimate
    12.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    24.8

    Secondary: Percentage of Participants with A1C at Goal (<7.0%) at Week 54

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    End point title
    Percentage of Participants with A1C at Goal (<7.0%) at Week 54
    End point description
    Percentage of participants with A1C at goal (<7.0%) at Week 54 was presented. The analysis population includes all randomized participants who received ≥1 dose of study medication and continued in the study beyond Week 20. Per protocol, only the pooled analysis groups were analyzed for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Week 54
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    70
    77
    Units: Percentage
        number (not applicable)
    31.4
    27.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with A1C at Goal (<6.5%) at Week 54

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    End point title
    Percentage of Participants with A1C at Goal (<6.5%) at Week 54
    End point description
    Percentage of participants with A1C at goal (<6.5%) at Week 54 was presented. The analysis population includes all randomized participants who received ≥1 dose of study medication and continued in the study beyond Week 20. Per protocol, only the pooled analysis groups were analyzed for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Week 54
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    70
    77
    Units: Percentage
        number (not applicable)
    18.6
    19.5
    No statistical analyses for this end point

    Secondary: Percentage  of Participants Initiating Glycemic Rescue Therapy by Week 20

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    End point title
    Percentage  of Participants Initiating Glycemic Rescue Therapy by Week 20
    End point description
    Percentage of participants who initiated glycemic rescue therapy prior to Week 20 was reported. The analysis population includes all randomized participants who received ≥1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to Week 20
    End point values
    Sitagliptin/Metformin Metformin Sitagliptin/Metformin XR Metformin XR Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    62
    62
    45
    51
    107
    113
    Units: Percentage
        number (not applicable)
    3.2
    19.4
    4.4
    13.7
    3.7
    16.8
    Statistical analysis title
    Difference in Percentage
    Statistical analysis description
    The percentage of participants initiating glycemic rescue therapy in the arm "Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled" is compared against that of "Metformin and Metformin XR Pooled."
    Comparison groups
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled v Metformin and Metformin XR Pooled
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    Log-Rank Test
    Parameter type
    Kaplan-Meier Difference in Percentage
    Point estimate
    -13.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.1
         upper limit
    -5.3

    Secondary: Percentage  of Participants Initiating Insulin Glargine During Weeks 20-54

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    End point title
    Percentage  of Participants Initiating Insulin Glargine During Weeks 20-54
    End point description
    Percentage of participants who initiated insulin glargine therapy from Weeks 20 through 54 was reported. The analysis population includes all randomized participants who received ≥1 dose of study medication and continued in the study beyond Week 20 without initiating glycemic rescue therapy before Week 20. Per protocol, only the pooled analysis groups were analyzed for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Week 20 up to Week 54
    End point values
    Sitagliptin/Metformin and Sitagliptin/Metformin XR Pooled Metformin and Metformin XR Pooled
    Number of subjects analysed
    66
    64
    Units: Percentage
        number (not applicable)
    22.7
    26.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 56 weeks for non serious adverse events. Up to approximately 8 years for serious adverse events and deaths.
    Adverse event reporting additional description
    "Pooled Sita/Met FDC" = "Sita/Met IR FDC" plus "Sita/Met XR FDC." "Pooled Metformin" = "Metformin IR" plus "Metformin XR."
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Sita/Met IR FDC
    Reporting group description
    -

    Reporting group title
    Metformin IR
    Reporting group description
    -

    Reporting group title
    Sita/Met XR FDC
    Reporting group description
    -

    Reporting group title
    Metformin XR
    Reporting group description
    -

    Reporting group title
    Pooled Sita/Met FDC
    Reporting group description
    -

    Reporting group title
    Pooled Metformin
    Reporting group description
    -

    Serious adverse events
    Sita/Met IR FDC Metformin IR Sita/Met XR FDC Metformin XR Pooled Sita/Met FDC Pooled Metformin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 62 (4.84%)
    3 / 45 (6.67%)
    3 / 51 (5.88%)
    7 / 107 (6.54%)
    6 / 113 (5.31%)
         number of deaths (all causes)
    1
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    0 / 107 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    1 / 107 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Type I hypersensitivity
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    1 / 107 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    0 / 107 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    1 / 107 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
    0 / 107 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
    0 / 107 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
    1 / 107 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
    0 / 107 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Synovial cyst
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    1 / 107 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
    0 / 107 (0.00%)
    2 / 113 (1.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
    1 / 107 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    1 / 51 (1.96%)
    0 / 107 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    1 / 107 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 45 (2.22%)
    0 / 51 (0.00%)
    1 / 107 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sita/Met IR FDC Metformin IR Sita/Met XR FDC Metformin XR Pooled Sita/Met FDC Pooled Metformin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 62 (54.84%)
    40 / 62 (64.52%)
    30 / 45 (66.67%)
    36 / 51 (70.59%)
    64 / 107 (59.81%)
    76 / 113 (67.26%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 62 (4.84%)
    3 / 45 (6.67%)
    3 / 51 (5.88%)
    5 / 107 (4.67%)
    6 / 113 (5.31%)
         occurrences all number
    3
    3
    3
    3
    6
    6
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 62 (4.84%)
    1 / 62 (1.61%)
    3 / 45 (6.67%)
    1 / 51 (1.96%)
    6 / 107 (5.61%)
    2 / 113 (1.77%)
         occurrences all number
    3
    1
    3
    1
    6
    2
    Blood glucose increased
         subjects affected / exposed
    3 / 62 (4.84%)
    0 / 62 (0.00%)
    2 / 45 (4.44%)
    3 / 51 (5.88%)
    5 / 107 (4.67%)
    3 / 113 (2.65%)
         occurrences all number
    4
    0
    2
    5
    6
    5
    Creatinine renal clearance increased
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 62 (0.00%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    4 / 107 (3.74%)
    0 / 113 (0.00%)
         occurrences all number
    4
    0
    0
    0
    4
    0
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 62 (3.23%)
    0 / 45 (0.00%)
    0 / 51 (0.00%)
    4 / 107 (3.74%)
    2 / 113 (1.77%)
         occurrences all number
    5
    2
    0
    0
    5
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 62 (4.84%)
    3 / 45 (6.67%)
    2 / 51 (3.92%)
    5 / 107 (4.67%)
    5 / 113 (4.42%)
         occurrences all number
    2
    4
    3
    2
    5
    6
    Oropharyngeal pain
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 62 (1.61%)
    3 / 45 (6.67%)
    1 / 51 (1.96%)
    5 / 107 (4.67%)
    2 / 113 (1.77%)
         occurrences all number
    2
    1
    3
    6
    5
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 62 (4.84%)
    8 / 62 (12.90%)
    2 / 45 (4.44%)
    10 / 51 (19.61%)
    5 / 107 (4.67%)
    18 / 113 (15.93%)
         occurrences all number
    4
    10
    4
    15
    8
    25
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 62 (6.45%)
    4 / 45 (8.89%)
    4 / 51 (7.84%)
    6 / 107 (5.61%)
    8 / 113 (7.08%)
         occurrences all number
    2
    4
    4
    4
    6
    8
    Abdominal pain upper
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 62 (3.23%)
    0 / 45 (0.00%)
    3 / 51 (5.88%)
    1 / 107 (0.93%)
    5 / 113 (4.42%)
         occurrences all number
    2
    2
    0
    4
    2
    6
    Diarrhoea
         subjects affected / exposed
    7 / 62 (11.29%)
    4 / 62 (6.45%)
    1 / 45 (2.22%)
    3 / 51 (5.88%)
    8 / 107 (7.48%)
    7 / 113 (6.19%)
         occurrences all number
    8
    4
    1
    10
    9
    14
    Nausea
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 62 (8.06%)
    4 / 45 (8.89%)
    2 / 51 (3.92%)
    6 / 107 (5.61%)
    7 / 113 (6.19%)
         occurrences all number
    5
    5
    6
    3
    11
    8
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 62 (8.06%)
    3 / 45 (6.67%)
    4 / 51 (7.84%)
    6 / 107 (5.61%)
    9 / 113 (7.96%)
         occurrences all number
    3
    6
    3
    4
    6
    10
    Hypoglycaemia
         subjects affected / exposed
    10 / 62 (16.13%)
    6 / 62 (9.68%)
    9 / 45 (20.00%)
    10 / 51 (19.61%)
    19 / 107 (17.76%)
    16 / 113 (14.16%)
         occurrences all number
    106
    15
    70
    45
    176
    60
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    5 / 62 (8.06%)
    3 / 62 (4.84%)
    3 / 45 (6.67%)
    2 / 51 (3.92%)
    8 / 107 (7.48%)
    5 / 113 (4.42%)
         occurrences all number
    6
    3
    3
    2
    9
    5
    Influenza
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
    2 / 45 (4.44%)
    3 / 51 (5.88%)
    3 / 107 (2.80%)
    7 / 113 (6.19%)
         occurrences all number
    1
    5
    3
    5
    4
    10
    Nasopharyngitis
         subjects affected / exposed
    7 / 62 (11.29%)
    7 / 62 (11.29%)
    1 / 45 (2.22%)
    2 / 51 (3.92%)
    8 / 107 (7.48%)
    9 / 113 (7.96%)
         occurrences all number
    11
    7
    2
    3
    13
    10
    Pharyngitis
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 62 (4.84%)
    1 / 45 (2.22%)
    5 / 51 (9.80%)
    2 / 107 (1.87%)
    8 / 113 (7.08%)
         occurrences all number
    1
    3
    1
    6
    2
    9
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 62 (14.52%)
    6 / 62 (9.68%)
    5 / 45 (11.11%)
    3 / 51 (5.88%)
    14 / 107 (13.08%)
    9 / 113 (7.96%)
         occurrences all number
    11
    8
    9
    5
    20
    13
    Urinary tract infection
         subjects affected / exposed
    0 / 62 (0.00%)
    5 / 62 (8.06%)
    3 / 45 (6.67%)
    1 / 51 (1.96%)
    3 / 107 (2.80%)
    6 / 113 (5.31%)
         occurrences all number
    0
    6
    3
    1
    3
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2012
    MK-0431A-170 AM01 (Base study): Incorporated procedural and administrative changes.
    17 Apr 2014
    MK-0431A-170 AM02 (Base study): Updated analyses to reflect the pooled analysis. Reduced the sample size from 240 to 90 participants and analysis was combined with study MK-0431A-289 with adequate power for the primary analysis at Week 20. The timeframe required for participants to be off insulin therapy before Visit 1 was reduced from 6 months to 12 weeks. A1C lower limit for inclusion changed from ≥7.0% to ≥6.5%.
    17 Apr 2014
    MK-0431A-170 AM03 (Extension study): Created the 34-week extension study.
    17 Apr 2014
    MK-0431A-289 AM04: Modified the timeframe for prior treatment with insulin from 6 months to 12 weeks. A1C lower limit for inclusion changed from ≥7% to ≥6.5%. Sample size was reduced from 240 to 90 participants and analysis was combined with study MK-0431A-170 with adequate power for the primary analysis at Week 20.
    09 Jan 2015
    MK-0431A-170 AM04 (Base study): Included participants on background insulin.
    09 Jan 2015
    MK-0431A-170 AM05 (Extension study): Included participants on background insulin.
    20 Jan 2015
    MK-0431A-289 AM05: Included participants on background insulin.
    10 Apr 2015
    MK-0431A-170 AM07 (Base study): Changed “adverse experience” to “adverse event.”
    10 Apr 2015
    MK-0431A-170 AM08 (Extension study): Changed “adverse experience” to “adverse event.”
    09 Sep 2015
    MK-0431A-289 AM07: Changed “adverse experience” to “adverse event.” Complied with recommendations from the FDA to minimize missing data.
    04 Nov 2015
    MK-0431A-170 AM11 (Base study): Complied with recommendations from the FDA to minimize missing data. Updated sample size from approximately 90 participants to approximately 130 participants.
    04 Nov 2015
    MK-0431A-170 AM12 (Extension study): Complied with recommendations from the FDA to minimize missing data. Updated sample size from approximately 90 participants to approximately 130 participants.
    12 Apr 2018
    MK-0431A-289 AM10: Complied with the recommendations from a health authority. Increased sample size. Clarified statistical methods for analyses using the Treatment Effect estimand. Added analyses using the Treatment Policy estimand.
    12 Apr 2018
    MK-0431A-170 AM15 (Base study): Modified sample size. Beginning and end of study were defined. Clarified statistical methods for analyses using the Treatment Effect estimand. Added analyses using the Treatment Policy estimand.
    12 Apr 2018
    MK-0431A-170 AM16 (Extension study): Modified sample size. Beginning and end of study were defined.

    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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