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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of MK-3102 in ≥18 and <45 Year-Old Subjects with Type 2 Diabetes Mellitus and Inadequate Glycemic Control

    Summary
    EudraCT number
    2012-004303-12
    Trial protocol
    RO  
    Global end of trial date
    14 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Sep 2016
    First version publication date
    14 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-3102-028
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01814748
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will examine the safety and efficacy of once-weekly omarigliptin in participants 18 to <45 years of age with Type 2 diabetes mellitus and inadequate glycemic control. The study hypothesis is that treatment with omarigliptin compared with placebo provides greater reduction in hemoglobin A1c (A1C) in participants after 24 weeks.
    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 participants: participants exceeding pre-specified glycemic thresholds after Day 1 of the double-blind treatment period were to have rescue therapy with open-label metformin initiated by the investigator.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Mexico: 23
    Country: Number of subjects enrolled
    Romania: 48
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    South Africa: 14
    Country: Number of subjects enrolled
    Ukraine: 49
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    203
    EEA total number of subjects
    48
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    203
    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 requirements include male and female participants with type 2 diabetes mellitus who were currently not on an antihyperglycemic agent (AHA) for at least the past 12 weeks and has not been treated with omarigliptin at any time prior to study participation.

    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
    Omarigliptin 25 mg
    Arm description
    Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.
    Arm type
    Experimental

    Investigational medicinal product name
    Omarigliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg administered orally once weekly

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Open-label metformin (dosed daily according to the country-specific product label) was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.

    Arm title
    Placebo
    Arm description
    Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.
    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
    Open-label metformin (dosed daily according to the country-specific product label) was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.

    Investigational medicinal product name
    Placebo to omarigliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to omarigliptin 25 mg administered orally once weekly

    Number of subjects in period 1
    Omarigliptin 25 mg Placebo
    Started
    102
    101
    Completed
    94
    94
    Not completed
    8
    7
         Consent withdrawn by subject
    6
    4
         Study site terminated by sponsor
    1
    1
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Omarigliptin 25 mg
    Reporting group description
    Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.

    Reporting group title
    Placebo
    Reporting group description
    Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.

    Reporting group values
    Omarigliptin 25 mg Placebo Total
    Number of subjects
    102 101 203
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    38.8 ± 4.7 39.5 ± 4.5 -
    Gender, Male/Female
    Units: Participants
        Female
    35 41 76
        Male
    67 60 127
    Hemoglobin A1c (A1C)
    Units: Percent
        arithmetic mean (standard deviation)
    7.9 ± 0.8 8.1 ± 0.9 -
    Fasting plasma glucose (FPG)
    Units: mg/dL
        arithmetic mean (standard deviation)
    164 ± 38.9 167.8 ± 40.6 -
    2-hour post-meal glucose (2-hr PMG)
    Participants with available data at baseline. Omarigliptin 25 mg, n=98; placebo, n=101
    Units: mg/dL
        arithmetic mean (standard deviation)
    204.9 ± 55.1 217.3 ± 67.7 -

    End points

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    End points reporting groups
    Reporting group title
    Omarigliptin 25 mg
    Reporting group description
    Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.

    Reporting group title
    Placebo
    Reporting group description
    Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.

    Primary: Change from baseline in A1C at Week 24

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    End point title
    Change from baseline in A1C at Week 24
    End point description
    A1C (%) is used to report average blood glucose levels over prolonged periods of time. Analysis population: Full analysis set (FAS) population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    Omarigliptin 25 mg Placebo
    Number of subjects analysed
    102
    101
    Units: Percent
        least squares mean (confidence interval 95%)
    -0.33 (-0.6 to -0.06)
    -0.45 (-0.72 to -0.18)
    Statistical analysis title
    Between group comparison
    Comparison groups
    Omarigliptin 25 mg v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.535 [1]
    Method
    Constrained longitudinal data analysis
    Parameter type
    Difference in least squares means
    Point estimate
    0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.26
         upper limit
    0.49
    Notes
    [1] - Terms for treatment, time, and the interaction of time by treatment, with the constraint that the mean baseline is the same for all treatment groups. Other method: Constrained longitudinal data analysis (cLDA)

    Primary: Percentage of participants who experienced at least one adverse event (AE)

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    End point title
    Percentage of participants who experienced at least one adverse event (AE)
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. Analysis population: All participants treated (APaT) population included all randomized participants who received at least one dose of study medication. The safety database was analyzed in a standard fashion in the APaT population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).
    End point type
    Primary
    End point timeframe
    Up to Week 27
    End point values
    Omarigliptin 25 mg Placebo
    Number of subjects analysed
    102
    101
    Units: Percentage of participants
        number (not applicable)
    39.2
    39.6
    Statistical analysis title
    Between group comparison
    Comparison groups
    Omarigliptin 25 mg v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in percent
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.8
         upper limit
    13

    Primary: Percentage of participants who discontinued study drug due to an AE

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    End point title
    Percentage of participants who discontinued study drug due to an AE
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. Analysis population: APaT population included all randomized participants who received at least one dose of study medication. The safety database was analyzed in a standard fashion in the APaT population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).
    End point type
    Primary
    End point timeframe
    Up to Week 24
    End point values
    Omarigliptin 25 mg Placebo
    Number of subjects analysed
    102
    101
    Units: Percentage of participants
        number (not applicable)
    0
    2
    Statistical analysis title
    Between group comparison
    Comparison groups
    Omarigliptin 25 mg v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Difference in percent
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -
         upper limit
    99999
    Notes
    [2] - Confidence interval (CI) was not calculated; therefore, 99999 = not calculated.

    Secondary: Change from baseline in 2-hr PMG at Week 24

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    End point title
    Change from baseline in 2-hr PMG at Week 24
    End point description
    Blood glucose was measured 120 minutes from start of meal. Analysis population: FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Omarigliptin 25 mg Placebo
    Number of subjects analysed
    100
    101
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -11.3 (-26.1 to 3.5)
    -15.5 (-30.6 to -0.3)
    Statistical analysis title
    Between group comparison
    Comparison groups
    Omarigliptin 25 mg v Placebo
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.685 [3]
    Method
    Constrained longitudinal data analysis
    Parameter type
    Difference in least squares means
    Point estimate
    4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.1
         upper limit
    24.4
    Notes
    [3] - Terms for treatment, time, and the interaction of time by treatment, with the constraint that the mean baseline is the same for all treatment groups.

    Secondary: Change in baseline in FPG at Week 24

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    End point title
    Change in baseline in FPG at Week 24
    End point description
    Blood glucose was measured on a fasting basis. Analysis population: FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Omarigliptin 25 mg Placebo
    Number of subjects analysed
    102
    101
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -5 (-14.6 to 4.6)
    -1.3 (-11.2 to 8.5)
    Statistical analysis title
    Between group comparison
    Comparison groups
    Omarigliptin 25 mg v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.586 [4]
    Method
    Constrained longitudinal data analysis
    Parameter type
    Difference in least squares means
    Point estimate
    -3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.1
         upper limit
    9.7
    Notes
    [4] - Terms for treatment, time, and the interaction of time by treatment, with the constraint that the mean baseline is the same for all treatment groups.

    Secondary: Percentage of participants attaining A1C glycemic goals of <7.0% at Week 24

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    End point title
    Percentage of participants attaining A1C glycemic goals of <7.0% at Week 24
    End point description
    Percentage of participants was estimated using standard multiple imputation techniques (cLDA model). Within-group CIs were calculated via the Wilson score method. FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Omarigliptin 25 mg Placebo
    Number of subjects analysed
    102
    101
    Units: Percentage of participants
        number (confidence interval 95%)
    33.5 (24.7 to 43.7)
    34 (25.1 to 44.1)
    Statistical analysis title
    Between group comparison
    Comparison groups
    Omarigliptin 25 mg v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Mietinnen and Nurminen
    Parameter type
    Between-group rate difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14
         upper limit
    13.1

    Secondary: Percentage of participants attaining A1C glycemic goals of <6.5% at Week 24

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    End point title
    Percentage of participants attaining A1C glycemic goals of <6.5% at Week 24
    End point description
    Percentage of participants was estimated using standard multiple imputation techniques (cLDA model). Within-group CIs were calculated via the Wilson score method. FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Omarigliptin 25 mg Placebo
    Number of subjects analysed
    102
    101
    Units: Percentage of participants
        number (confidence interval 95%)
    21.7 (14.5 to 31.1)
    17.6 (11.3 to 26.5)
    Statistical analysis title
    Between group comparison
    Comparison groups
    Omarigliptin 25 mg v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Mietinnen and Nurminen
    Parameter type
    Between-group rate difference
    Point estimate
    4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.4
         upper limit
    15.5

    Secondary: Percentage of participants who required glycemic rescue by Week 24

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    End point title
    Percentage of participants who required glycemic rescue by Week 24
    End point description
    Participants exceeding pre-specified glycemic thresholds after starting the double-blind treatment period may have received rescue therapy (per protocol) with open-label metformin initiated by the investigator. Analysis population: all randomized participants. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    Omarigliptin 25 mg Placebo
    Number of subjects analysed
    102
    101
    Units: Percentage of participants
        number (not applicable)
    10.8
    12.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 27 weeks; Serious adverse events (SAEs) were collected up to 24 weeks during treatment + 3 week follow-up, non-serious adverse events (NSAEs) were collected up to 24 weeks during treatment
    Adverse event reporting additional description
    SAEs include data after glycemic rescue; NSAEs exclude data after glycemic rescue. Investigations performed by the Sponsor revealed that many participants had used a prohibited antihyperglycemic agent—metformin (i.e., not as rescue medication; see efficacy results description above).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.

    Reporting group title
    Omarigliptin 25 mg
    Reporting group description
    Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.

    Serious adverse events
    Placebo Omarigliptin 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 101 (2.97%)
    1 / 102 (0.98%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis acute
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Omarigliptin 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 101 (6.93%)
    10 / 102 (9.80%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 101 (5.94%)
    6 / 102 (5.88%)
         occurrences all number
    6
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 101 (1.98%)
    6 / 102 (5.88%)
         occurrences all number
    2
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2013
    Amendment 1: primary reason was to add amylase and lipase to the chemistry 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.
    Investigations indicate that the presence of metformin in future biomedical research (FBR) samples from non-rescued participants was due to participant self-administration of metformin outside of the protocol and without investigator knowledge.
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