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    Clinical Trial Results:
    A Phase IIa, Multicenter, Placebo- and Active-controlled, Randomized, Double-Blind, Clinical Trial to Evaluate the Safety and Efficacy of MK-8521 Compared to Placebo in Subjects with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    		 2016-002056-25
    Trial protocol
    		 ES  
    Global end of trial date
    18 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2018
    First version publication date
    08 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8521-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02492763
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study number: MK-8521-004
    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
    Senior Vice President, Global Clinical Development, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    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
    18 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This is a multicenter randomized, double-blind, placebo- and active-controlled (liraglutide; Victoza®), parallel-group, clinical trial of MK-8521 in participants with type 2 diabetes mellitus (T2DM) with inadequate glycemic control while on a stable dose of metformin (≥1000 mg/day). The trial will include a 1-week screening period; at least an 8-week antihyperglycemic agent (AHA) washout period, if required; a 14-week blinded therapy period (which includes single-blind run-in and double-blind therapy); and a 14-day post-treatment visit, 2 weeks after the last dose of investigational product. The primary hypothesis of the trial is that MK-8521 provides greater reduction in hemoglobin A1C relative to placebo after 12 weeks of once-daily administration in participants with T2DM with inadequate glycemic control on metformin monotherapy.
    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
    		 Subjects will continue on their stable dose of metformin monotherapy (≥1000 mg/day) throughout the trial including the 14-day post-treatment visit.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jul 2015
    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
    Australia: 1
    Country: Number of subjects enrolled
    Colombia: 11
    Country: Number of subjects enrolled
    Guatemala: 12
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United States: 142
    Worldwide total number of subjects
    176
    EEA total number of subjects
    6
    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)
    169
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 84 clinical trial sites in Australia, Colombia, Guatemala, Israel, New Zealand, Spain, and in the United States.

    Pre-assignment
    Screening details
    		 Five hundred participants were screened and 176 randomized. Participants were males or females who had Type 2 diabetes mellitus.

    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
    		 MK-8521 180 μg
    Arm description
    		 Participants received double-blind MK-8521 180 μg daily (QD), subcutaneously, over 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-8521
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received double-blind MK-8521 180 μg daily (QD), subcutaneously, over 12 weeks.

    Arm title
    		 MK-8521 300 μg
    Arm description
    		 Participants received double-blind MK-8521 300 μg, QD, subcutaneously, over 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-8521
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received double-blind MK-8521 300 μg QD, subcutaneously, over 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching double-blind placebo QD over 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to MK-8521
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received matching double-blind placebo QD over 12 weeks.

    Arm title
    		 Liraglutide 1.8 mg
    Arm description
    		 Participants received open-label liraglutide, 1.8 mg QD, subcutaneously, over 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received open-label liraglutide 0.6 escalated up to 1.8 mg QD, subcutaneously, for up to 12 weeks.

    Number of subjects in period 1
    		MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Started
    46
    44
    43
    43
    Treated
    46
    44
    43
    42
    Completed
    30
    29
    33
    30
    Not completed
    16
    15
    10
    13
         Hyperglycemia Discontinuation Criteria
    -
    1
    -
    -
         Adverse event, serious fatal
    -
    -
    1
    -
         Consent withdrawn by subject
    -
    2
    1
    -
         Screen Failure
    -
    -
    -
    1
         Adverse event, non-fatal
    3
    1
    1
    2
         Non-Compliance With Study Drug
    -
    1
    -
    -
         Study Terminated by Sponsor
    13
    10
    6
    10
         Lost to follow-up
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MK-8521 180 μg
    Reporting group description
    		 Participants received double-blind MK-8521 180 μg daily (QD), subcutaneously, over 12 weeks.

    Reporting group title
    MK-8521 300 μg
    Reporting group description
    		 Participants received double-blind MK-8521 300 μg, QD, subcutaneously, over 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching double-blind placebo QD over 12 weeks.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Participants received open-label liraglutide, 1.8 mg QD, subcutaneously, over 12 weeks.

    Reporting group values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg Total
    Number of subjects
    		 46 44 43 43 176
    Age categorical
    The baseline analysis population consisted of all participants randomized.
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 44 43 41 41 169
        From 65-84 years
    		 2 1 2 2 7
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    The baseline analysis population consisted of all participants randomized.
    Units: years
        arithmetic mean (standard deviation)
    		 54.0 ( 7.6 ) 54.2 ( 7.9 ) 51.5 ( 10.1 ) 52.9 ( 9.4 ) -
    Sex: Female, Male
    The baseline analysis population consisted of all participants randomized.
    Units: Subjects
        Female
    		 26 18 24 20 88
        Male
    		 20 26 19 23 88
    Hemoglobin A1C Classification by Levels
    Hemoglobin A1C classification by levels: <8.5% or >=8.5%. The baseline analysis population consisted of all participants randomized.
    Units: Subjects
        <8.5%|
    		 22 24 24 21 91
        >=8.5%|
    		 24 20 19 22 85
    Antihyperglycemic agent (AHA) Washout Status
    AHA washout status (yes/no). The trial included an 8-week AHA washout period for participants taking a AHA. The baseline analysis population consisted of all participants randomized.
    Units: Subjects
        Yes|
    		 5 5 5 5 20
        No|
    		 41 39 38 38 156
    Body Mass Index (BMI)
    Number of participants with a BMI <30 kg/m^2 or BMI>=30 kg/m^2. The baseline analysis population consisted of all participants randomized.
    Units: Subjects
        <30 kg/m^2|
    		 18 14 15 15 62
        >=30 kg/m^2|
    		 28 30 28 28 114
    Race (NIH/OMB)
    The baseline analysis population consisted of all participants randomized.
    Units: Subjects
        American Indian or Alaska Native
    		 4 3 2 4 13
        Asian
    		 2 3 4 0 9
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 8 9 12 7 36
        White
    		 27 25 23 31 106
        More than one race
    		 5 4 2 1 12
        Unknown or Not Reported
    		 0 0 0 0 0
    Fasting Low Density Lipoprotein (LDL) Cholesterol
    The baseline analysis population consisted of all randomized participants who had a baseline LDL cholesterol value.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 103.3 ( 28.1 ) 95.6 ( 33.8 ) 100.5 ( 42.8 ) 93.0 ( 29.5 ) -
    Fasting High Density Lipoprotein (HDL) Cholesterol
    The baseline analysis population consisted of all randomized participants who had a baseline HDL cholesterol value.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 47.4 ( 12.3 ) 41.7 ( 9.5 ) 43.1 ( 12.0 ) 46.8 ( 13.8 ) -
    Fasting Triglycerides
    The baseline analysis population consisted of all randomized participants who had a baseline fasting triglycerides value.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 171.5 ( 104.6 ) 167.1 ( 79.5 ) 168.7 ( 96.1 ) 154.0 ( 89.5 ) -
    Systolic Blood Pressure (SBP)
    The baseline analysis population consisted of all randomized participants who had a baseline SBP value.
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 125.1 ( 10.8 ) 126.0 ( 12.0 ) 124.6 ( 14.3 ) 126.3 ( 11.0 ) -
    Diastolic Blood Pressure (DBP)
    The baseline analysis population consisted of all randomized participants who had a baseline DBP value.
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 76.6 ( 6.3 ) 77.9 ( 7.4 ) 77.6 ( 8.3 ) 78.9 ( 5.7 ) -
    Hemoglobin A1C
    The baseline analysis population consisted of all randomized participants who had a baseline A1C value.
    Units: Percent
        arithmetic mean (standard deviation)
    		 8.54 ( 0.82 ) 8.43 ( 0.78 ) 8.46 ( 0.83 ) 8.72 ( 1.03 ) -
    Body Weight
    The baseline analysis population consisted of all randomized participants who had a baseline body weight value.
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 85.4 ( 18.1 ) 89.4 ( 20.0 ) 90.2 ( 19.0 ) 92.4 ( 16.5 ) -
    Heart Rate
    The baseline analysis population consisted of all randomized participants who had a baseline heart rate value.
    Units: Beats/minute
        arithmetic mean (standard deviation)
    		 72.5 ( 7.7 ) 72.2 ( 9.9 ) 73.8 ( 8.6 ) 74.7 ( 8.9 ) -
    Fasting Plasma Glucose (FPG)
    The baseline analysis population consisted of all randomized participants who had a baseline FPG value.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 171.4 ( 41.0 ) 175.0 ( 49.5 ) 172.0 ( 39.2 ) 187.5 ( 44.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    MK-8521 180 μg
    Reporting group description
    		 Participants received double-blind MK-8521 180 μg daily (QD), subcutaneously, over 12 weeks.

    Reporting group title
    MK-8521 300 μg
    Reporting group description
    		 Participants received double-blind MK-8521 300 μg, QD, subcutaneously, over 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching double-blind placebo QD over 12 weeks.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Participants received open-label liraglutide, 1.8 mg QD, subcutaneously, over 12 weeks.

    Primary: Change from Baseline in Hemoglobin A1C (A1C) at Week 12

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    End point title
    		 Change from Baseline in Hemoglobin A1C (A1C) at Week 12
    End point description
    A1C is the percentage of hemoglobin that has glucose bound to it and is a blood marker used to report average blood glucose levels over prolonged periods of time. A1C is reported as a percentage (%). This change from baseline reflects the Week 12 A1C minus the Week 0 A1C. The analysis population consisted of all randomized, treated participants with at least one A1C measurement (baseline or post-baseline).
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: Percent
        least squares mean (confidence interval 95%)
    -0.82 (-1.16 to -0.49)
    -1.05 (-1.41 to -0.69)
    -0.44 (-0.80 to -0.08)
    -1.42 (-1.77 to -1.07)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.126
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 0.11
    Notes
    [1] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.017
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 1.08
    Notes
    [2] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.018
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 -0.1
    Notes
    [3] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.146
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.87
    Notes
    [4] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    Placebo v Liraglutide 1.8 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 < 0.001
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.49
         upper limit
    		 -0.48
    Notes
    [5] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment

    Primary: Number of Participants With an Adverse Event (AE)

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    End point title
    		 Number of Participants With an Adverse Event (AE) [6]
    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. The analysis population consisted of all randomized participants who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to Week 14
    Notes
    [6] - 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 primary end point.
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: Participants
    24
    29
    25
    22
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued Study Treatment due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Treatment due to an AE [7]
    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. The analysis population consisted of all randomized participants who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to Week 12
    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 primary end point.
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: Participants
    3
    1
    2
    2
    No statistical analyses for this end point

    Primary: Number of Participants With an AE of Symptomatic Hypoglycemia

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    End point title
    		 Number of Participants With an AE of Symptomatic Hypoglycemia
    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. Hypoglycemia episodes are those with glucose values ≤70 mg/dL (3.9 mmol/L). Symptomatic hypoglycemia episodes were episodes with clinical symptoms reported by the investigator as hypoglycemia and classified as adverse events. The analysis population consisted of all randomized participants who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to Week 14
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: Participants
    0
    2
    1
    1
    Statistical analysis title
    		 Difference in % vs Placebo
    Comparison groups
    MK-8521 180 μg v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.301
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in % vs Placebo
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.1
         upper limit
    		 5.6
    Statistical analysis title
    		 Difference in % vs Placebo
    Comparison groups
    MK-8521 300 μg v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.573
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in % vs Placebo
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.1
         upper limit
    		 13.2
    Statistical analysis title
    		 Difference in % vs Liraglutide
    Comparison groups
    MK-8521 180 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.295
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in % vs Liraglutide
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.4
         upper limit
    		 5.5
    Statistical analysis title
    		 Difference in % vs Liraglutide
    Comparison groups
    MK-8521 300 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.587
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in % vs Liraglutide
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 13.2

    Primary: Change from Baseline in Heart Rate at Week 12

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    End point title
    		 Change from Baseline in Heart Rate at Week 12
    End point description
    This change from baseline reflects the Week 12 heart rate minus the Week 0 heart rate. The analysis population consisted of all randomized, treated participants with at least one heart rate measurement (baseline or post-baseline).
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: Beats/minute
        least squares mean (confidence interval 95%)
    5.47 (2.99 to 7.96)
    6.28 (3.72 to 8.84)
    -1.42 (-3.92 to 1.07)
    1.63 (-0.88 to 4.14)
    Statistical analysis title
    		 Difference in the LS Means vs. Placebo
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    Parameter type
    		 Difference in the LS Means vs. Placebo
    Point estimate
    6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.42
         upper limit
    		 10.37
    Notes
    [8] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in the LS Means vs. Liraglutide
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    Method
    Parameter type
    		 Difference in LS Means vs. Liraglutide
    Point estimate
    3.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 7.33
    Notes
    [9] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in the LS Means vs. Placebo
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    Method
    Parameter type
    		 Difference in LS Means vs. Placebo
    Point estimate
    7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.17
         upper limit
    		 11.23
    Notes
    [10] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in the LS Means vs. Liraglutide
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    Method
    Parameter type
    		 Difference in LS Means vs. Liraglutide
    Point estimate
    4.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 8.19
    Notes
    [11] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment

    Secondary: Change from Baseline in Body Weight at Week 12

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    End point title
    		 Change from Baseline in Body Weight at Week 12
    End point description
    This change from baseline reflects the Week 12 body weight minus the Week 0 body weight. The analysis population consisted of all randomized, treated participants with at least one body weight measurement (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: Kilograms
        least squares mean (confidence interval 95%)
    -2.0 (-2.9 to -1.1)
    -3.0 (-4.0 to -2.1)
    -1.3 (-2.2 to -0.3)
    -2.9 (-3.8 to -1.9)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.285
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 0.6
    Notes
    [12] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.183
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 2.2
    Notes
    [13] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.01
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 -0.4
    Notes
    [14] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.811
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 1.2
    Notes
    [15] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    Placebo v Liraglutide 1.8 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.018 [17]
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 -0.3
    Notes
    [16] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    [17] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG) at Week 12

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG) at Week 12
    End point description
    This change from baseline reflects the Week 12 FPG minus the Week 0 FPG. The analysis population consisted of all randomized, treated participants with at least one FPG measurement (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -13.7 (-27.7 to 0.3)
    -34.6 (-49.3 to -19.9)
    -5.1 (-19.4 to 9.2)
    -42.9 (-57.0 to -28.7)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 [18]
    P-value
    		 = 0.385
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -8.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.2
         upper limit
    		 10.9
    Notes
    [18] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 [19]
    P-value
    		 = 0.004
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    29.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.7
         upper limit
    		 48.6
    Notes
    [19] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 [20]
    P-value
    		 = 0.004
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -29.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.6
         upper limit
    		 -9.4
    Notes
    [20] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 [21]
    P-value
    		 = 0.416
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.7
         upper limit
    		 28.2
    Notes
    [21] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    Placebo v Liraglutide 1.8 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 [22]
    P-value
    		 < 0.001
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -37.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.5
         upper limit
    		 -18
    Notes
    [22] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment

    Secondary: Change from Baseline in Fasting Low Density Lipoprotein (LDL) Cholesterol at Week 12

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    End point title
    		 Change from Baseline in Fasting Low Density Lipoprotein (LDL) Cholesterol at Week 12
    End point description
    This change from baseline reflects the Week 12 fasting LDL cholesterol minus the Week 0 fasting LDL cholesterol. The analysis population consisted of all randomized, treated participants with at least one fasting LDL cholesterol measurement (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    27
    26
    28
    29
    Units: mg/dL
        arithmetic mean (standard deviation)
    -9.3 ( 23.5 )
    8.8 ( 41.8 )
    4.5 ( 33.5 )
    0.3 ( 18.0 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting High Density Lipoprotein (HDL) Cholesterol at Week 12

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    End point title
    		 Change from Baseline in Fasting High Density Lipoprotein (HDL) Cholesterol at Week 12
    End point description
    This change from baseline reflects the Week 12 fasting HDL cholesterol minus the Week 0 fasting HDL cholesterol. The analysis population consisted of all randomized, treated participants with at least one fasting HDL cholesterol measurement (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    27
    26
    28
    29
    Units: mg/dL
        arithmetic mean (standard deviation)
    -0.4 ( 12.3 )
    -0.5 ( 6.0 )
    3.8 ( 6.6 )
    0.4 ( 5.7 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Triglycerides at Week 12

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    End point title
    		 Change from Baseline in Fasting Triglycerides at Week 12
    End point description
    This change from baseline reflects the Week 12 fasting triglycerides minus the Week 0 fasting triglycerides. The analysis population consisted of all randomized, treated participants with at least one fasting triglycerides measurement (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    31
    27
    31
    30
    Units: mg/dL
        arithmetic mean (standard deviation)
    -2.9 ( 91.9 )
    -26.6 ( 71.2 )
    -15.6 ( 68.9 )
    -20.5 ( 48.6 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Systolic Blood Pressure (SBP) at Week 12

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    End point title
    		 Change from Baseline in Systolic Blood Pressure (SBP) at Week 12
    End point description
    This change from baseline reflects the Week 12 SBP minus the Week 0 SBP. The analysis population consisted of all randomized, treated participants with at least one SBP measurement (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: mmHg
        least squares mean (confidence interval 95%)
    -2.7 (-6.4 to 0.9)
    -1.5 (-5.2 to 2.3)
    1.0 (-2.6 to 4.6)
    -1.7 (-5.3 to 2.0)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.151
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 1.4
    Notes
    [23] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.682
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 4.1
    Notes
    [24] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.344
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.7
         upper limit
    		 2.7
    Notes
    [25] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.948
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 5.4
    Notes
    [26] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    Placebo v Liraglutide 1.8 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 [27]
    P-value
    		 = 0.306
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 2.5
    Notes
    [27] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment

    Secondary: Change from Baseline in Diastolic Blood Pressure (DBP) at Week 12

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    End point title
    		 Change from Baseline in Diastolic Blood Pressure (DBP) at Week 12
    End point description
    This change from baseline reflects the Week 12 DBP minus the Week 0 DBP. The analysis population consisted of all randomized, treated participants with at least one DBP measurement (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 MK-8521 180 μg MK-8521 300 μg Placebo Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    43
    42
    Units: mmHg
        least squares mean (confidence interval 95%)
    0.5 (-1.7 to 2.8)
    0.4 (-1.9 to 2.8)
    -1.0 (-3.3 to 1.3)
    0.6 (-1.7 to 2.9)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 [28]
    P-value
    		 = 0.347
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 4.8
    Notes
    [28] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 180 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.963
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 3.2
    Notes
    [29] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 [30]
    P-value
    		 = 0.394
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 4.7
    Notes
    [30] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    MK-8521 300 μg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.905
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 3.1
    Notes
    [31] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Longitudinal data analysis
    Comparison groups
    Placebo v Liraglutide 1.8 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.325
    Method
    		 Longitudinal data analysis
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 4.9
    Notes
    [32] - Terms for treatment, time, A1C (<8.5%, ≥8.5%), BMI (<30 kg/m^2, ≥30 kg/m^2) and AHA washout status (Yes, No), and the interaction of time by treatment

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 14
    Adverse event reporting additional 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. The analysis population included all treated participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    MK-8521 180 μg
    Reporting group description
    		 Participants received double-blind MK-8521 180 μg daily (QD), subcutaneously, over 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching double-blind placebo QD over 12 weeks.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Participants received open-label liraglutide, 1.8 mg QD, subcutaneously, over 12 weeks.

    Reporting group title
    MK-8521 300 μg
    Reporting group description
    		 Participants received double-blind MK-8521 300 μg, QD, subcutaneously, over 12 weeks.

    Serious adverse events
    		 MK-8521 180 μg Placebo Liraglutide 1.8 mg MK-8521 300 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    1 / 44 (2.27%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MK-8521 180 μg Placebo Liraglutide 1.8 mg MK-8521 300 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 46 (39.13%)
    15 / 43 (34.88%)
    13 / 42 (30.95%)
    21 / 44 (47.73%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 43 (6.98%)
    0 / 42 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    1
    3
    0
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    4 / 44 (9.09%)
         occurrences all number
    0
    1
    0
    5
    Headache
         subjects affected / exposed
    0 / 46 (0.00%)
    4 / 43 (9.30%)
    3 / 42 (7.14%)
    1 / 44 (2.27%)
         occurrences all number
    0
    5
    3
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 43 (2.33%)
    1 / 42 (2.38%)
    3 / 44 (6.82%)
         occurrences all number
    0
    1
    1
    3
    Diarrhoea
         subjects affected / exposed
    4 / 46 (8.70%)
    1 / 43 (2.33%)
    3 / 42 (7.14%)
    3 / 44 (6.82%)
         occurrences all number
    5
    2
    4
    3
    Nausea
         subjects affected / exposed
    6 / 46 (13.04%)
    1 / 43 (2.33%)
    9 / 42 (21.43%)
    7 / 44 (15.91%)
         occurrences all number
    8
    1
    12
    10
    Vomiting
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    3 / 44 (6.82%)
         occurrences all number
    2
    0
    1
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 46 (13.04%)
    4 / 43 (9.30%)
    1 / 42 (2.38%)
    1 / 44 (2.27%)
         occurrences all number
    7
    4
    1
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    1
    0
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 46 (8.70%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    5 / 44 (11.36%)
         occurrences all number
    4
    1
    0
    5
    Hypoglycaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 43 (2.33%)
    1 / 42 (2.38%)
    3 / 44 (6.82%)
         occurrences all number
    2
    2
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2016
    Amendment 1 - Broadening the subject population by permitting screening of subjects on metformin + other (AHA) who agree to washing off the other AHA and permit the previous use of GLP-1 agonists that were discontinued >6 months prior to screening.
    09 Jan 2017
    Amendment 2 - Provided clarity and details regarding the aspects of interim analyses to be performed as well as re-evaluation of sample size, guidelines for potential termination of the study, and differentiation of the safety triggered review from the planned interim analyses.

    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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