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    Clinical Trial Results:
    A Study to Assess the Pharmacokinetics and the Ability for Pediatric Patients with Type 2 Diabetes to Swallow MK-0431A XR Tablets

    Summary
    EudraCT number
    		 2020-003731-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    29 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2020
    First version publication date
    04 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0431A-296
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01557504
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-0431A-296
    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
    29 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess: (1) The safety and tolerability of two sitagliptin 50 mg/metformin 1000 mg XR tablets in pediatric participants with type 2 diabetes mellitus (T2DM), aged 10 to 17 years (2) The ability of pediatric participants with T2DM, aged 10 to 17 years, to swallow two sitagliptin 50 mg/metformin 1000 mg XR tablets or two matching placebo tablets (excluding marking) (3) The pharmacokinetics of sitagliptin and metformin following the administration of two sitagliptin 50 mg/metformin 1000 mg XR tablets to pediatric participants with T2DM, aged 10 to 17 years.
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    1
    Adolescents (12-17 years)
    24
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participant is a male or female, between 10 and 17 years of age.

    Pre-assignment
    Screening details
    		 1. Female participants of reproductive potential must demonstrate a nongravid state. 2. Participants must have: - Type 2 diabetes (T2D) diagnosed by American Diabetes Association (ADA) criteria. - No clinically significant abnormality on electrocardiogram (ECG). - No clinical or laboratory evidence of type 1 diabetes.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sitagliptin/Metformin XR Followed by Placebo
    Arm description
    		 Day 1 (Period 1): participants received a single dose of two sitagliptin/metformin XR tablets with a low- to moderate-fat meal (breakfast). Days 2-4 (Period 1): participants received a single dose of two matching placebo tablets. Days 5-9 (Period 2): participants received a single dose of two matching placebo tablets with the evening meal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sitagliptin/Metformin XR
    Investigational medicinal product code
    Other name
    MK-0431A XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin phosphate 50mg/Metformin hydrochloride 1000mg

    Investigational medicinal product name
    Placebo for Sitagliptin/Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0mg/0mg

    Investigational medicinal product name
    Thyroid Hormone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Concomitant use of thyroid hormone (TH) will also be permitted during the study provided the participant has been receiving a stable dose for at least 12 weeks prior to study drug administration and is euthyroid as documented by thyroid-stimulation hormone (TSH) testing at prestudy. TH should also be held prior to study drug administration and for 24 hours postdose. TH administration can be re-initiated following completion of the 24-hour procedures.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Concomitant use of metformin will be permitted during the study provided the participant has been receiving a stable metformin dose for at least 12 weeks prior to the dose of study drug. Metformin should be held prior to study drug administration and for 24 hours postdose. Metformin administration can be re-initiated following completion of the 24-hour postdose procedures.

    Arm title
    		 Placebo
    Arm description
    		 Days 1-4 (Period 1): participants received a single dose of two matching placebo tablets. Days 5-9 (Period 2): participants received a single dose of two matching placebo tablets with the evening meal.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for Sitagliptin/Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0mg/0mg

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Concomitant use of metformin will be permitted during the study provided the participant has been receiving a stable metformin dose for at least 12 weeks prior to the dose of study drug. Metformin should be held prior to study drug administration and for 24 hours postdose. Metformin administration can be re-initiated following completion of the 24-hour postdose procedures.

    Investigational medicinal product name
    Thyroid Hormone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Concomitant use of thyroid hormone (TH) will also be permitted during the study provided the participant has been receiving a stable dose for at least 12 weeks prior to study drug administration and is euthyroid as documented by thyroid-stimulation hormone (TSH) testing at prestudy. TH should also be held prior to study drug administration and for 24 hours postdose. TH administration can be re-initiated following completion of the 24-hour procedures.

    Number of subjects in period 1
    		Sitagliptin/Metformin XR Followed by Placebo Placebo
    Started
    13
    12
    Completed
    12
    12
    Not completed
    1
    0
         Physician decision
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin/Metformin XR Followed by Placebo
    Reporting group description
    		 Day 1 (Period 1): participants received a single dose of two sitagliptin/metformin XR tablets with a low- to moderate-fat meal (breakfast). Days 2-4 (Period 1): participants received a single dose of two matching placebo tablets. Days 5-9 (Period 2): participants received a single dose of two matching placebo tablets with the evening meal.

    Reporting group title
    Placebo
    Reporting group description
    		 Days 1-4 (Period 1): participants received a single dose of two matching placebo tablets. Days 5-9 (Period 2): participants received a single dose of two matching placebo tablets with the evening meal.

    Reporting group values
    		 Sitagliptin/Metformin XR Followed by Placebo Placebo Total
    Number of subjects
    		 13 12 25
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 1 1
        Adolescents (12-17 years)
    		 13 11 24
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.7 ( 1.8 ) 14.8 ( 2.0 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 9 8 17
        Male
    		 4 4 8

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin/Metformin XR Followed by Placebo
    Reporting group description
    		 Day 1 (Period 1): participants received a single dose of two sitagliptin/metformin XR tablets with a low- to moderate-fat meal (breakfast). Days 2-4 (Period 1): participants received a single dose of two matching placebo tablets. Days 5-9 (Period 2): participants received a single dose of two matching placebo tablets with the evening meal.

    Reporting group title
    Placebo
    Reporting group description
    		 Days 1-4 (Period 1): participants received a single dose of two matching placebo tablets. Days 5-9 (Period 2): participants received a single dose of two matching placebo tablets with the evening meal.

    Subject analysis set title
    All Treated Participants
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants who completed at least one period of treatment and had available data.

    Subject analysis set title
    Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Day 1 (Period 1): participants received a single dose of two sitagliptin/metformin XR tablets with a low- to moderate-fat meal (breakfast). Days 2-4 (Period 1): participants received a single dose of two matching placebo tablets. Days 5-9 (Period 2): participants received a single dose of two matching placebo tablets with the evening meal.

    Subject analysis set title
    Metformin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Day 1 (Period 1): participants received a single dose of two sitagliptin/metformin XR tablets with a low- to moderate-fat meal (breakfast). Days 2-4 (Period 1): participants received a single dose of two matching placebo tablets. Days 5-9 (Period 2): participants received a single dose of two matching placebo tablets with the evening meal.

    Primary: Number of Participants Who Successfully Swallowed Study Medication (Med) on Day 2

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    End point title
    		 Number of Participants Who Successfully Swallowed Study Medication (Med) on Day 2 [1]
    End point description
    The Swallowing Ability Questionnaire was completed on Day 2 after the participant received two matching placebo tablets (excluding marking) following consumption of a low-to-moderate-fat meal in pediatric participants aged 10 to 17 years. The questionnaire consisted of 5 parts: 1. Could only swallow study med with help; 2. Easy to start swallowing study med; 3. Easy to swallow study med; 4. Felt like study med got stuck in throat, and 5. Had to swallow study med more than once. The number of participants who strongly agreed or agreed in each of the 5 parts is reported. Per protocol population defined as all participants who completed at least one period of treatment and had available data. On Day 2, all participants received matching placebo, so the two treatment groups were pooled on Day 2.
    End point type
    Primary
    End point timeframe
    Day 2
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 All Treated Participants
    Number of subjects analysed
    24
    Units: Participants
        Strongly Agreed: 1. Could Swallow Med With Help
    6
        Agreed: 1. Could Only Swallow Med With Help
    7
        Strongly Agreed: 2. Easy to Start Swallowing Med
    10
        Agreed: 2. Easy to Start Swallowing Med
    12
        Strongly Agreed: 3. Easy to Swallow Med
    13
        Agreed: 3. Easy to Swallow Med
    10
        Strongly Agreed: 4. Felt Like Med Stuck in Throat
    0
        Agreed: 4. Felt Like Med Got Stuck in Throat
    4
        Strongly Agreed: 5. Had to Swallow Med >1
    2
        Agreed: 5. Had to Swallow Med >1
    3
    No statistical analyses for this end point

    Primary: Number of Participants Who Successfully Swallowed Study Med on Day 4

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    End point title
    		 Number of Participants Who Successfully Swallowed Study Med on Day 4 [2]
    End point description
    The Swallowing Ability Questionnaire was completed on Day 4 after the participant received two matching placebo tablets (excluding marking) following consumption of a low- to moderate-fat meal in pediatric participants aged 10 to 17 years. The questionnaire consisted of 5 parts: 1. Could only swallow study med with help; 2. Easy to start swallowing study med; 3. Easy to swallow study med; 4. Felt like study med got stuck in throat, and 5. Had to swallow study med more than once. The number of participants who strongly agreed or agreed in each of the 5 parts is reported. Per protocol population defined as all participants who completed at least one period of treatment and had available data. On Day 4, all participants received matching placebo, so the two treatment groups were pooled on Day 4.
    End point type
    Primary
    End point timeframe
    Day 4
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 All Treated Participants
    Number of subjects analysed
    24
    Units: Participants
        Strongly Agreed: 1. Could Swallow Med With Help
    6
        Agreed: 1. Could Only Swallow Med With Help
    6
        Strongly Agreed: 2. Easy to Start Swallowing Med
    8
        Agreed: 2. Easy to Start Swallowing Med
    14
        Strongly Agreed: 3. Easy to Swallow Med
    8
        Agreed: 3. Easy to Swallow Med
    15
        Strongly Agreed: 4. Felt Like Med Stuck in Throat
    0
        Agreed: 4. Felt Like Med Got Stuck in Throat
    4
        Strongly Agreed: 5. Had to Swallow Med >1
    0
        Agreed: 5. Had to Swallow Med >1
    5
    No statistical analyses for this end point

    Primary: Number of Participants Who Successfully Swallowed Study Med on Day 6

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    End point title
    		 Number of Participants Who Successfully Swallowed Study Med on Day 6 [3]
    End point description
    The Swallowing Ability Questionnaire was completed on Day 6 after the participant received two matching placebo tablets (excluding marking) following consumption of a low- to moderate-fat meal in pediatric participants aged 10 to 17 years. The questionnaire consisted of 5 parts: 1. Could only swallow study med with help; 2. Easy to start swallowing study med; 3. Easy to swallow study med; 4. Felt like study med got stuck in throat, and 5. Had to swallow study med more than once. The number of participants who strongly agreed or agreed in each of the 5 parts is reported. Per protocol population defined as all participants who completed at least one period of treatment and had available data. On Day 6, all participants received matching placebo, so the two treatment groups were pooled on Day 6.
    End point type
    Primary
    End point timeframe
    Day 6
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 All Treated Participants
    Number of subjects analysed
    24
    Units: Participants
        Strongly Agreed: 1. Could Swallow Med With Help
    5
        Agreed: 1. Could Only Swallow Med With Help
    7
        Strongly Agreed: 2. Easy to Start Swallowing Med
    10
        Agreed: 2. Easy to Start Swallowing Med
    11
        Strongly Agreed: 3. Easy to Swallow Med
    11
        Agreed: 3. Easy to Swallow Med
    12
        Strongly Agreed: 4. Felt Like Med Stuck in Throat
    0
        Agreed: 4. Felt Like Med Got Stuck in Throat
    3
        Strongly Agreed: 5. Had to Swallow Med >1
    2
        Agreed: 5. Had to Swallow Med >1
    5
    No statistical analyses for this end point

    Primary: Number of Participants Who Successfully Swallowed Study Med on Day 9

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    End point title
    		 Number of Participants Who Successfully Swallowed Study Med on Day 9 [4]
    End point description
    The Swallowing Ability Questionnaire was completed on Day 9 after the participant received two matching placebo tablets (excluding marking) following consumption of a low- to moderate-fat meal in pediatric participants aged 10 to 17 years. The questionnaire consisted of 5 parts: 1. Could only swallow study med with help; 2. Easy to start swallowing study med; 3. Easy to swallow study med; 4. Felt like study med got stuck in throat, and 5. Had to swallow study med more than once. The number of participants who strongly agreed or agreed in each of the 5 parts is reported. Per protocol population defined as all participants who completed at least one period of treatment and had available data. On Day 9, all participants received matching placebo, so the two treatment groups were pooled on Day 9.
    End point type
    Primary
    End point timeframe
    Day 9
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 All Treated Participants
    Number of subjects analysed
    24
    Units: Participants
        Strongly Agreed: 1. Could Swallow Med With Help
    9
        Agreed: 1. Could Only Swallow Med With Help
    5
        Strongly Agreed: 2. Easy to Start Swallowing Med
    9
        Agreed: 2. Easy to Start Swallowing Med
    13
        Strongly Agreed: 3. Easy to Swallow Med
    12
        Agreed: 3. Easy to Swallow Med
    11
        Strongly Agreed: 4. Felt Like Med Stuck in Throat
    1
        Agreed: 4. Felt Like Med Got Stuck in Throat
    1
        Strongly Agreed: 5. Had to Swallow Med >1
    2
        Agreed: 5. Had to Swallow Med >1
    5
    No statistical analyses for this end point

    Primary: Area Under the Curve 0 to Last (AUC 0-last) of Sitagliptin Following Single Administration of Sitagliptin/Metformin XR

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    End point title
    		 Area Under the Curve 0 to Last (AUC 0-last) of Sitagliptin Following Single Administration of Sitagliptin/Metformin XR [5] [6]
    End point description
    AUC0-last is a measure of the total amount of drug in the plasma from the dose to the last measurable sample at which the concentration is at or above lower limit of quantification (LLQ). In this study, metformin products were withheld 24 hours (hrs.) prior to sitagliptin/metformin XR administration and were permitted to re-initiate 24 hrs. post study drug administration. Owing to resumption of therapeutic metformin administration 24 hrs. after sitagliptin/metformin XR administration for all participants, metformin pharmacokinetic analyses were restricted to maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and area under the curve 0 to 24 hrs. (AUC0-24hr). Therefore, metformin arm is not included in this endpoint. Per protocol population defined as all participants who completed at least one period of treatment (Sitagliptin/Metformin XR Followed by Placebo arm) and had available data.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours post-dose
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo
    Number of subjects analysed
    12
    Units: nM*hr
        geometric mean (geometric coefficient of variation)
    5940 ( 25.7 )
    No statistical analyses for this end point

    Primary: AUC 0-24 of Sitagliptin Following Single Administration of Sitagliptin/Metformin XR

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    End point title
    		 AUC 0-24 of Sitagliptin Following Single Administration of Sitagliptin/Metformin XR [7] [8]
    End point description
    AUC0-24 is a measure of the total amount of drug in the plasma from the dose to 24 hours after the dose. Due different units of measure for sitagliptin and metformin, metformin data are presented in another endpoint. Per protocol population defined as all participants who completed at least one period of treatment (Sitagliptin/Metformin XR Followed by Placebo arm) and had available data.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours post-dose
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo
    Number of subjects analysed
    12
    Units: nM*hr
        geometric mean (geometric coefficient of variation)
    5310 ( 22.4 )
    No statistical analyses for this end point

    Primary: AUC 0-24 of Metformin Following Single Administration of Sitagliptin/Metformin XR

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    End point title
    		 AUC 0-24 of Metformin Following Single Administration of Sitagliptin/Metformin XR [9] [10]
    End point description
    AUC0-24 is a measure of the total amount of drug in the plasma from the dose to 24 hours after the dose. In this study, metformin products were withheld 24 hours prior to sitagliptin/metformin XR administration and were permitted to re-initiate 24 hours post study drug administration. Due different units of measure for sitagliptin and metformin, sitagliptin data are presented in another endpoint. Per protocol population defined as all participants who completed at least one period of treatment (Sitagliptin/Metformin XR Followed by Placebo arm) and had available data.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours post-dose
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo
    Number of subjects analysed
    12
    Units: ng*hr/mL
        geometric mean (geometric coefficient of variation)
    14200 ( 39.7 )
    No statistical analyses for this end point

    Primary: Area Under the Curve 0 to Infinity (AUC 0-∞) of Sitagliptin Following Single Administration of Sitagliptin/Metformin XR

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    End point title
    		 Area Under the Curve 0 to Infinity (AUC 0-∞) of Sitagliptin Following Single Administration of Sitagliptin/Metformin XR [11] [12]
    End point description
    AUC0-∞ is a measure of the mean concentration levels of drug in the plasma after the dose. In this study, metformin products were withheld 24 hours prior to sitagliptin/metformin XR administration and were permitted to re-initiate 24 hours post study drug administration. Owing to resumption of therapeutic metformin administration 24 hours after sitagliptin/metformin XR administration for all participants, metformin pharmacokinetic analyses were restricted to Cmax, Tmax and AUC0-24hr. Therefore, metformin arm is not included in this endpoint. Per protocol population defined as all participants who completed at least one period of treatment (Sitagliptin/Metformin XR Followed by Placebo arm) and had available data.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours post-dose
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo
    Number of subjects analysed
    12
    Units: nM*hr
        geometric mean (geometric coefficient of variation)
    6020 ( 24.8 )
    No statistical analyses for this end point

    Primary: Cmax of Sitagliptin Following Single Dose Administration of Sitagliptin/Metformin XR

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    End point title
    		 Cmax of Sitagliptin Following Single Dose Administration of Sitagliptin/Metformin XR [13] [14]
    End point description
    Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Due different units of measure for sitagliptin and metformin, metformin data are presented in another endpoint. Per protocol population defined as all participants who completed at least one period of treatment (Sitagliptin/Metformin XR Followed by Placebo arm) and had available data.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours post-dose
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo
    Number of subjects analysed
    12
    Units: nM
        geometric mean (geometric coefficient of variation)
    757 ( 40.1 )
    No statistical analyses for this end point

    Primary: Cmax of Metformin Following Single Dose Administration of Sitagliptin/Metformin XR

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    End point title
    		 Cmax of Metformin Following Single Dose Administration of Sitagliptin/Metformin XR [15] [16]
    End point description
    Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Due different units of measure for sitagliptin and metformin, sitagliptin data are presented in another endpoint. In this study, metformin products were withheld 24 hours prior to sitagliptin/metformin XR administration and were permitted to re-initiate 24 hours post study drug administration. Per protocol population defined as all participants who completed at least one period of treatment (Sitagliptin/Metformin XR Followed by Placebo arm) and had available data.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours post-dose
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo
    Number of subjects analysed
    12
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1490 ( 29.1 )
    No statistical analyses for this end point

    Primary: Tmax of Sitagliptin and Metformin Following Single Dose Administration of Sitagliptin/Metformin XR

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    End point title
    		 Tmax of Sitagliptin and Metformin Following Single Dose Administration of Sitagliptin/Metformin XR [17]
    End point description
    Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. In this study, metformin products were withheld 24 hours prior to sitagliptin/metformin XR administration and were permitted to re-initiate 24 hours post study drug administration. Per protocol population defined as all participants who completed at least one period of treatment (Sitagliptin/Metformin XR followed by placebo arm) and had available data.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours post-dose
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin Metformin
    Number of subjects analysed
    12
    12
    Units: Hour
        median (full range (min-max))
    1.52 (0.97 to 3.05)
    5.00 (3.98 to 7.22)
    No statistical analyses for this end point

    Primary: Apparent Terminal Half Life (t1/2) of Sitagliptin Following Single Dose Administration of Sitagliptin/Metformin XR

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    End point title
    		 Apparent Terminal Half Life (t1/2) of Sitagliptin Following Single Dose Administration of Sitagliptin/Metformin XR [18]
    End point description
    Apparent terminal half-life is the time required to divide the plasma (serum) concentration of drug by two after reaching pseudo-equilibrium. (Note: it is not the time required to eliminate half the administered dose.) In this study, metformin products were withheld 24 hours prior to sitagliptin/metformin XR administration and were permitted to re-initiate 24 hours post study drug administration. Owing to resumption of therapeutic metformin administration 24 hours after sitagliptin/metformin XR administration for all participants, metformin pharmacokinetic analyses were restricted to Cmax, Tmax, and AUC0-24hr. Therefore, metformin arm is not included in this endpoint. Per protocol population defined as all participants who completed at least one period of treatment (Sitagliptin/Metformin XR Followed by Placebo arm) and had available data.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours post-dose
    Notes
    [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin
    Number of subjects analysed
    12
    Units: Hour
        geometric mean (geometric coefficient of variation)
    10.0 ( 27.3 )
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE) [19]
    End point description
    An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. The analysis population included all participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 23 days (including approximately 10 to 14 days after the last dose of study drug)
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo Placebo
    Number of subjects analysed
    13
    12
    Units: Participants
    5
    5
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced an Abnormal Vital Sign Value

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    End point title
    		 Number of Participants Who Experienced an Abnormal Vital Sign Value [20]
    End point description
    Vital sign measurements included blood pressure, heart rate, respiratory rate, and oral temperature. The analysis population included all participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 23 days (including approximately 10 to 14 days after the last dose of study drug)
    Notes
    [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo Placebo
    Number of subjects analysed
    13
    12
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued Study Drug Due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an AE [21]
    End point description
    An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an IMP, regardless of causal relationship and even if no IMP has been administered. The analysis population included all participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 9 days
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this endpoint.
    End point values
    		 Sitagliptin/Metformin XR Followed by Placebo Placebo
    Number of subjects analysed
    13
    12
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 23 days (including approximately 10 to 14 days after the last dose of study drug)
    Adverse event reporting additional description
    An AE was any untoward medical occurrence of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship or administration. The analysis population included all participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Sitagliptin/Metformin XR Followed by Placebo
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Sitagliptin/Metformin XR Followed by Placebo Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Sitagliptin/Metformin XR Followed by Placebo Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 13 (38.46%)
    5 / 12 (41.67%)
    Investigations
    Urine analysis abnormal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Plantar fasciitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Mar 2013
    Various changes to diet restrictions and requirements, safety laboratory tests, and other blood draws.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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