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    Clinical Trial Results:
    A Single-Dose Study to Assess the Pharmacokinetics, Safety, and Tolerability of Sitagliptin in Adolescents

    Summary
    EudraCT number
    		 2014-004993-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    14 Feb 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Apr 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0431-081
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00730275
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme, Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme, Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme, Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000470-PIP01-08 EMEA-000471-PIP01-08 EMEA-000472-PIP01-08
    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
    14 Feb 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will assess the safety, tolerability and pharmacokinetics of sitagliptin in 10 to 17 year old participants with type 2 diabetes.
    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: the initiation of administering sitagliptin 200 mg was dependent on the review of safety and pharmacokinetic (PK) data from sitagliptin 50 mg and 100 mg.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jul 2008
    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: 35
    Worldwide total number of subjects
    35
    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)
    3
    Adolescents (12-17 years)
    32
    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
    		 -

    Pre-assignment
    Screening details
    		 Eligibility criteria included male and female participants who were between 10 to 17 years of age with a history of type 2 diabetes.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sitagliptin 50 mg
    Arm description
    		 Participants who received a single oral dose of sitagliptin 50 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sitagliptin phosphate
    Investigational medicinal product code
    Other name
    Januvia, MK-0431
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were to fast 8 hours prior to dosing. All doses were to be given with 240 ml of water. Sitagliptin 50 mg and/or 100 mg tablet was to be administered as a single dose of 50 mg, 100 mg, or 200 mg.

    Arm title
    		 Sitagliptin 100 mg
    Arm description
    		 Participants who received a single oral dose of sitagliptin 100 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sitagliptin phosphate
    Investigational medicinal product code
    Other name
    Januvia, MK-0431
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were to fast 8 hours prior to dosing. All doses were to be given with 240 ml of water. Sitagliptin 50 mg and/or 100 mg tablet was to be administered as a single dose of 50 mg, 100 mg, or 200 mg.

    Arm title
    		 Sitagliptin 200 mg
    Arm description
    		 Participants who received a single oral dose of sitagliptin 200 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sitagliptin phosphate
    Investigational medicinal product code
    Other name
    Januvia, MK-0431
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were to fast 8 hours prior to dosing. All doses were to be given with 240 ml of water. Sitagliptin 50 mg and/or 100 mg tablet was to be administered as a single dose of 50 mg, 100 mg, or 200 mg.

    Arm title
    		 Placebo
    Arm description
    		 Participants who received a single oral dose of matching placebo to sitagliptin 50 mg, 100 mg or 200 mg.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to sitagliptin 50 mg and/or 100 mg administered as a single dose

    Number of subjects in period 1
    		Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg Placebo
    Started
    9
    9
    8
    9
    Completed
    9
    9
    8
    8
    Not completed
    0
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin 50 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 50 mg.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 100 mg.

    Reporting group title
    Sitagliptin 200 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 200 mg.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received a single oral dose of matching placebo to sitagliptin 50 mg, 100 mg or 200 mg.

    Reporting group values
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg Placebo Total
    Number of subjects
    		 9 9 8 9 35
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.9 ± 2.52 14.3 ± 1.41 14.8 ± 1.75 14.1 ± 2.26 -
    Gender categorical
    Units: Subjects
        Female
    		 6 5 5 8 24
        Male
    		 3 4 3 1 11

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin 50 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 50 mg.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 100 mg.

    Reporting group title
    Sitagliptin 200 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 200 mg.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received a single oral dose of matching placebo to sitagliptin 50 mg, 100 mg or 200 mg.

    Primary: Number of participants who experienced at least one adverse event

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    End point title
    		 Number of participants who experienced at least one adverse event [1]
    End point description
    An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor’s product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor’s product, is also an adverse event. Population for analysis included all enrolled participants.
    End point type
    Primary
    End point timeframe
    Up to 14 days following administration of study drug
    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: There was no plan to perform a between group statistical comparison for this endpoint.
    End point values
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg Placebo
    Number of subjects analysed
    9
    9
    8
    9
    Units: Participants
    3
    1
    1
    2
    No statistical analyses for this end point

    Primary: Area under the concentration time curve (AUC) from time 0 to infinity following a single dose of sitagliptin

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    End point title
    		 Area under the concentration time curve (AUC) from time 0 to infinity following a single dose of sitagliptin [2]
    End point description
    Serum samples were used to determine the AUC from time 0 to infinity for sitagliptin. The placebo group is not included in the table below; this endpoint only evaluated the sitagliptin groups. Analysis population includes all participants who received a single dose of sitagliptin 50 mg, 100 mg, or 200 mg.
    End point type
    Primary
    End point timeframe
    Pre-dose through 72 hours post-dose
    Notes
    [2] - 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: This endpoint only reported values for participants from arms treated with sitagliptin, since no pharmacokinetic parameters were available for participants treated with placebo.
    End point values
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg
    Number of subjects analysed
    9
    9
    8
    Units: nM*hour
        geometric mean (confidence interval 95%)
    3438 (2881 to 4103)
    5869 (4918 to 7003)
    12965 (10749 to 15638)
    Statistical analysis title
    		 Dose-adjusted (to 100 mg) AUC: Pooled across Doses
    Statistical analysis description
    Geometric Mean across all dose strengths. Back-transformed mean and confidence interval from univariate analysis performed on natural log-transformed values.
    Comparison groups
    Sitagliptin 100 mg v Sitagliptin 50 mg v Sitagliptin 200 mg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric mean
    Point estimate
    6392
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5766
         upper limit
    		 7086

    Secondary: Maximum concentration (Cmax) following a single dose of sitagliptin

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    End point title
    		 Maximum concentration (Cmax) following a single dose of sitagliptin [3]
    End point description
    Serum samples were used to determine the Cmax for sitagliptin. The placebo group is not included in the table below; this endpoint only evaluated the sitagliptin groups. Analysis population includes all participants who received a single dose of sitagliptin 50 mg, 100 mg, or 200 mg.
    End point type
    Secondary
    End point timeframe
    Pre-dose through 72 hours post-dose
    Notes
    [3] - 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: This endpoint only reported values for participants from arms treated with sitagliptin, since no pharmacokinetic parameters were available for participants treated with placebo.
    End point values
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg
    Number of subjects analysed
    9
    9
    8
    Units: nM
        geometric mean (confidence interval 95%)
    366 (288 to 464)
    666 (526 to 845)
    1876 (1458 to 2413)
    No statistical analyses for this end point

    Secondary: Time of occurrence of maximum concentration (Tmax) following a single dose of sitagliptin

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    End point title
    		 Time of occurrence of maximum concentration (Tmax) following a single dose of sitagliptin [4]
    End point description
    Serum samples were used to determine the Tmax for sitagliptin. The placebo group is not included in the table below; this endpoint only evaluated the sitagliptin groups. Analysis population includes all participants who received a single dose of sitagliptin 50 mg, 100 mg, or 200 mg.
    End point type
    Secondary
    End point timeframe
    Pre-dose through 72 hours post-dose
    Notes
    [4] - 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: This endpoint only reported values for participants from arms treated with sitagliptin, since no pharmacokinetic parameters were available for participants treated with placebo.
    End point values
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg
    Number of subjects analysed
    9
    9
    8
    Units: Hours
        median (full range (min-max))
    3 (1.5 to 5)
    3 (2 to 4.5)
    2.5 (1 to 3.1)
    No statistical analyses for this end point

    Secondary: Apparent terminal half-life (apparent t1/2) following a single dose of sitagliptin

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    End point title
    		 Apparent terminal half-life (apparent t1/2) following a single dose of sitagliptin [5]
    End point description
    Serum samples were used to determine the apparent t1/2 for sitagliptin. The placebo group is not included in the table below; this endpoint only evaluated the sitagliptin groups. Analysis population includes all participants who received a single dose of sitagliptin 50 mg, 100 mg, or 200 mg. Summary statistics presented are the harmonic mean and Jackknife-standard deviation.
    End point type
    Secondary
    End point timeframe
    Pre-dose through 72 hours post-dose
    Notes
    [5] - 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: This endpoint only reported values for participants from arms treated with sitagliptin, since no pharmacokinetic parameters were available for participants treated with placebo.
    End point values
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg
    Number of subjects analysed
    9
    9
    8
    Units: Hours
        arithmetic mean (standard deviation)
    12.1 ± 1.7
    11.2 ± 2.1
    11.7 ± 1.8
    No statistical analyses for this end point

    Secondary: Plasma Dipeptidyl Peptidase-4 (DPP-4) activity following a single dose of sitagliptin or placebo

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    End point title
    		 Plasma Dipeptidyl Peptidase-4 (DPP-4) activity following a single dose of sitagliptin or placebo
    End point description
    Plasma DPP-4 activity was analyzed using the 24-hour weighted average inhibition (WAI) and percent inhibition at 24 hours post-dose. WAI was defined as the AUC of inhibition divided by the length of the post-dose time interval. Positive values of WAI represent a decrease in DPP-4 activity. Analysis population includes all participants who received a single dose of sitagliptin or placebo.
    End point type
    Secondary
    End point timeframe
    Pre-dose through 24 hours post-dose
    End point values
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg Placebo
    Number of subjects analysed
    9
    9
    8
    8
    Units: Percent inhibition
    least squares mean (confidence interval 95%)
        24-hour WAI of DPP-4 activity
    73.98 (70.59 to 76.99)
    80.53 (77.98 to 82.78)
    87.96 (86.29 to 89.43)
    6.76 (-6.21 to 18.14)
        DPP-4 activity at 24 hours post-dose
    53.98 (46.74 to 60.24)
    62.78 (56.92 to 67.84)
    75.76 (71.7 to 79.24)
    3.57 (-12.6 to 17.43)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 14 days after study drug administration
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Sitagliptin 50 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 50 mg.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 100 mg.

    Reporting group title
    Sitagliptin 200 mg
    Reporting group description
    		 Participants who received a single oral dose of sitagliptin 200 mg.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received a single oral dose of matching placebo to sitagliptin 50 mg, 100 mg or 200 mg.

    Serious adverse events
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    2 / 9 (22.22%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Infusion site pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infusion site swelling
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2008
    Amendment 1: The primary reason for this amendment was to add that Panel C will be conducted regardless of whether the pre-specified drug exposures are achieved in Panels A or B.
    19 Mar 2009
    Amendment 2: The primary reason for this amendment was to permit enrollment of participants with a history of thyroid disease that has been clinically stable for at least 3 months prior to randomization at the discretion of the investigator, and with the concurrence of the Merck clinical monitor. Concomitant therapy with thyroid hormone was to be permitted if the participant had been taking a stable dose for at least 3 months prior to administration of study drug, and is euthyroid as documented by thyroid stimulating hormone testing at prestudy.
    21 Apr 2009
    Amendment 3: The primary reason for this amendment was to increase the total number of participants with type 2 diabetes mellitus in the study from 24 to at least 36 (12 subjects per panel).

    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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