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    Clinical Trial Results:
    An Exploratory Phase 2a, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Effect of MEDI0382 on Energy Balance in Overweight and Obese Subjects with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    		 2018-001220-19
    Trial protocol
    		 GB  
    Global end of trial date
    22 Dec 2019

    Results information
    Results version number
    		 v1
    This version publication date
    01 Jan 2021
    First version publication date
    01 Jan 2021
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D5670C00021
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03596177
    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
    Victoria Parker, MedImmune, LLC, +44 747 1357172, information.center@astrazeneca.com
    Scientific contact
    Victoria Parker, MedImmune, LLC, +44 747 1357172, 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
    30 Sep 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the effect of MEDI0382 titrated up to a dose level of 300 μg on body weight versus placebo.
    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
    26 Sep 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
    United Kingdom: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    17
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in United Kingdom from 26Sep2018 to 22Dec2019.

    Pre-assignment
    Screening details
    		 A total of 28 participants were randomized in the study.

    Period 1
    Period 1 title
    Single Blind Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received subcutaneous (SC) injection of placebo for 16 days in the single-blind treatment period, and then SC injection of placebo matched to MEDI0382 for 42 days in double-blind treatment period.
    Arm type
    		 Placebo

    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
    SC injection of placebo for 16 days.

    Arm title
    		 MEDI0382
    Arm description
    		 Participants received SC injection of placebo for 16 days in the single-blind treatment period, and then SC injection of MEDI0382 titrated up to 300 μg for 42 days (100 μg for 4 days, followed by 200 μg for 4 days, and finally 300 μg for 34 days) in double-blind treatment period.
    Arm type
    		 Experimental

    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
    SC injection of placebo for 16 days.

    Number of subjects in period 1
    		Placebo MEDI0382
    Started
    9
    19
    Completed
    7
    18
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    1
         Not Specified
    1
    -
    Period 2
    Period 2 title
    Double Blind Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received subcutaneous (SC) injection of placebo for 16 days in the single-blind treatment period, and then SC injection of placebo matched to MEDI0382 for 42 days in double-blind treatment period.
    Arm type
    		 Placebo

    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
    SC injection of placebo matched to MEDI0382 for 42 days.

    Arm title
    		 MEDI0382
    Arm description
    		 Participants received SC injection of placebo for 16 days in the single-blind treatment period, and then SC injection of MEDI0382 titrated up to 300 μg for 42 days (100 μg for 4 days, followed by 200 μg for 4 days, and finally 300 μg for 34 days) in double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cotadutide
    Investigational medicinal product code
    Other name
    MEDI0382
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SC injection of MEDI0382 titrated up to 300 μg for 42 days (100 μg for 4 days, followed by 200 μg for 4 days, and finally 300 μg for 34 days).

    Number of subjects in period 2
    		Placebo MEDI0382
    Started
    7
    18
    Completed
    7
    12
    Not completed
    0
    6
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    -
    1
         Not Specified
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received subcutaneous (SC) injection of placebo for 16 days in the single-blind treatment period, and then SC injection of placebo matched to MEDI0382 for 42 days in double-blind treatment period.

    Reporting group title
    MEDI0382
    Reporting group description
    		 Participants received SC injection of placebo for 16 days in the single-blind treatment period, and then SC injection of MEDI0382 titrated up to 300 μg for 42 days (100 μg for 4 days, followed by 200 μg for 4 days, and finally 300 μg for 34 days) in double-blind treatment period.

    Reporting group values
    		 Placebo MEDI0382 Total
    Number of subjects
    		 9 19 28
    Age categorical
    Units: Participants
        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)
    		 4 13 17
        From 65-84 years
    		 5 6 11
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.2 ± 7.2 59.5 ± 8.4 -
    Sex: Female, Male
    Units: Participants
        Female
    		 2 1 3
        Male
    		 7 18 25
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 1 0 1
        White
    		 8 18 26
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 9 18 27
        Unknown or Not Reported
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received subcutaneous (SC) injection of placebo for 16 days in the single-blind treatment period, and then SC injection of placebo matched to MEDI0382 for 42 days in double-blind treatment period.

    Reporting group title
    MEDI0382
    Reporting group description
    		 Participants received SC injection of placebo for 16 days in the single-blind treatment period, and then SC injection of MEDI0382 titrated up to 300 μg for 42 days (100 μg for 4 days, followed by 200 μg for 4 days, and finally 300 μg for 34 days) in double-blind treatment period.
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received subcutaneous (SC) injection of placebo for 16 days in the single-blind treatment period, and then SC injection of placebo matched to MEDI0382 for 42 days in double-blind treatment period.

    Reporting group title
    MEDI0382
    Reporting group description
    		 Participants received SC injection of placebo for 16 days in the single-blind treatment period, and then SC injection of MEDI0382 titrated up to 300 μg for 42 days (100 μg for 4 days, followed by 200 μg for 4 days, and finally 300 μg for 34 days) in double-blind treatment period.

    Primary: Percent Change in Body Weight From Baseline to Day 59

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    End point title
    		 Percent Change in Body Weight From Baseline to Day 59
    End point description
    Percent change in body weight is reported. The last observation carried forward (LOCF) analysis was used for missing data imputation for Day 59. Modified intent-to-treat (ITT) population was analysed which included participants in ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Primary
    End point timeframe
    Baseline (Day 17) and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    14
    Units: Percent change in body weight
        least squares mean (confidence interval 90%)
    -1.40 (-2.66 to -0.13)
    -3.98 (-4.85 to -3.10)
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.58
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.15
         upper limit
    		 -1

    Secondary: Percent Change in Total Energy Intake From the ad Libitum Lunch From Baseline to Day 32 and Day 59

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    End point title
    		 Percent Change in Total Energy Intake From the ad Libitum Lunch From Baseline to Day 32 and Day 59
    End point description
    Total energy intake in kilojoules (kJ) were recorded in a food diary after ad libitum lunch on Days 16, 32, and 59. The ad libitum lunch was a standardised solid meal with food of known macronutrient content. Participants were advised to eat freely until they feel comfortably full and the meal duration was flexible according to participant's preference. During the meal, the quantity of food ingested was recorded by study site staff without participants’ awareness that food consumption was recorded. Percent change in total energy intake from the ad libitum lunch is reported. The LOCF analysis was used for missing data imputation for Day 59. The mITT population population was analysed whihc included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 16), Day 32, and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    14
    Units: Percent change in total energy intake
    least squares mean (confidence interval 90%)
        Percent change at Day 32
    -5.170 (-23.344 to 13.003)
    -50.652 (-63.480 to -37.823)
        Percent change at Day 59
    -10.598 (-31.316 to 10.119)
    -51.922 (-66.546 to -37.297)
    Statistical analysis title
    		 Statistical Analysis for Day 32
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -45.481
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -67.777
         upper limit
    		 -23.186
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -41.323
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -66.74
         upper limit
    		 -15.907

    Secondary: Change in Total Energy Intake From the ad Libitum Lunch From Baseline to Day 32 and Day 59

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    End point title
    		 Change in Total Energy Intake From the ad Libitum Lunch From Baseline to Day 32 and Day 59
    End point description
    Total energy intake in kilojoules (kJ) were recorded in a food diary after ad libitum lunch on Days 16, 32, and 59. The ad libitum lunch was a standardised solid meal with food of known macronutrient content. Participants were advised to eat freely until they feel comfortably full and the meal duration was flexible according to participant's preference. During the meal, the quantity of food ingested was recorded by study site staff without participants’ awareness that food consumption was recorded. Change in total energy intake from the ad libitum lunch is reported. The LOCF analysis was used for missing data imputation for Day 59. The mITT population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 16) to Day 32 and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    14
    Units: Kilojoules
    least squares mean (confidence interval 90%)
        Change at Day 32
    -126.271 (-647.387 to 394.846)
    -1677.465 (-2045.322 to -1309.607)
        Change at Day 59
    -410.816 (-1107.896 to 286.263)
    -1743.331 (-2235.400 to -1251.261)
    Statistical analysis title
    		 Statistical Analysis for Day 32
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1551.194
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2190.52
         upper limit
    		 -911.873
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1332.515
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2187.71
         upper limit
    		 -477.318

    Secondary: Percent Change in Total Energy Expenditure (TEE) as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58

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    End point title
    		 Percent Change in Total Energy Expenditure (TEE) as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58
    End point description
    A whole room calorimetry assessment was used to measure gaseous exchange while excercising and therefore indirect estimates of energy expenditure over a 24-hour period. For the assessment, participants had to enter the whole room calorimeter for up to 36 hours and reside inside for this entire duration (this will include toilet visits too). During the time in the calorimeter participants were asked to exercise on an exercise bike for 15-minute intervals at 4 times. During these sessions participants were asked to aim for a heart rate of 65% of maximum (defined as 220 beats per minute minus age) and complete the full 15-minute session. In addition, participants abstained from caffeinated drinks for at least 24 hours prior to measurements as caffeine may increase energy expenditure (EE) and dietary advice was given to ensure participants had a neutral energy balance prior to whole calorimetry assessments. Percent change in TEE is reported. The mITT population was analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 15) and Day 58
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Percent change in TEE
        least squares mean (confidence interval 90%)
    2.032 (-2.833 to 6.898)
    -1.141 (-4.825 to 2.544)
    Statistical analysis title
    		 Statistical Analysis for Day 58
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.384
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.173
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.368
         upper limit
    		 3.022

    Secondary: Change in TEE as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58

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    End point title
    		 Change in TEE as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58
    End point description
    A whole room calorimetry assessment was used to measure gaseous exchange while excercising and therefore indirect estimates of energy expenditure over a 24-hour period. For the assessment, participants had to enter the whole room calorimeter for up to 36 hours and reside inside for this entire duration (this will include toilet visits too). During the time in the calorimeter participants were asked to exercise on an exercise bike for 15-minute intervals at 4 times. During these sessions participants were asked to aim for a heart rate of 65% of maximum (defined as 220 beats per minute minus age) and complete the full 15-minute session. In addition, participants abstained from caffeinated drinks for at least 24 hours prior to measurements as caffeine may increase EE and dietary advice was given to ensure participants had a neutral energy balance prior to whole calorimetry assessments. Change in TEE is reported. The mITT population was analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 15) and Day 58
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: kilojoules/kg fat body mass
        least squares mean (confidence interval 90%)
    5.969 (-8.364 to 20.302)
    -4.070 (-14.924 to 6.783)
    Statistical analysis title
    		 Statistical Analysis for Day 58
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.351
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -10.039
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -28.287
         upper limit
    		 8.209

    Secondary: Percent Change in Activity Energy Expenditure (AEE) as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58

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    End point title
    		 Percent Change in Activity Energy Expenditure (AEE) as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58
    End point description
    A whole room calorimetry assessment was used to measure gaseous exchange while excercising and therefore indirect estimates of energy expenditure over a 24-hour period. For the assessment, participants had to enter the whole room calorimeter for up to 36 hours and reside inside for this entire duration (this will include toilet visits too). During the time in the calorimeter participants were asked to exercise on an exercise bike for 15-minute intervals at 4 times. During these sessions participants were asked to aim for a heart rate of 65% of maximum (defined as 220 beats per minute minus age) and complete the full 15-minute session. In addition, participants abstained from caffeinated drinks for at least 24 hours prior to measurements as caffeine may increase EE and dietary advice was given to ensure participants had a neutral energy balance prior to whole calorimetry assessments. Percent change in AEE is reported. The mITT population was analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 15) and Day 58
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Percent change in AEE
        least squares mean (confidence interval 90%)
    -0.446 (-6.836 to 5.943)
    -0.261 (-5.139 to 4.618)
    Statistical analysis title
    		 Statistical Analysis for Day 58
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.968
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.186
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -7.858
         upper limit
    		 8.229

    Secondary: Change in AEE as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58

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    End point title
    		 Change in AEE as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58
    End point description
    A whole room calorimetry assessment was used to measure gaseous exchange while excercising and therefore indirect estimates of energy expenditure over a 24-hour period. For the assessment, participants had to enter the whole room calorimeter for up to 36 hours and reside inside for this entire duration (this will include toilet visits too). During the time in the calorimeter participants were asked to exercise on an exercise bike for 15-minute intervals at 4 times. During these sessions participants were asked to aim for a heart rate of 65% of maximum (defined as 220 beats per minute minus age) and complete the full 15-minute session. In addition, participants abstained from caffeinated drinks for at least 24 hours prior to measurements as caffeine may increase EE and dietary advice was given to ensure participants had a neutral energy balance prior to whole calorimetry assessments. Change in AEE is reported. The mITT population was analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 15) and Day 58
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: kilojoules/kg fat body mass
        least squares mean (confidence interval 90%)
    -1.132 (-3.259 to 0.995)
    -0.265 (-1.889 to 1.359)
    Statistical analysis title
    		 Statistical Analysis for Day 58
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.867
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 3.545

    Secondary: Percent Change in Resting Energy Expenditure (REE) as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58

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    End point title
    		 Percent Change in Resting Energy Expenditure (REE) as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58
    End point description
    The REE represents the amount of calories required for a 24-hour period by the body during a non-active period and is assessed by whole room indirect calorimetry method. Percent change in REE is reported. The mITT population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 15) and Day 58
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Percent change in REE
        least squares mean (confidence interval 90%)
    8.113 (3.254 to 12.972)
    4.468 (0.816 to 8.120)
    Statistical analysis title
    		 Statistical Analysis for Day 58
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.324
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.645
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.894
         upper limit
    		 2.603

    Secondary: Change in REE as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58

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    End point title
    		 Change in REE as Measured by Whole Room Indirect Calorimetry From Baseline to Day 58
    End point description
    The REE represents the amount of calories required for a 24-hour period by the body during a non-active period and is assessed by whole room indirect calorimetry method. Change in REE is reported. The mITT population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 15) and Day 58
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: kilojoules/kg fat body mass
        least squares mean (confidence interval 90%)
    13.237 (4.104 to 22.369)
    7.565 (0.701 to 14.429)
    Statistical analysis title
    		 Statistical Analysis for Day 58
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.412
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.672
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -17.415
         upper limit
    		 6.072

    Secondary: Percent Change in REE as Measured by Hood Indirect Calorimetry From Baseline to Day 32

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    End point title
    		 Percent Change in REE as Measured by Hood Indirect Calorimetry From Baseline to Day 32
    End point description
    Hood calorimetry assessment was used to measure REE. A large plastic hood is placed over participants head for 20 minutes and measurements of gaseous exchange are undertaken. Participants were rested for at least 1 hour prior to hood calorimetry measures; during a hood calorimetry assessment the participants were asked to remain quiet and rested for 40 minutes in total with 10 minutes before and after the assessment to allow for room air assessment. Percent change in REE is reported. The mITT population population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analyzed according to their randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 16) and Day 32
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Percent Change in REE
        least squares mean (confidence interval 90%)
    1.189 (-5.955 to 8.332)
    8.546 (3.138 to 13.954)
    Statistical analysis title
    		 Statistical Analysis for Day 32
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.177
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    7.357
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.742
         upper limit
    		 16.456

    Secondary: Change in REE as Measured by Hood Indirect Calorimetry From Baseline to Day 32

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    End point title
    		 Change in REE as Measured by Hood Indirect Calorimetry From Baseline to Day 32
    End point description
    Hood calorimetry assessment was used to measure REE. A large plastic hood is placed over participants head for 20 minutes and measurements of gaseous exchange are undertaken. Participants were rested for at least 1 hour prior to hood calorimetry measures; during a hood calorimetry assessment the participants were asked to remain quiet and rested for 40 minutes in total with 10 minutes before and after the assessment to allow for room air assessment. Change in REE is reported. The mITT population population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 16) and Day 32
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: kilojoules/kg fat body mass
        least squares mean (confidence interval 90%)
    3.316 (-11.080 to 17.712)
    18.502 (7.604 to 29.400)
    Statistical analysis title
    		 Statistical Analysis for Day 32
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.168
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    15.186
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.151
         upper limit
    		 33.523

    Secondary: Change in Body Weight From Baseline to Day 59

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    End point title
    		 Change in Body Weight From Baseline to Day 59
    End point description
    Change in body weight is reported. The LOCF analysis was used for missing data imputation for Day 59. The mITT population population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 17) and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    14
    Units: kg
        least squares mean (confidence interval 90%)
    -1.26 (-2.48 to -0.05)
    -3.80 (-4.65 to -2.96)
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.54
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.05
         upper limit
    		 -1.03

    Secondary: Percent Change in Total Body fat Mass as Measured by Dual-energy X-ray Absorptiometry (DXA) From Baseline to Day 59

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    End point title
    		 Percent Change in Total Body fat Mass as Measured by Dual-energy X-ray Absorptiometry (DXA) From Baseline to Day 59
    End point description
    The total body fat mass was measured in kilograms (kg) using DXA. Participants body was scanned using DXA scanner and total body fat mass was determined. Percent change in total body fat mass is reported. The mITT population population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1) and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Percent change in total body fat mass
        least squares mean (confidence interval 90%)
    -4.218 (-8.249 to -0.186)
    -9.340 (-12.343 to -6.337)
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.107
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.122
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -10.364
         upper limit
    		 0.119

    Secondary: Change in Total Body fat Mass as Measured by DXA From Baseline to Day 59

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    End point title
    		 Change in Total Body fat Mass as Measured by DXA From Baseline to Day 59
    End point description
    The total body fat mass was measured in kg using DXA. Participants body was scanned using DXA scanner and total body fat mass was determined. Change in total body fat mass is reported. The mITT population population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1) and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Kg
        least squares mean (confidence interval 90%)
    -1.455 (-2.806 to -0.103)
    -3.303 (-4.310 to -2.296)
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.848
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.605
         upper limit
    		 -0.091

    Secondary: Percent Change in Total Body fat Mass: Lean Mass Ratio as Measured by DXA From Baseline to Day 59

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    End point title
    		 Percent Change in Total Body fat Mass: Lean Mass Ratio as Measured by DXA From Baseline to Day 59
    End point description
    The total body fat mass and lean body mass was measured in kg using DXA. Participants body was scanned using DXA scanner and total body fat mass and lean mass was determined. Percent change in total body fat mass:lean mass (TBFM:LM) ratio is reported. The mITT population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1) and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Percent change in TBFM:LM ratio
        least squares mean (confidence interval 90%)
    -1.667 (-4.934 to 1.600)
    -4.827 (-7.298 to -2.355)
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.204
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.159
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -7.326
         upper limit
    		 1.007

    Secondary: Change in Total Body fat Mass: Lean Mass Ratio as Measured by DXA From Baseline to Day 59

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    End point title
    		 Change in Total Body fat Mass: Lean Mass Ratio as Measured by DXA From Baseline to Day 59
    End point description
    The total body fat mass and lean body mass was measured in kg using DXA. Participants body was scanned using DXA scanner and total body fat mass and lean mass was determined. Change in total body fat mass:lean mass (TBFM:LM) ratio is reported. The mITT population population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1) and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Ratio
        least squares mean (confidence interval 90%)
    -0.010 (-0.027 to 0.007)
    -0.029 (-0.042 to -0.016)
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.145
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.019
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.041
         upper limit
    		 0.003

    Secondary: Change in Fasting Glucose During a Mixed-meal Tolerance Test (MMTT) from Baseline to Day 59

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    End point title
    		 Change in Fasting Glucose During a Mixed-meal Tolerance Test (MMTT) from Baseline to Day 59
    End point description
    The MMTT involves consumption of a standardized solid breakfast meal within 5 minutes, following a minimum 12 hours fast, and timed serial blood samples are obtained for measurement of glucose levels through 240 minutes with no additional food intake during this time. Change in fasting glucose is reported. The mITT population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1) and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: mg/dL
        least squares mean (confidence interval 90%)
    -12.600 (-21.673 to -3.527)
    -38.601 (-45.360 to -31.842)
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -26.001
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -37.801
         upper limit
    		 -14.201

    Secondary: Percent Change in Glucose Area Under the Concentration-time Curve at 0 to 4 hours (AUC0-4hrs) During a MMTT From Baseline to Day 59

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    End point title
    		 Percent Change in Glucose Area Under the Concentration-time Curve at 0 to 4 hours (AUC0-4hrs) During a MMTT From Baseline to Day 59
    End point description
    The MMTT involves consumption of a standardized solid breakfast meal within 5 minutes, following a minimum 12 hours fast, and timed serial blood samples are obtained for measurement of glucose levels through 240 minutes with no additional food intake during this time. Percent change in glucose AUC0-4hrs during MMTT is reported. The mITT population was analysed which included participants in the ITT population (who received any study drug) who received at least one dose of the study drug in the double-blind treatment period, and analysed according to their randomized treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1) and Day 59
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    12
    Units: Percentage change in glucose AUC0-4hrs
        least squares mean (confidence interval 90%)
    -6.773 (-12.528 to -1.018)
    -19.105 (-23.434 to -14.777)
    Statistical analysis title
    		 Statistical Analysis for Day 59
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -12.332
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -19.726
         upper limit
    		 -4.938

    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, and congenital anomaly. 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. Participants who received any study drug in the double-blind treatment period and were analysed according to the treatment they received were analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Day 17 through 28 days post last dose (approximately 14 months)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    18
    Units: Participants
        Any TEAEs
    5
    17
        Any TESAEs
    0
    2
    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 clinical laboratory abnormalities reported as TEAEs are reported. Clinical laboratory abnormalities are defined as any abnormal findings in analysis of serum chemistry, hematology, and urinalysis. Participants who received any study drug in the double-blind treatment period and were analysed according to the treatment they received were analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Day 17 through 28 days post last dose (approximately 14 months)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    18
    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. Abnormal vital signs reported as TEAEs included any abnormal findings in body temperature, blood pressure, pulse rate, and respiratory rate. Participants who received any study drug in the double-blind treatment period and were analysed according to the treatment they received were analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Day 17 through 28 days post last dose (approximately 14 months)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    18
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs
    End point description
    Number of participants with abnormal ECG reported as TEAEs are reported. Participants who received any study drug in the double-blind treatment period and were analysed according to the treatment they received were analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Day 17 through 28 days post last dose (approximately 14 months)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    18
    Units: Participants
        Electrocardiogram T wave amplitude decreased
    0
    4
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants With Positive Anti-drug Antibodies (ADAs) to MEDI0382
    End point description
    Number of participants with positive ADA to MEDI0382 are reported. Treatment-boosted ADA is defined as baseline ADA titer that was boosted to a 4-fold or higher level following drug administration. Treatment-emergent ADA is defined as the sum of treatment-induced ADA (post-baseline positive only) and treatment-boosted ADA. Participants who received any study drug in the double-blind treatment period and were analysed according to the treatment they received were considered for this end point. Participants with post-baseline ADA results were analysed.
    End point type
    Secondary
    End point timeframe
    Day 17 (predose), Day 32 (predose), Day 59; and 28 days post last dose (approximately 14 months)
    End point values
    		 Placebo MEDI0382
    Number of subjects analysed
    7
    14
    Units: Participants
        ADA positive post-BL
    0
    3
        Treatment-boosted ADA
    0
    0
        Treatment-emergent ADA
    0
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 17 through 28 days post last dose (approximately 14 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    MEDI0382
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo MEDI0382
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Coronary artery thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Haematoma muscle
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo MEDI0382
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 7 (71.43%)
    16 / 18 (88.89%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Injection site haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Coital bleeding
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Depressed mood
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Investigations
    Electrocardiogram T wave amplitude decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    0
    4
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    4
    Eye contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 18 (11.11%)
         occurrences all number
    5
    2
    Lethargy
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    3
    Restless legs syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Breath odour
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    5
    Dental caries
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 18 (16.67%)
         occurrences all number
    5
    6
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Eructation
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    3
    Flatulence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    2 / 7 (28.57%)
    13 / 18 (72.22%)
         occurrences all number
    2
    19
    Retching
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 18 (22.22%)
         occurrences all number
    1
    5
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 18 (27.78%)
         occurrences all number
    0
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2018
    Inclusion criteria was amended and additional text sections were revised to allow the inclusion of participants using sodium-glucose co-transporter inhibitors. Exclusion criteria was amended to allow the use of chronic kidney disease-epidemiology collaboration to estimate impaired renal function. Text describing manual randomisation procedures was amended to use an interactive voice/web response system. Double-blind study drug administration row was added to the treatment period study procedures table. Two additional time points for in clinic administration of study drugs were added for Visit 4. Text describing the administration of study drug procedures was updated. Text describing the timing of samples from intravenous glucose tolerance test was amended. Blood volume estimations were updated. New section added that allowed for and described procedures for early discontinuation or unscheduled study visits. Text describing discontinuation of study drug in the event of unblinding of study drug allocation was removed.
    17 Jul 2018
    Text was added clarifying the procedures in the event of severe persistent hyperglycemia. Specific amylase and lipase values were added to exclusion criterion. Pancreatic lipase and amylase assessments were added to the Schedule of Screening Procedures. Serum pregnancy test was added to the Schedule of Screening Procedures, Days -1 and 17 of the Treatment Period Study Procedures table, and to the clinical laboratory tests section. Pregnancy test was clarified as a urine pregnancy test in the Early Discontinuation Visit or Unscheduled Study Visit table. The time period for the collection of AEs was changed to start from the time of signature of informed consent.
    20 Aug 2018
    Updated exercise times for when participants were to be inside the whole room calorimeter in Treatment Period Study Procedures table footnote. Amended Treatment Period Study Procedures table footnote to remove sentence around pre and post meal and to clarify that it was the visual analog scale questionnaire that is to be repeated during the day. Added Day 15/16 to clarify the timing of the collection of urine for protein estimation. Additional paragraph added to describe measures that were taken to ensure the blind.
    31 Aug 2018
    Replaced carbon dioxide ‘consumption’ with ‘production’ in an exploratory endpoint. Removed instruction relating to study drug in Treatment Period Study Procedures table footnote. Changed the time of doubly labelled water urine collection from 1 to 3 hours in Treatment Period Study Procedures table footnote.
    20 Mar 2019
    The secondary objective and related endpoint pertaining to the effect of placebo treatment on ad libitum lunchtime energy intake was removed. The rationale for the single group crossover analyses was removed. Text describing which participants were to be included in the treatment groups for certain endpoints was removed. Analysis populations were added and revised. The analysis populations were changed for the efficacy and patient reported outcome (PRO) analyses. Added information related to ADA samples to be taken pre-dose on Day 17 and 32. ADA ligand binding ‘bridging’ assay details removed. Association of ADA positive status with efficacy and safety data added. Dose escalation text altered to state time period for placebo or cotadutide treatment following the single blind placebo treatment period. Minor procedural changes were made regarding the randomised treatment period, muscle biopsy, and IVGTT. Storage of residual blood samples from main study ‘for future analysis’ modified to ‘potential future analysis’. Processes for evaluation of Hy’s Law were updated.

    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.
    The analysis of endpoints change and percent change in TEE measured by doubly labelled water is not yet complete, so results of these endpoints will be reported post finalization of addendum Clinical Study Report.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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