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    Clinical Trial Results:
    An Exploratory Phase 2a Randomized, Placebo-controlled, Double-blind Study to Evaluate the Efficacy and Safety of MEDI0382 versus Placebo in Overweight/Obese Subjects with Type 2 Diabetes Mellitus Treated with Dapagliflozin and Metformin

    Summary
    EudraCT number
    		 2017-002817-78
    Trial protocol
    		 HU   DE  
    Global end of trial date
    06 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2019
    First version publication date
    21 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5670C00007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03444584
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MedImmune, LLC
    Sponsor organisation address
    Milstein Building, Granta Park, Cambridge, United Kingdom, CB21 6GH
    Public contact
    Armando Flor, MedImmune, LLC, +1 3013981955, information.center@astrazeneca.com
    Scientific contact
    Armando Flor, MedImmune, LLC, +1 3013981955, information.center@astrazeneca.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
    20 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare the change in glucose area under the concentration time-curve (AUC) as measured by a standardized mixed-meal tolerance test (MMTT) in participants treated with dapagliflozin and metformin receiving MEDI0382 or placebo for 28 days.
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 May 2018
    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
    Germany: 25
    Country: Number of subjects enrolled
    Hungary: 24
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    32
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in Germany and Hungary between 08May2018 and 06Dec2018.

    Pre-assignment
    Screening details
    		 A total of 128 participants consented to participate in the study, of which 79 were screen failures. A total of 49 participants were randomised to the study.

    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, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received subcutaneous dose of placebo matched to MEDI0382 daily for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous (SC) dose of placebo matched to MEDI0382 daily for 28 days.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral metformin tablet (Maximum tolerated dose >1 g) throughout the study including screening period (up to 60 days), 4-week run-in period (for 28 days), and study treatment period for 28 days.

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral dapagliflozin 10 mg per day was provided during the 4-week run-in period (for 28 days) for participants treated with metformin monotherapy during the screening period (up to 60 days). During the study treatment period, oral dapagliflozin 10 mg per day was provided for all participants for 28 days.

    Arm title
    		 MEDI0382
    Arm description
    		 Participants received subcutaneous dose of MEDI0382 daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 300 μg for 14 days) for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDI0382
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous (SC) dose of MEDI0382 daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 300 μg for 14 days) for 28 days.

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral dapagliflozin 10 mg per day was provided during the 4-week run-in period (for 28 days) for participants treated with metformin monotherapy during the screening period (up to 60 days). During the study treatment period, oral dapagliflozin 10 mg per day was provided for all participants for 28 days.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral metformin tablet (Maximum tolerated dose >1 g) throughout the study including screening period (up to 60 days), 4-week run-in period (for 28 days), and study treatment period for 28 days.

    Number of subjects in period 1
    		Placebo MEDI0382
    Started
    24
    25
    Completed
    24
    23
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    1
         Not specified
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received subcutaneous dose of placebo matched to MEDI0382 daily for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period.

    Reporting group title
    MEDI0382
    Reporting group description
    		 Participants received subcutaneous dose of MEDI0382 daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 300 μg for 14 days) for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period.

    Reporting group values
    		 Placebo MEDI0382 Total
    Number of subjects
    		 24 25 49
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 16 16 32
        From 65-84 years
    		 8 9 17
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.4 ± 10.0 61.0 ± 8.2 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 12 10 22
        Male
    		 12 15 27
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 24 25 49
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 23 25 48
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received subcutaneous dose of placebo matched to MEDI0382 daily for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period.

    Reporting group title
    MEDI0382
    Reporting group description
    		 Participants received subcutaneous dose of MEDI0382 daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 300 μg for 14 days) for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period.

    Primary: Change From Baseline to Day 28 in Plasma Glucose Area Under the Concentration Time-curve From Time 0 to 4 Hours (AUC0-4hrs) as Measured by Mixed-meal Tolerance Test (MMTT)

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    End point title
    		 Change From Baseline to Day 28 in Plasma Glucose Area Under the Concentration Time-curve From Time 0 to 4 Hours (AUC0-4hrs) as Measured by Mixed-meal Tolerance Test (MMTT)
    End point description
    The MMTT test involved the consumption of a standardised liquid meal (nutritional supplement of fat, carbohydrate, and protein) within 5 minutes. On Day -1 and on Day 28, following a minimum 10-hour fast, serial of blood samples were obtained prior and through 240 minutes after consumption of standardized meal for the measurement of glucose metabolism (with no additional food intake during this time). Intent-to-treat (ITT) population was analysed which included all participants who received any dose of study drugs analysed according to their randomized treatment group. Here, number of participants analysed "N" signifies participants who were analyzed for the specified end point.
    End point type
    Primary
    End point timeframe
    Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised meal on Day -1 (Baseline) and Day 28
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    22
    24
    Units: hr·mg/dL
        least squares mean (confidence interval 95%)
    -11.28 (-51.05 to 28.50)
    -154.37 (-192.45 to -116.29)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -143.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -198.2
         upper limit
    		 -87.98

    Primary: Percent Change From Baseline to Day 28 in Plasma Glucose AUC0-4hrs as Measured by MMTT

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    End point title
    		 Percent Change From Baseline to Day 28 in Plasma Glucose AUC0-4hrs as Measured by MMTT
    End point description
    The MMTT test involved the consumption of a standardised liquid meal (nutritional supplement of fat, carbohydrate, and protein) within 5 minutes. On Day -1 and on Day 28, following a minimum 10-hour fast, serial of blood samples were obtained prior and through 240 minutes after consumption of standardized meal for the measurement of glucose metabolism (with no additional food intake during this time). An ITT population was analysed which included all participants who received any dose of study drugs analysed according to their randomised treatment group. Here, number of participants analysed "N" signifies participants who were analysed for the specified end point.
    End point type
    Primary
    End point timeframe
    Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised meal on Day -1 (Baseline) and Day 28
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    22
    24
    Units: Percent change in Glucose AUC0-4hrs
        least squares mean (confidence interval 95%)
    -0.13 (-5.96 to 5.69)
    -22.30 (-27.88 to -16.73)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -22.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.24
         upper limit
    		 -14.1

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience(immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population was analysed which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 28 days after the last dose of MEDI0382 (approximately 8 weeks)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Participants
        TEAEs
    14
    13
        TESAEs
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Reported as TEAEs
    End point description
    Number of participants with abnormal 12-lead ECG reported as TEAEs are reported. As-treated population was analysed which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 28 days after the last dose of MEDI0382 (approximately 8 weeks)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Vital Signs Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Vital Signs Reported as TEAEs
    End point description
    Number of participants with abnormal vital signs reported as TEAEs are reported. As-treated population was analysed which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 28 days after the last dose of MEDI0382 (approximately 8 weeks)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Participants
        Tachycardia
    2
    1
        Tachycardia paroxysmal
    1
    0
        Palpitations
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Physical Examinations Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Physical Examinations Reported as TEAEs
    End point description
    Number of participants with abnormal physical examinations reported as TEAEs are reported. As-treated population was analysed which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 28 days after the last dose of MEDI0382 (approximately 8 weeks)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
    End point description
    Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. As-treated population was analysed which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through 28 days after the last dose of MEDI0382 (approximately 8 weeks)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Participants
        Hypoglycemia
    1
    0
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC [0-∞]) of MEDI0382

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    End point title
    		 Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC [0-∞]) of MEDI0382 [1]
    End point description
    Area under the plasma concentration time curve from time zero to infinity (AUC [0-∞]) of MEDI0382 is reported. MEDI0382 pharmacokinetic (PK) population was analysed which included all participants who received at least 1 dose of MEDI0382 and had at least 1 MEDI0382 PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days 7, 14, and 28
    Notes
    [1] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 MEDI0382
    Number of subjects analysed
    25
    Units: ng.hr/mL
    geometric mean (full range (min-max))
        Day 7 (MEDI0382 100 µg) (n=9)
    106.4 (57.7 to 251.8)
        Day 14 ( MEDI0382 200 µg) (n=9)
    196.7 (99.4 to 472.0)
        Day 28 (MEDI0382 300 µg) (n=9)
    314.6 (211.0 to 537.3)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC [0-∞]) of Dapagliflozin

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    End point title
    		 Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC [0-∞]) of Dapagliflozin
    End point description
    Area under the plasma concentration time curve from time zero to infinity (AUC [0-∞]) of Dapagliflozin is reported. Dapagliflozin PK population was analysed which included all participants who received at least 1 dose of dapagliflozin and had at least 1 dapagliflozin PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days -1, 7, 14, and 28
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: ng.hr/mL
    geometric mean (full range (min-max))
        Day -1 (n= 20, 24)
    432.6 (271.5 to 918.6)
    473.8 (288.8 to 1073.2)
        Day 7 (n=15, 12)
    410.2 (209.9 to 1024.2)
    438.0 (222.2 to 833.6)
        Day 14 (n=16, 8)
    421.0 (219.0 to 1327.8)
    448.6 (247.0 to 615.9)
        Day 28 (n=15, 16)
    405.7 (261.1 to 799.5)
    523.4 (319.5 to 946.0)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve During the Dosing Period (AUCtau) of MEDI0382

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    End point title
    		 Area Under the Plasma Concentration-time Curve During the Dosing Period (AUCtau) of MEDI0382 [2]
    End point description
    Area under the plasma concentration-time curve during the dosing period (AUCtau) of MEDI0382 is reported. MEDI0382 pharmacokinetic (PK) population was analysed which included all participants who received at least 1 dose of MEDI0382 and had at least 1 MEDI0382 PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days 7, 14, and 28
    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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 MEDI0382
    Number of subjects analysed
    25
    Units: ng.hr/mL
    geometric mean (full range (min-max))
        Day 7 (MEDI0382 100 µg) (n=23)
    89.6 (43.1 to 199.4)
        Day 14 ( MEDI0382 200 µg) (n=23)
    165.0 (86.9 to 365.5)
        Day 28 (MEDI0382 300 µg) (n=22)
    265.9 (101.7 to 795.1)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve During the Dosing Period (AUCtau) of Dapagliflozin

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    End point title
    		 Area Under the Plasma Concentration-time Curve During the Dosing Period (AUCtau) of Dapagliflozin
    End point description
    Area under the plasma Concentration-time curve during the dosing period (AUCtau) of Dapagliflozin is reported. Dapagliflozin PK population was analysed which included all participants who received at least 1 dose of dapagliflozin and had at least 1 dapagliflozin PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days -1, 7, 14, and 28
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: ng.hr/mL
    geometric mean (full range (min-max))
        Day -1 (n= 24, 24)
    400.9 (182.4 to 1011.5)
    430.3 (252.5 to 815.2)
        Day 7 (n=24, 25)
    377.5 (76.4 to 910.7)
    406.8 (211.5 to 1142.6)
        Day 14 (n= 23, 23)
    417.1 (209.0 to 1107.7)
    396.8 (215.4 to 669.7)
        Day 28 (n= 23, 24)
    423.1 (180.6 to 977.3)
    463.8 (284.3 to 1245.7)
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of MEDI0382

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of MEDI0382 [3]
    End point description
    Maximum observed serum concentration (Cmax) of MEDI0382 is reported. MEDI0382 pharmacokinetic (PK) population was analysed which included all participants who received at least 1 dose of MEDI0382 and had at least 1 MEDI0382 PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days 7, 14, and 28
    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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 MEDI0382
    Number of subjects analysed
    25
    Units: ng/mL
    geometric mean (full range (min-max))
        Day 7 (MEDI0382 100 µg) (n = 25)
    5.2 (2.7 to 11.9)
        Day 14 ( MEDI0382 200 µg) (n= 24)
    10.1 (4.4 to 21.7)
        Day 28 (MEDI0382 300 µg) (n= 22)
    17.2 (6.1 to 45.4)
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Dapagliflozin

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Dapagliflozin
    End point description
    Maximum observed serum concentration (Cmax) of Dapagliflozin is reported. Dapagliflozin PK population was analysed which included all participants who received at least 1 dose of dapagliflozin and had at least 1 dapagliflozin PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days -1, 7, 14, and 28
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: ng/mL
    geometric mean (full range (min-max))
        Day -1 (n= 24,25)
    110.1 (46.3 to 208.3)
    116.7 (38.2 to 206.8)
        Day 7 (n= 24, 25)
    92.0 (5.2 to 256.7)
    84.4 (24.1 to 211.7)
        Day 14 (n= 23, 24)
    95.6 (33.5 to 280.7)
    61.1 (15.8 to 149.9)
        Day 28 (n= 23, 24)
    112.2 (47.0 to 235.4)
    94.2 (25.2 to 182.2)
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI0382

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    End point title
    		 Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI0382 [4]
    End point description
    Time to reach maximum observed serum concentration (Tmax) of MEDI0382 is reported. MEDI0382 pharmacokinetic (PK) population was analysed which included all participants who received at least 1 dose of MEDI0382 and had at least 1 MEDI0382 PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days 7, 14, and 28
    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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 MEDI0382
    Number of subjects analysed
    25
    Units: Hours
    median (full range (min-max))
        Day 7 (MEDI0382 100 µg) (n= 25)
    5.5 (2 to 8)
        Day 14 ( MEDI0382 200 µg) (n= 24)
    5.1 (2 to 8)
        Day 28 (MEDI0382 300 µg) (n= 22)
    4 (1.9 to 8.1)
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Serum Concentration (Tmax) of Dapagliflozin

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    End point title
    		 Time to Reach Maximum Observed Serum Concentration (Tmax) of Dapagliflozin
    End point description
    Time to reach maximum observed serum concentration (Tmax) of Dapagliflozin is reported. Dapagliflozin PK population was analysed which included all participants who received at least 1 dose of dapagliflozin and had at least 1 dapagliflozin PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days -1, 7, 14, and 28
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Hours
    median (full range (min-max))
        Day -1 (n= 24, 25)
    1 (0.5 to 2)
    1 (0.4 to 23.9)
        Day 7 (n= 24, 25)
    1 (0.5 to 11.4)
    1 (0.5 to 4)
        Day 14 (23, 24)
    1.1 (0.5 to 6)
    1 (0 to 8.1)
        Day 28 (23, 24)
    1 (0.2 to 1.8)
    1 (0.5 to 8.1)
    No statistical analyses for this end point

    Secondary: Terminal Elimination Half-life (t½) of MEDI0382

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    End point title
    		 Terminal Elimination Half-life (t½) of MEDI0382 [5]
    End point description
    Terminal half-life is the time required for the plasma concentration to fall by 50% during the terminal phase. The t½ of MEDI0382 is reported. MEDI0382 pharmacokinetic (PK) population was analysed which included all participants who received at least 1 dose of MEDI0382 and had at least 1 MEDI0382 PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days 7, 14, and 28
    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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 MEDI0382
    Number of subjects analysed
    25
    Units: Hours
    geometric mean (full range (min-max))
        Day 7 (MEDI0382 100 µg) (n= 9)
    8.8 (6.1 to 11.9)
        Day 14 ( MEDI0382 200 µg) (n= 9)
    9 (5.6 to 11.8)
        Day 28 (MEDI0382 300 µg) (n= 9)
    9.1 (5.1 to 11.6)
    No statistical analyses for this end point

    Secondary: Terminal Elimination Half-life (t½) of Dapagliflozin

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    End point title
    		 Terminal Elimination Half-life (t½) of Dapagliflozin
    End point description
    Terminal half-life is the time required for the plasma concentration to fall by 50% during the terminal phase. The t½ of Dapagliflozin is reported. Dapagliflozin PK population was analysed which included all participants who received at least 1 dose of dapagliflozin and had at least 1 dapagliflozin PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days -1, 7, 14, and 28
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Hours
    geometric mean (full range (min-max))
        Day -1 (n= 20, 24)
    8.2 (5.3 to 11.2)
    7.8 (5.4 to 11.3)
        Day 7 (n= 15, 12)
    7.9 (4.1 to 10.4)
    8.3 (5.8 to 11.1)
        Day 14 (n= 16, 8)
    7.0 (5.1 to 11.4)
    8.5 (7 to 10)
        Day 28 (15, 16)
    7.6 (5.8 to 11.0)
    9.1 (6.1 to 11.8)
    No statistical analyses for this end point

    Secondary: Apparent clearance (CL/F) of MEDI0382

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    End point title
    		 Apparent clearance (CL/F) of MEDI0382 [6]
    End point description
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The CL/F of MEDI0382 is reported. MEDI0382 pharmacokinetic (PK) population was analysed which included all participants who received at least 1 dose of MEDI0382 and had at least 1 MEDI0382 PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days 7, 14, and 28
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 MEDI0382
    Number of subjects analysed
    25
    Units: L/hr
    geometric mean (full range (min-max))
        Day 7 (MEDI0382 100 µg) (n= 9)
    1.1 (0.5 to 1.9)
        Day 14 ( MEDI0382 200 µg) (n= 9)
    1.3 (0.5 to 2.2)
        Day 28 (MEDI0382 300 µg) (n= 9)
    1.2 (0.8 to 1.8)
    No statistical analyses for this end point

    Secondary: Apparent clearance (CL/F) of Dapagliflozin

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    End point title
    		 Apparent clearance (CL/F) of Dapagliflozin
    End point description
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The CL/F of Dapagliflozin is reported. Dapagliflozin PK population was analysed which included all participants who received at least 1 dose of dapagliflozin and had at least 1 dapagliflozin PK sample above the lower limit of quantitation. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Days -1, 7, 14, and 28
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: L/Hr
    geometric mean (full range (min-max))
        Day -1 (n= 20, 24)
    25.5 (13.3 to 38.9)
    23.3 (12.3 to 39.6)
        Day 7 (n= 15, 12)
    26.7 (11.0 to 52.8)
    25.7 (14.2 to 47.3)
        Day 14 (n= 16, 8)
    25.9 (9.0 to 47.7)
    25.5 (18.8 to 46.4)
        Day 28 (n= 15, 16)
    26.8 (13.8 to 40.2)
    22.2 (13.4 to 35.2)
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive Anti-drug Antibodies (ADA) Titer to MEDI0382

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    End point title
    		 Number of Participants With Positive Anti-drug Antibodies (ADA) Titer to MEDI0382
    End point description
    Number of participants with positive Anti-drug antibodies (ADA) titer to MEDI0382 are reported. Immunogenicity population included was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to the treatment they actually received and had at least one serum sample for immunogenicity testing. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose), on Day 29 , and 28 days post last dose (end of study visit; approximately 8 weeks)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Participants
        Day 1 (n= 24, 25)
    0
    3
        Day 29 (n= 24, 24)
    0
    1
        End of Study (n= 24, 24)
    1
    2
    No statistical analyses for this end point

    Secondary: Change From Baseline in Plasma Glucose AUC24-hrs to the end of Each Dosing Level as Measured by Continuous Glucose Monitoring (CGM)

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    End point title
    		 Change From Baseline in Plasma Glucose AUC24-hrs to the end of Each Dosing Level as Measured by Continuous Glucose Monitoring (CGM)
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: hr.mg/dL
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    49.14 ± 667.30
    -832.66 ± 506.22
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    57.30 ± 379.95
    -666.05 ± 647.63
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    229.47 ± 589.19
    -726.85 ± 710.71
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean 24-hrs Plasma Glucose to the end of Each Dosing Level as Measured by CGM

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    End point title
    		 Change From Baseline in Mean 24-hrs Plasma Glucose to the end of Each Dosing Level as Measured by CGM
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: mg/dL
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    2.59 ± 28.96
    -34.74 ± 20.34
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    2.83 ± 17.01
    -28.34 ± 27.12
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    9.70 ± 24.73
    -30.55 ± 29.82
    No statistical analyses for this end point

    Secondary: Change From Baseline in Standard Deviation of 24-hrs Plasma Glucose Readings to the end of Each Dosing Level as Measured by CGM

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    End point title
    		 Change From Baseline in Standard Deviation of 24-hrs Plasma Glucose Readings to the end of Each Dosing Level as Measured by CGM
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: mg/dL
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    -3.01 ± 13.84
    -7.21 ± 11.05
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    1.38 ± 9.47
    -7.52 ± 9.73
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    -4.39 ± 10.67
    -9.76 ± 10.18
    No statistical analyses for this end point

    Secondary: Change From Baseline in Coefficient of Variation of 24-hrs Plasma Glucose Readings to the end of Each Dosing Level as Measured by CGM

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    End point title
    		 Change From Baseline in Coefficient of Variation of 24-hrs Plasma Glucose Readings to the end of Each Dosing Level as Measured by CGM
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Percent of coefficient of variation
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    -2.37 ± 9.06
    -0.45 ± 6.68
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    0.96 ± 8.74
    -2.06 ± 6.59
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    -4.26 ± 7.16
    -3.21 ± 7.25
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Amplitude of Glucose Excursions (MAGE) of 24-hrs Plasma Glucose Readings to the end of Each Dosing Level as Measured by CGM

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    End point title
    		 Change From Baseline in Mean Amplitude of Glucose Excursions (MAGE) of 24-hrs Plasma Glucose Readings to the end of Each Dosing Level as Measured by CGM
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: mg/dL
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    -13.46 ± 32.07
    -25.74 ± 35.06
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    18.05 ± 47.60
    -26.59 ± 25.60
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    -8.09 ± 27.68
    -27.92 ± 23.17
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Percentage of 24-hrs Glucose Readings That Falls Within the Euglycemic Range to the end of Each Dosing as Measured by CGM

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    End point title
    		 Change From Baseline in the Percentage of 24-hrs Glucose Readings That Falls Within the Euglycemic Range to the end of Each Dosing as Measured by CGM
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. Euglycemic range is defined as glucose levels of >= 70 mg/dL (>= 3.9 mmol/L) and <= 180 mg/dL (<= 10.0 mmol/L). An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Percent of Euglycemic Range
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    -5.61 ± 19.65
    7.12 ± 20.60
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    -2.79 ± 10.16
    5.31 ± 17.71
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    -4.17 ± 15.80
    6.54 ± 24.37
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Percentage of 24-hrs Glucose Readings That Falls Within the Hyperglycemic Range to the end of Each Dosing as Measured by CGM

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    End point title
    		 Change From Baseline in the Percentage of 24-hrs Glucose Readings That Falls Within the Hyperglycemic Range to the end of Each Dosing as Measured by CGM
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. Hyperglycemic (high glucose) range is defined as glucose levels of >180 mg/dL (> 10.0 mmol/L). An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Percent of hyperglycemic range
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    3.62 ± 17.80
    -13.99 ± 14.95
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    0.36 ± 10.50
    -9.81 ± 13.68
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    6.08 ± 16.96
    -9.72 ± 20.97
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Percentage of 24-hrs Glucose Readings That Falls Within the Hypoglycemic Range to the end of Each Dosing as Measured by CGM

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    End point title
    		 Change From Baseline in the Percentage of 24-hrs Glucose Readings That Falls Within the Hypoglycemic Range to the end of Each Dosing as Measured by CGM
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. Hypoglycemic range is defined as glucose levels of < 70 mg/dL (< 3.9 mmol/L). An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Percent of hypoglycemic range
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    1.17 ± 5.64
    6.08 ± 10.36
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    2.00 ± 3.79
    3.44 ± 12.72
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    -2.08 ± 4.14
    2.84 ± 12.20
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Percentage of 24-hrs Glucose Readings That Falls Within Clinically Significant Hypoglycemic Range to the end of Each Dosing as Measured by CGM

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    End point title
    		 Change From Baseline in the Percentage of 24-hrs Glucose Readings That Falls Within Clinically Significant Hypoglycemic Range to the end of Each Dosing as Measured by CGM
    End point description
    Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Continuous glucose monitoring measures glucose excursions during different meals and at different times of the day. End of dosing: Day 7 for MEDI0382 100 μg; Day 14 for MEDI0382 200 μg; and Day 28 for MEDI0382 300 μg. Clinically significant hypoglycemic range is defined as glucose levels of < 54 mg/dL (3.0 mmol/L). An ITT population was analysed which included all participants who received any dose of study drug (MEDI0382 or placebo) and analysed according to their randomized treatment group. Here, number analysed "n" signifies participants who were analysed for the specified day.
    End point type
    Secondary
    End point timeframe
    Day -1 (Baseline) through Day 7 for MEDI0382 100 μg, Day 14 for MEDI0382 200 μg, and Day 28 for MEDI0382 300 μg
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    24
    25
    Units: Percent of hypoglycemic range
    arithmetic mean (standard deviation)
        Day 7 (MEDI0382 100 μg) (n= 10, 12)
    0.76 ± 3.64
    1.61 ± 5.03
        Day 14 (MEDI0382 200 μg) (n= 9, 13)
    0.27 ± 1.19
    -0.06 ± 2.18
        Day 28 (MEDI0382 300 μg) (n= 12, 18)
    -0.26 ± 0.90
    0.93 ± 4.91
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day -2 through 28 days post last dose (approximately 07 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    MEDI0382
    Reporting group description
    		 Participants received subcutaneous dose of MEDI0382 daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 300 μg for 14 days) for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received subcutaneous dose of placebo matched to MEDI0382 daily for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period.

    Serious adverse events
    		 MEDI0382 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 MEDI0382 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 25 (52.00%)
    14 / 24 (58.33%)
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Procedural nausea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 24 (8.33%)
         occurrences all number
    3
    2
    Palpitations
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 25 (20.00%)
    1 / 24 (4.17%)
         occurrences all number
    5
    1
    Dizziness
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Constipation
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Nausea
         subjects affected / exposed
    5 / 25 (20.00%)
    2 / 24 (8.33%)
         occurrences all number
    7
    4
    Vomiting
         subjects affected / exposed
    5 / 25 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    6
    0
    Abdominal distension
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pruritus genital
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Rash pruritic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 24 (12.50%)
         occurrences all number
    3
    3
    Bronchitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Genital infection fungal
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Food craving
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Hypoglycaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Dec 2017
    Amended rationale for conducting the study, schedule of treatment period procedures, treatment regimen, and schedule of treatment period procedures. Updated selection of participants with type 2 diabetes mellitus with a glycated haemoglobin (Range of 7.0% to 10.0%). Added Inclusion criteria allowing participants on stable doses of metformin (maximum tolerated dose [MTD] > 1 g) with canagliflozin (maximum dose of 300 mg/day) or metformin (MTD > 1 g) with empagliflozin (maximum dose of 25 mg/day) for at least 3 months prior to screening to enter the study, after switching to dapagliflozin 10 mg at least 2 weeks prior to Day -2. Updated exclusion criterion to clarify that investigational sodium-glucose cotransporter-2 (SGLT2)-containing preparations (excluding canagliflozin and empagliflozin) within the last 30 days or 5 half-lives of the drug (whichever is longest) at the time of screening are exclusionary. Corrected schedule of run-in period procedures. Added Day -2 for training of participant on glucose and ketone monitoring. Added triglycerides test (screening only) to the serum chemistry and “Plasma glucose” was amended to “FPG”. The starting point for AE and SAE collection was changed from “the time of admission to the clinic (Day -2)” to “from the time of informed consent”.

    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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