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    Clinical Trial Results:
    A Phase1/2, Randomized, Blinded, Placebo controlled, Multiple-ascending-dose Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Overweight and Obese Subjects with a History of Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    2014-003716-36
    Trial protocol
    DE  
    Global end of trial date
    24 Feb 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    25 Jan 2019
    First version publication date
    30 May 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D5670C00002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02548585
    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
    Philip Ambery, MedImmune, LLC, +44 1223 895997, information.center@astrazeneca.com
    Scientific contact
    Philip Ambery, MedImmune, LLC, +44 1223 895997, 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
    24 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the effect of MEDI0382 on glucose control (as measured by the standardized mixed-meal test [MMT] glucose data) and body weight from baseline to the end of a 4-week period at a stable dose.
    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 were consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Subjects 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
    09 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 113
    Worldwide total number of subjects
    113
    EEA total number of subjects
    113
    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)
    104
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted from 09 Dec 2015 to 24 Feb 2017 in Germany.

    Pre-assignment
    Screening details
    A total of 422 subjects were screened, of which 113 subjects were randomized in the study. One subject was randomized but not treated with study drug.

    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, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo (matched to either 100 micrograms [mcg], or 150 mcg or 200 mcg or 300 mcg of MEDI0382) subcutaneously (SC) once daily from Day 1 to Day 7 (Cohort 1); or Day 1 to Day 11 (Cohort 2); or Day 1 to Day 15 (Cohort 3); or Day 1 to Day 41 (Cohort 4); or Day 1 to Day 22 (Cohort 5); or Day 1 to Day 17 (Cohort 6).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Sterile solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to either 100 mcg, or 150 mcg or 200 mcg or 300 mcg of MEDI0382 was administered subcutaneously (SC) once daily from Day 1 to Day 7 (Cohort 1); or Day 1 to Day 11 (Cohort 2); or Day 1 to Day 15 (Cohort 3); or Day 1 to Day 41 (Cohort 4); or Day 1 to Day 22 (Cohort 5); or Day 1 to Day 17 (Cohort 6).

    Arm title
    Cohort 1: MEDI0382 100 mcg
    Arm description
    Subjects received MEDI0382 100 mcg SC once daily from Day 1 to Day 7.
    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
    MEDI0382 100 mcg was administered SC once daily from Day 1 to Day 7.

    Arm title
    Cohort 2: MEDI0382 150 mcg
    Arm description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).
    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
    MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter an uptitrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

    Arm title
    Cohort 3: MEDI0382 200 mcg
    Arm description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 7 days (Day 9 to Day 15).
    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
    MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter an uptitrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by a second uptitrated dose of MEDI0382 200 mcg SC once daily for 7 days (Day 9 to Day 15).

    Arm title
    Cohort 4: MEDI0382 200 mcg
    Arm description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12), then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).
    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
    MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter an uptitrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by a second uptitrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12); then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).

    Arm title
    Cohort 5: MEDI0382 300 mcg
    Arm description
    Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22).
    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
    MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter an uptitrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second uptitrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third uptitrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22). for 4 days (Day 9 to Day 12); then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).

    Arm title
    Cohort 6: MEDI0382 300 mcg
    Arm description
    Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17).
    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
    MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter an uptitrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second uptitrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17).

    Number of subjects in period 1 [1]
    Placebo Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg
    Started
    45
    6
    6
    7
    25
    11
    12
    Completed
    43
    6
    6
    5
    22
    10
    11
    Not completed
    2
    0
    0
    2
    3
    1
    1
         Consent withdrawn by subject
             -
             -
             -
             -
             -
             1
             -
         Not Specified
             1
             -
             -
             2
             3
             -
             1
         Lost to follow-up
             1
             -
             -
             -
             -
             -
             -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Total subjects enrolled worldwide were 113; of which 1 subject was randomized but not treated. This 1 subject was not included in As-treated population and data for the subject was not captured for baseline characteristics.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo (matched to either 100 micrograms [mcg], or 150 mcg or 200 mcg or 300 mcg of MEDI0382) subcutaneously (SC) once daily from Day 1 to Day 7 (Cohort 1); or Day 1 to Day 11 (Cohort 2); or Day 1 to Day 15 (Cohort 3); or Day 1 to Day 41 (Cohort 4); or Day 1 to Day 22 (Cohort 5); or Day 1 to Day 17 (Cohort 6).

    Reporting group title
    Cohort 1: MEDI0382 100 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily from Day 1 to Day 7.

    Reporting group title
    Cohort 2: MEDI0382 150 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

    Reporting group title
    Cohort 3: MEDI0382 200 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 7 days (Day 9 to Day 15).

    Reporting group title
    Cohort 4: MEDI0382 200 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12), then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).

    Reporting group title
    Cohort 5: MEDI0382 300 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22).

    Reporting group title
    Cohort 6: MEDI0382 300 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17).

    Reporting group values
    Placebo Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Total
    Number of subjects
    45 6 6 7 25 11 12 112
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0 0
        Adults (18-64 years)
    42 4 6 7 23 10 11 103
        From 65-84 years
    3 2 0 0 2 1 1 9
        85 years and over
    0 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    57.2 ± 6.0 62.5 ± 2.9 60.2 ± 4.2 57.0 ± 4.9 56.0 ± 7.2 54.8 ± 6.8 54.6 ± 6.5 -
    Sex: Female, Male
    Units: Subjects
        Male
    27 5 2 5 13 7 9 68
        Female
    18 1 4 2 12 4 3 44
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0 0 0 0
        Asian
    0 0 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0 0 0
        Black or African American
    1 0 0 0 0 0 0 1
        White
    44 6 6 7 25 11 12 111
        More than one race
    0 0 0 0 0 0 0 0
        Unknown or Not Reported
    0 0 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0 0 0 0 0 0 0
        Not Hispanic or Latino
    45 6 6 7 25 11 12 112
        Unknown or Not Reported
    0 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo (matched to either 100 micrograms [mcg], or 150 mcg or 200 mcg or 300 mcg of MEDI0382) subcutaneously (SC) once daily from Day 1 to Day 7 (Cohort 1); or Day 1 to Day 11 (Cohort 2); or Day 1 to Day 15 (Cohort 3); or Day 1 to Day 41 (Cohort 4); or Day 1 to Day 22 (Cohort 5); or Day 1 to Day 17 (Cohort 6).

    Reporting group title
    Cohort 1: MEDI0382 100 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily from Day 1 to Day 7.

    Reporting group title
    Cohort 2: MEDI0382 150 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

    Reporting group title
    Cohort 3: MEDI0382 200 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 7 days (Day 9 to Day 15).

    Reporting group title
    Cohort 4: MEDI0382 200 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12), then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).

    Reporting group title
    Cohort 5: MEDI0382 300 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22).

    Reporting group title
    Cohort 6: MEDI0382 300 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17).

    Subject analysis set title
    Cohort 4: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 4 days (Day 9 to Day 12), then a further placebo (matched to MEDI0382 200 mcg) SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by placebo (matched to MEDI0382 200 mcg) SC once daily for 1 day in hospital (Day 41).

    Subject analysis set title
    Cohort 1: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received placebo matched to (MEDI0382 100 mcg) SC once daily from Day 1 to Day 7.

    Subject analysis set title
    Cohort 2: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 7 days (Day 5 to Day 11).

    Subject analysis set title
    Cohort 3: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 7 days (Day 9 to Day 15).

    Subject analysis set title
    Cohort 5: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received placebo (matched to MEDI0382 100 mcg ) SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of placebo (matched to MEDI0382 300 mcg) SC once daily for 7 days (Day 16 to Day 22).

    Subject analysis set title
    Cohort 6: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of placebo (matched to MEDI0382 300 mcg) SC once daily for 7 days (Day 11 to Day 17).

    Primary: Percent Change From Baseline in Mixed-meal Test (MMT) Glucose Area Under the Concentration-time Curve From Time 0 to 4 hours to the End of Treatment (EOT) (Cohort 4)

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    End point title
    Percent Change From Baseline in Mixed-meal Test (MMT) Glucose Area Under the Concentration-time Curve From Time 0 to 4 hours to the End of Treatment (EOT) (Cohort 4) [1]
    End point description
    Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hours (hrs) after consumption of the standardized meal (with no additional food intake during this time). Pharmacodynamic (PD) population was analysed for this end point, which included all subjects who received at least 1 dose of study drug and had at least 1 post-MMT PD blood sample.
    End point type
    Primary
    End point timeframe
    0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post standardized meal intake (SMI) on Baseline (Day -1) and EOT (Day 41)
    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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 4: MEDI0382 200 mcg Cohort 4: Placebo
    Number of subjects analysed
    25
    26
    Units: Percent change
        arithmetic mean (standard deviation)
    -33.81 ± 18.62
    -9.24 ± 12.30
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Cohort 4: MEDI0382 200 mcg v Cohort 4: Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Confidence interval
    Notes
    [2] - p-value was based on pairwise comparison using analysis of covariance (ANCOVA) adjusted by baseline value.

    Primary: Change From Baseline in Body Weight to the EOT (Cohort 4)

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    End point title
    Change From Baseline in Body Weight to the EOT (Cohort 4) [3]
    End point description
    Intent-to-treat (ITT) population was analysed for this end point, which included all subjects who were randomised and received any study drug and analysed according to the initial randomisation.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and EOT (Day 42)
    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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 4: MEDI0382 200 mcg Cohort 4: Placebo
    Number of subjects analysed
    25
    26
    Units: Kilograms (Kg)
        arithmetic mean (standard deviation)
    -3.83 ± 2.09
    -1.71 ± 2.10
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Cohort 4: MEDI0382 200 mcg v Cohort 4: Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008 [4]
    Method
    ANCOVA
    Confidence interval
    Notes
    [4] - p-value was based on pairwise comparison using ANCOVA adjusted by baseline value.

    Secondary: Percent Change From Baseline in MMT Glucose AUC0-4h to the EOT (Cohorts 1, 2, 3, 5, and 6)

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    End point title
    Percent Change From Baseline in MMT Glucose AUC0-4h to the EOT (Cohorts 1, 2, 3, 5, and 6) [5]
    End point description
    Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 22 for Cohort 5; and Day 17 for Cohort 6)
    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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    11
    12
    3
    3
    3
    5
    5
    Units: Percent change
        arithmetic mean (standard deviation)
    -41.80 ± 11.07
    -36.73 ± 10.09
    -39.58 ± 5.27
    -41.66 ± 9.97
    -38.19 ± 12.51
    -14.60 ± 5.56
    -15.07 ± 13.46
    -0.47 ± 15.16
    -14.52 ± 8.12
    -4.80 ± 3.45
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Weight to the EOT (Cohorts 1, 2, 3, 5, and 6)

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    End point title
    Change From Baseline in Body Weight to the EOT (Cohorts 1, 2, 3, 5, and 6) [6]
    End point description
    ITT population was analysed for this end point. Subjects who did not complete the treatment were not included in this analysis.
    End point type
    Secondary
    End point timeframe
    Cohort 1: Baseline (Day 1) to EOT (Day 8); Cohort 2: Baseline (Day 1) to EOT (Day 12); Cohort 3: Baseline (Day 1) to EOT (Day 16); Cohort 5: Baseline (Day 1) to EOT (Day 22); Cohort 6: Baseline (Day 1) to EOT (Day 17)
    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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    11
    12
    3
    3
    3
    5
    5
    Units: Kg
        arithmetic mean (standard deviation)
    -2.32 ± 1.29
    -1.52 ± 0.57
    -4.63 ± 1.98
    -3.26 ± 1.99
    -2.04 ± 1.52
    -1.20 ± 0.44
    -1.00 ± 1.13
    -2.90 ± 1.05
    -0.98 ± 2.12
    -0.94 ± 3.09
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Hemoglobin A1c (HbA1c) to the EOT (Cohorts 4, 5, and 6)

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    End point title
    Percent Change From Baseline in Hemoglobin A1c (HbA1c) to the EOT (Cohorts 4, 5, and 6) [7]
    End point description
    ITT population was analysed for this end point. Subjects who did not complete the treatment were not included in this analysis.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Baseline (Day -2) to EOT (Day 42); Cohort 5: Baseline (Day -2) to EOT (Day 22); Cohort 6: Baseline (Day -2) to EOT (Day 17)
    Notes
    [7] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    25
    11
    12
    26
    5
    5
    Units: Percent change
        arithmetic mean (standard deviation)
    -0.92 ± 0.41
    -0.55 ± 0.35
    -0.42 ± 0.27
    -0.58 ± 0.30
    -0.10 ± 0.29
    -0.18 ± 0.19
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fructosamine to the EOT (Cohorts 4, 5, and 6)

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    End point title
    Change From Baseline in Fructosamine to the EOT (Cohorts 4, 5, and 6) [8]
    End point description
    ITT population was analysed for this end point. Subjects who did not complete the treatment were not included in this analysis.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Baseline (Day -2) to EOT (Day 41); Cohort 5: Baseline (Day -2) to EOT (Day 22); Cohort 6: Baseline (Day -2) to EOT (Day 17)
    Notes
    [8] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    25
    11
    12
    26
    5
    5
    Units: micromol/L
        arithmetic mean (standard deviation)
    -67.9 ± 44.4
    -47.4 ± 15.7
    -47.5 ± 55.3
    -33.7 ± 44.6
    -27.8 ± 25.8
    -48.8 ± 43.7
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Glucose prior to MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Change From Baseline in Fasting Glucose prior to MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6) [9]
    End point description
    Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Cohort 1: Baseline (Day-1) to EOT (Day7); Cohort 2: Baseline (Day-1) to EOT (Day11); Cohort 3: Baseline (Day-1) to EOT (Day15); Cohort 4: Baseline (Day-1) to EOT (Day41); Cohort 5: Baseline (Day-1) to EOT (Day22); Cohort 6: Baseline (Day-1) to EOT (Day17)
    Notes
    [9] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    26
    3
    3
    3
    5
    5
    Units: mg/dL
        arithmetic mean (standard deviation)
    -74.48 ± 24.59
    -54.06 ± 19.51
    -63.67 ± 11.93
    -50.62 ± 33.61
    -54.42 ± 19.75
    -55.21 ± 31.13
    -18.52 ± 18.88
    -32.44 ± 17.19
    -49.86 ± 23.24
    -4.20 ± 33.73
    -32.08 ± 17.49
    -16.58 ± 12.45
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Glucose Area Under the Concentration-time Curve From Time 0 to 24 hours (AUC0-24h) after MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Percent Change From Baseline in Glucose Area Under the Concentration-time Curve From Time 0 to 24 hours (AUC0-24h) after MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6) [10]
    End point description
    Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    0 minutes before; and 15, 30, 45, 60, 90, 120, 180, 240 minutes, and 24 hrs post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4; Day 22 for Cohort 5; and Day 17 for Cohort 6)
    Notes
    [10] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    26
    3
    3
    3
    5
    5
    Units: Percent change
        arithmetic mean (standard deviation)
    -28.34 ± 13.52
    -29.32 ± 17.24
    -27.07 ± 10.82
    -13.50 ± 18.19
    -34.51 ± 11.25
    -26.95 ± 9.45
    -1.06 ± 11.47
    -21.80 ± 1.41
    0.80 ± 39.55
    -13.80 ± 15.95
    -4.20 ± 28.58
    -10.10 ± 14.69
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [11]
    End point description
    An Adverse Event (AE) is any unfavourable and unintended sign, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. Serious adverse events (SAE) is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs and TESAEs are defined as AEs and SAEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). As-treated Population (ATP) was analysed for this end point, which included all subjects who received any study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
    Notes
    [11] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    26
    3
    3
    3
    5
    5
    Units: Subjects
        TEAEs
    6
    5
    7
    22
    10
    10
    23
    2
    3
    3
    4
    2
        TESAEs
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Vital Signs and Physical Examination Reported as TEAEs

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    End point title
    Number of Subjects With Abnormal Vital Signs and Physical Examination Reported as TEAEs [12]
    End point description
    TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of subjects with TEAEs related to vital signs and physical examination abnormalities were reported. As-treated population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
    Notes
    [12] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    26
    3
    3
    3
    5
    5
    Units: Subjects
        Blood Pressure increased
    0
    0
    0
    1
    0
    0
    2
    0
    0
    0
    0
    0
        Blood pressure systolic increased
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
        Blood pressure diastolic increased
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
        Physical Examinations
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal 12 Lead Electrocardiogram (ECG) Reported as TEAEs

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    End point title
    Number of Subjects With Abnormal 12 Lead Electrocardiogram (ECG) Reported as TEAEs [13]
    End point description
    TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of subjects with TEAEs related to ECG abnormalities were reported. As-treated population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
    Notes
    [13] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    26
    3
    3
    3
    5
    5
    Units: Subjects
        Arrhythmia
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Atrial fibrillation
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
        Atrioventricular block first degree
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Atrioventricular block second degree
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Electrocardiogram ST segment depression
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Extrasystoles
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
        Sinus tachycardia
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
        Supraventricular extrasystoles
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
        Supraventricular tachycardia
    1
    0
    1
    0
    0
    0
    0
    1
    1
    1
    0
    0
        Tachycardia
    1
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Ventricular extrasystoles
    1
    1
    0
    1
    0
    0
    1
    0
    1
    0
    0
    0
        Ventricular tachycardia
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Clinical Laboratory Reported as TEAEs

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    End point title
    Number of Subjects With Abnormal Clinical Laboratory Reported as TEAEs [14]
    End point description
    TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of subjects with TEAEs related to laboratory abnormalities were reported. As-treated population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
    Notes
    [14] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    26
    3
    3
    3
    5
    5
    Units: Subjects
        Lipase increased
    0
    1
    0
    1
    2
    1
    0
    0
    0
    0
    0
    0
        Hypokalemia
    0
    0
    0
    1
    0
    1
    1
    0
    0
    0
    0
    0
        C-reactive protein increased
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Hypoglycemia
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
        Chromaturia
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Any Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score (Cohorts 4, 5, and 6)

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    End point title
    Number of Subjects With Any Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score (Cohorts 4, 5, and 6) [15]
    End point description
    The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behaviour of subjects. Yes/No responses are mapped to C-SSRS to assess whether subject experienced suicidal behaviour and suicidal ideation. Suicidal behaviour questions includes preparatory acts or behaviour, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation questions includes wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intent to act, active suicidal ideation with some intent to act (without specific plan), and active suicidal ideation with specific plan and intent. Subjects with yes response to any category for suicidal ideation were reported. As-treated population was used for analysis. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was evaluable for specified time point.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Day -1, and Days 13, 20, 27, 34, and 40; Cohort 5: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 36 days); Cohort 6: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 31 days)
    Notes
    [15] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    25
    11
    12
    26
    5
    5
    Units: Subjects
        Day -1 (n = 25, 11, 12, 26, 5, 5)
    4
    2
    2
    1
    0
    0
        Day 13 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    1
    99999
    99999
        Day 20 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    0
    99999
    99999
        Day 27 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    0
    99999
    99999
        Day 34 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    0
    99999
    99999
        Day 40 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    0
    99999
    99999
        Days 7-14 post last dose (n = 0, 11, 12, 0, 5, 5)
    99999
    1
    0
    99999
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Any Suicidal Behaviour as Assessed by C-SSRS Score (Cohorts 4, 5, and 6)

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    End point title
    Number of Subjects With Any Suicidal Behaviour as Assessed by C-SSRS Score (Cohorts 4, 5, and 6) [16]
    End point description
    The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behaviour of subjects. Yes/No responses are mapped to C-SSRS to assess whether subject experienced suicidal behaviour and suicidal ideation. Suicidal behaviour questions includes preparatory acts or behaviour, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation questions includes wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intent to act, active suicidal ideation with some intent to act (without specific plan), and active suicidal ideation with specific plan and intent. Subjects with yes response to any category for suicidal ideation were reported. As-treated population was used for analysis. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was evaluable for specified time point.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Day -1, and Days 13, 20, 27, 34, and 40; Cohort 5: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 36 days); Cohort 6: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 31 days)
    Notes
    [16] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    25
    11
    12
    26
    5
    5
    Units: Subjects
        Day -1 (n = 25, 11, 12, 26, 5, 5)
    2
    1
    1
    2
    0
    0
        Day 13 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    1
    99999
    99999
        Day 20 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    0
    99999
    99999
        Day 27 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    0
    99999
    99999
        Day 34 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    0
    99999
    99999
        Day 40 (n = 25, 0, 0, 26, 0, 0)
    0
    99999
    99999
    0
    99999
    99999
        Days 7-14 post last dose (n = 0, 11, 12, 0, 5, 5)
    99999
    0
    0
    99999
    0
    0
    No statistical analyses for this end point

    Secondary: Terminal Elimination Half Life (t1/2) of MEDI0382 (Cohorts 1, 2, and 3)

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    End point title
    Terminal Elimination Half Life (t1/2) of MEDI0382 (Cohorts 1, 2, and 3) [17]
    End point description
    Terminal elimination half Life is the time measured for the plasma concentration of MEDI0382 to decrease by one half. Pharmacokinetic (PK) population was analysed for this end point, which included all subjects who received at least 1 dose of study drug and had at least one PK sample taken that was above the lower limit of quantitation. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was analysed for the specified time points. 95% confidence interval (CI) data was not applicable as only one subject was evaluable; therefore, lower and upper CI values are presented with arbitrary values of '0.999999' and '99.9999', respectively for the specified time points.
    End point type
    Secondary
    End point timeframe
    Cohort (C) 1 (Day [D] 1 and [&] D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose; and additional 48 hr post C1D7, C2D11, C3D15 dose
    Notes
    [17] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg
    Number of subjects analysed
    6
    6
    7
    Units: hr
    geometric mean (confidence interval 95%)
        Day 1 (n = 1, 0, 0)
    8.5 (0.999999 to 99.9999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 5 (n = 0, 2, 0)
    99999 (99999 to 99999)
    10.3 (7.8 to 13.5)
    99999 (99999 to 99999)
        Day 7 (n = 3, 0, 0)
    11.7 (5.5 to 25.1)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 9 (n = 0, 0, 1)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    8.3 (0.999999 to 99.9999)
        Day 11 (n = 0, 6, 0)
    99999 (99999 to 99999)
    11.3 (5.9 to 21.7)
    99999 (99999 to 99999)
        Day 15 (n = 0, 0, 5)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    11.3 (8.2 to 15.5)
    No statistical analyses for this end point

    Secondary: Accumulation Ratio (Rac) of MEDI0382 (Cohorts 1, 2, and 3)

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    End point title
    Accumulation Ratio (Rac) of MEDI0382 (Cohorts 1, 2, and 3) [18]
    End point description
    Accumulation ratio was calculated as, Rac obtained from area under the curve from time zero to end of dosing interval (AUC[0-tau]) of Nth day divided by AUC(0-tau) of Day 1. PK population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was evaluable for the specified time points and arbitrary value '999999' signifies data not reported, since accumulation ratio as described by the formula could not be derived for Cohort 1 Day 1, Cohort 2 Day 5, and for Cohort 3 Day 9.
    End point type
    Secondary
    End point timeframe
    C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose; and additional 48 hr post C1D7, C2D11, C3D15 dose
    Notes
    [18] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg
    Number of subjects analysed
    6
    6
    7
    Units: Ratio
    geometric mean (confidence interval 95%)
        Day 1 (n = 6, 0, 0)
    999999 (999999 to 999999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 5 (n = 0, 6, 0)
    99999 (99999 to 99999)
    999999 (999999 to 999999)
    99999 (99999 to 99999)
        Day 7 (n = 6, 0, 0)
    1.3 (1.1 to 1.5)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 9 (n = 0, 0, 6)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    999999 (999999 to 999999)
        Day 11 (n = 0, 6, 0)
    99999 (99999 to 99999)
    1.1 (0.9 to 1.8)
    99999 (99999 to 99999)
        Day 15 (n = 0, 0, 5)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    1.3 (1.1 to 1.5)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Area Under the Concentration Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) [19]
    End point description
    PK population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was analysed for the specified time points.
    End point type
    Secondary
    End point timeframe
    C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose
    Notes
    [19] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    Units: ng*hr/mL
    geometric mean (confidence interval 95%)
        Day 1 (n = 6, 0, 0, 0, 0, 0)
    82.21 (44.56 to 151.69)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 5 (n = 0, 6, 0, 0, 0, 0)
    99999 (99999 to 99999)
    174.58 (87.41 to 348.67)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 7 (n = 6, 0, 0, 0, 0, 0)
    107.01 (54.10 to 211.64)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 9 (n = 0, 0, 4, 23, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    194.78 (146.17 to 259.56)
    164.05 (42.67 to 630.76)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 11 (n = 0, 6, 0, 0, 0, 11)
    99999 (99999 to 99999)
    157.31 (82.45 to 421.12)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    275.29 (169.33 to 447.48)
        Day 15 (n = 0, 0, 5, 0, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    195.40 (89.8 to 425.17)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 16 (n = 0, 0, 0, 0, 11, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    261.90 (166.58 to 411.74)
    99999 (99999 to 99999)
        Day 17 (n = 0, 0, 0, 0, 0, 11)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    246.06 (130.34 to 464.51)
        Day 22 (n = 0, 0, 0, 0, 10, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    254.35 (196.10 to 329.9)
    99999 (99999 to 99999)
        Day 41 (n = 0, 0, 0, 22, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    199.10 (84.57 to 468.75)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - inf)] of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - inf)] of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) [20]
    End point description
    PK population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was analysed for the specified time points. 95% CI data was not applicable as only one subject was evaluable; therefore, lower and upper CI values are presented with arbitrary values of '9.99999' and '999.999', respectively for the specified time points.
    End point type
    Secondary
    End point timeframe
    C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose
    Notes
    [20] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    Units: ng*hr/mL
    geometric mean (confidence interval 95%)
        Day 1 (n = 1, 0, 0, 0, 0, 0)
    103.46 (9.99999 to 999.999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 5 (n = 0, 2, 0, 0, 0, 0)
    99999 (99999 to 99999)
    207.15 (11.98 to 3580.41)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 7 (n = 3, 0, 0, 0, 0, 0)
    184.68 (107.76 to 316.51)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 9 (n = 0, 0, 1, 13, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    242.60 (9.99999 to 999.999)
    238.22 (80.99 to 700.67)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 11 (0, 6, 0, 0, 0, 0)
    99999 (99999 to 99999)
    215.80 (112.90 to 412.47)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 15 (n = 0, 0, 5, 0, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    271.84 (119.33 to 619.24)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 16 (n = 0, 0, 0, 0, 6, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    317.93 (182.24 to 554.64)
    99999 (99999 to 99999)
        Day 17 (n = 0, 0, 0, 0, 0, 4)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    327.28 (249.98 to 428.49)
        Day 22 (n = 0,0, 0, 0, 4, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    294.60 (172.52 to 503.05)
    99999 (99999 to 99999)
        Day 41 (n = 0, 0, 0, 11, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    262.17 (99.79 to 688.77)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Maximum Observed Plasma Concentration (Cmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) [21]
    End point description
    PK population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was analysed for the specified time points.
    End point type
    Secondary
    End point timeframe
    C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose
    Notes
    [21] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    Units: ng/mL
    geometric mean (confidence interval 95%)
        Day 1 (n = 6, 0, 0, 0, 0, 0)
    4.97 (0.33 to 7.41)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 5 (n = 0, 6, 0, 0, 0,0)
    99999 (99999 to 99999)
    9.66 (4.68 to 19.95)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 7 (n = 6, 0, 0, 0, 0, 0)
    6.26 (3.36 to 11.67)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 9 (n = 0, 0, 6, 23, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    10.57 (6.33 to 17.66)
    11.64 (3.16 to 42.94)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 11 (n = 0, 6, 0, 0, 0, 11)
    99999 (99999 to 99999)
    9.57 (4.63 to 19.79)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    13.69 (5.73 to 32.71)
        Day 15 (n = 0, 0, 5, 0, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    10.97 (4.62 to 26.06)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 16 (n = 0, 0, 0, 0, 11, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    17.65 (8.82 to 35.29)
    99999 (99999 to 99999)
        Day 17 (n = 0, 0, 0, 0, 0, 11)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    15.55 (7.55 to 32.01)
        Day 22 (n = 0, 0, 0, 0, 10, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    15.77 (10.02 to 24.8)
    99999 (99999 to 99999)
        Day 41 (n = 0, 0, 0, 22, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    13.42 (4.77 to 37.75)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration (Cmin) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Minimum Observed Plasma Concentration (Cmin) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) [22]
    End point description
    PK population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was analysed for the specified time points.
    End point type
    Secondary
    End point timeframe
    C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose
    Notes
    [22] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    Units: ng/mL
    geometric mean (confidence interval 95%)
        Day 1 (n = 6, 0, 0, 0, 0, 0)
    0.705 (0.33 to 1.49)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 5 (n = 0, 6, 0, 0, 0, 0)
    99999 (99999 to 99999)
    2.685 (1.06 to 6.79)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 7 (n = 6, 0, 0, 0, 0, 0)
    2.372 (1.18 to 4.78)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 9 (n = 0, 0, 6, 23, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    3.521 (2.16 to 5.75)
    2.635 (0.79 to 8.83)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 11 (n = 0, 6, 0, 0, 0, 11)
    99999 (99999 to 99999)
    3.59 (1.62 to 7.94)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    3.586 (1.45 to 8.88)
        Day 15 (n = 0, 0, 5, 0, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    4.973 (2.24 to 11.05)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 16 (n = 0, 0, 0, 0, 11, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    4.062 (1.68 to 9.84)
    99999 (99999 to 99999)
        Day 17 (n = 0, 0, 0, 0, 0, 11)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    4.766 (2.74 to 8.3)
        Day 22 (n = 0, 0, 0, 0, 10, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    5.21 (1.97 to 13.81)
    99999 (99999 to 99999)
        Day 41 (n = 0, 0, 0, 22, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    3.378 (1.03 to 11.04)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) [23]
    End point description
    PK population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified time points. Arbitrary value '99999' signifies data not applicable as no subject was analysed for the specified time points.
    End point type
    Secondary
    End point timeframe
    C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose
    Notes
    [23] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    Units: hr
    median (full range (min-max))
        Day 1 (n = 6, 0, 0, 0, 0, 0)
    8 (6 to 8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 5 (0, 6, 0, 0, 0, 0)
    99999 (99999 to 99999)
    6 (4 to 8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 7 (n = 6, 0, 0, 0, 0, 0)
    6 (4 to 6)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 9 (n = 0, 0, 6, 23, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    6 (6 to 8)
    4 (1 to 6)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 11 (n = 0, 6, 0, 0, 0, 11)
    99999 (99999 to 99999)
    6 (4 to 6)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    6 (4 to 12)
        Day 15 (n = 0, 0, 5, 0, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    6 (4 to 8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Day 16 (n = 0, 0, 0, 0, 11, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    4 (2 to 8)
    99999 (99999 to 99999)
        Day 17 (n = 0, 0, 0, 0, 0, 11)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    4 (2 to 6)
        Day 22 (n = 0, 0, 0, 0, 10, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    4 (4 to 8)
    99999 (99999 to 99999)
        Day 41 (n = 0, 0, 0, 22, 0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    4 (4 to 8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Anti-drug Antibodies to MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Number of Subjects With Positive Anti-drug Antibodies to MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) [24]
    End point description
    As-treated population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 7-14 days post-last dose of MEDI0382 for all cohorts (Approximately 60 days)
    Notes
    [24] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    26
    3
    3
    3
    5
    5
    Units: Subjects
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Insulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, 4, 5, and 6)

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    End point title
    Percent Change From Baseline in Insulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, 4, 5, and 6) [25]
    End point description
    Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4; Day 22 for Cohort 5; and Day 17 for Cohort 6)
    Notes
    [25] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 5: MEDI0382 300 mcg Cohort 6: MEDI0382 300 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 5: Placebo Cohort 6: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    11
    12
    26
    3
    3
    3
    5
    5
    Units: Percent change
        arithmetic mean (standard deviation)
    -9.37 ± 29.17
    36.32 ± 35.21
    -17.47 ± 38.84
    -1.17 ± 44.20
    1.01 ± 31.00
    -7.72 ± 37.03
    -8.63 ± 32.33
    10.83 ± 21.33
    -3.67 ± 13.76
    -20.43 ± 68.82
    -17.70 ± 16.47
    -8.18 ± 28.34
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Proinsulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

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    End point title
    Percent Change From Baseline in Proinsulin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4) [26]
    End point description
    Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4)
    Notes
    [26] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    26
    3
    3
    3
    Units: Percent change
        arithmetic mean (standard deviation)
    -52.10 ± 36.29
    -36.77 ± 19.62
    -54.13 ± 26.40
    -47.93 ± 22.12
    -29.72 ± 31.13
    -3.27 ± 38.92
    -33.13 ± 40.07
    81.27 ± 77.21
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in C-peptide AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

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    End point title
    Percent Change From Baseline in C-peptide AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4) [27]
    End point description
    Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). PD population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4)
    Notes
    [27] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    26
    3
    3
    3
    Units: Percent change
        arithmetic mean (standard deviation)
    -3.82 ± 21.29
    39.78 ± 32.88
    -9.07 ± 27.27
    15.66 ± 42.35
    8.08 ± 32.12
    10.17 ± 5.05
    -1.43 ± 6.02
    79.37 ± 91.56
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Incretin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4)

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    End point title
    Percent Change From Baseline in Incretin AUC0-4h after MMT to EOT (Cohorts 1, 2, 3, and 4) [28]
    End point description
    Mixes-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). Incretins included glucagon-like peptide-1 (GLP-1; active and inactive both), glucagon, and gastric inhibitory peptide (GIP). PD population was analysed for this end point. Here, 'n' denotes number of subjects analysed for specified parameters. Arbitrary value '999999' signifies standard deviation not applicable as only one subject was evaluable for the specified parameter.
    End point type
    Secondary
    End point timeframe
    0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4)
    Notes
    [28] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Cohort 1: MEDI0382 100 mcg Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: MEDI0382 200 mcg Cohort 4: Placebo Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo
    Number of subjects analysed
    6
    6
    7
    25
    26
    3
    3
    3
    Units: Percent change
    arithmetic mean (standard deviation)
        GLP-1, Active: Change at EOT (n=6,6,5,19,2,3,3,24)
    -33.67 ± 16.84
    -50.45 ± 12.30
    -40.36 ± 26.90
    -49.73 ± 22.88
    1.63 ± 26.43
    8.30 ± 13.15
    -10.40 ± 10.47
    -2.87 ± 20.32
        GLP-1, Inactive:Change at EOT (n=1,3,3,8,1,1,2,14)
    0.70 ± 99999
    -10.93 ± 22.36
    -8.07 ± 11.30
    -28.85 ± 16.73
    3.99 ± 29.59
    -20.30 ± 99999
    -22.90 ± 99999
    1.75 ± 29.20
        Glucagon: Change at EOT (n=4,5,2,12,2,3,3,18)
    -20.25 ± 25.45
    -38.12 ± 16.33
    -3.05 ± 36.56
    -30.17 ± 25.56
    -1.76 ± 21.47
    -13.85 ± 18.60
    -17.53 ± 19.46
    -18.73 ± 21.59
        GIP: Change at EOT (n=2,5,5,12,2,2,2,17)
    -46.50 ± 14.85
    -27.08 ± 25.03
    -21.34 ± 39.48
    -37.38 ± 23.14
    -6.60 ± 19.43
    18.00 ± 2.83
    4.10 ± 24.61
    -6.30 ± 7.35
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Cohort 1: MEDI0382 100 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily from Day 1 to Day 7.

    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    Subjects received placebo matched to (MEDI0382 100 mcg) SC once daily from Day 1 to Day 7.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 7 days (Day 5 to Day 11).

    Reporting group title
    Cohort 3: Placebo
    Reporting group description
    Participants received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 7 days (Day 9 to Day 15).

    Reporting group title
    Cohort 2: MEDI0382 150 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11).

    Reporting group title
    Cohort 3: MEDI0382 200 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 7 days (Day 9 to Day 15). )

    Reporting group title
    Cohort 4: Placebo
    Reporting group description
    Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 4 days (Day 9 to Day 12), then a further placebo (matched to MEDI0382 200 mcg) SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by placebo (matched to MEDI0382 200 mcg) SC once daily for 1 day in hospital (Day 41).

    Reporting group title
    Cohort 4: MEDI0382 200 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12), then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41).

    Reporting group title
    Cohort 5: Placebo
    Reporting group description
    Subjects received placebo (matched to MEDI0382 100 mcg ) SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of placebo (matched to MEDI0382 150 mcg) SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of placebo (matched to MEDI0382 300 mcg) SC once daily for 7 days (Day 16 to Day 22).

    Reporting group title
    Cohort 5: MEDI0382 300 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22).

    Reporting group title
    Cohort 6: Placebo
    Reporting group description
    Subjects received placebo (matched to MEDI0382 100 mcg) SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of placebo (matched to MEDI0382 200 mcg) SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of placebo (matched to MEDI0382 300 mcg) SC once daily for 7 days (Day 11 to Day 17).

    Reporting group title
    Cohort 6: MEDI0382 300 mcg
    Reporting group description
    Subjects received MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17).

    Serious adverse events
    Cohort 1: MEDI0382 100 mcg Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: Placebo Cohort 4: MEDI0382 200 mcg Cohort 5: Placebo Cohort 5: MEDI0382 300 mcg Cohort 6: Placebo Cohort 6: MEDI0382 300 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Cohort 1: MEDI0382 100 mcg Cohort 1: Placebo Cohort 2: Placebo Cohort 3: Placebo Cohort 2: MEDI0382 150 mcg Cohort 3: MEDI0382 200 mcg Cohort 4: Placebo Cohort 4: MEDI0382 200 mcg Cohort 5: Placebo Cohort 5: MEDI0382 300 mcg Cohort 6: Placebo Cohort 6: MEDI0382 300 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    5 / 6 (83.33%)
    7 / 7 (100.00%)
    23 / 26 (88.46%)
    22 / 25 (88.00%)
    4 / 5 (80.00%)
    10 / 11 (90.91%)
    2 / 5 (40.00%)
    10 / 12 (83.33%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Thrombophlebitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Immune system disorders
    Allergic oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    2
    Early satiety
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    5 / 25 (20.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    5
    0
    2
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Injection site discolouration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    3 / 25 (12.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    4
    0
    0
    0
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Injection site haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    0
    2
    0
    0
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    2
    0
    0
    Injection site pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Injection site reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    6
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    1
    0
    0
    Medical device site erosion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Medical device site erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 26 (7.69%)
    3 / 25 (12.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    2
    3
    0
    1
    0
    1
    Medical device site injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Medical device site irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    3 / 26 (11.54%)
    3 / 25 (12.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    4
    0
    0
    0
    0
    Medical device site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Medical device site pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 26 (7.69%)
    3 / 25 (12.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    3
    0
    0
    0
    0
    Medical device site rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Medical device site reaction
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    5
    0
    0
    0
    0
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    4
    0
    Body temperature increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Electrocardiogram st segment depression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Heart rate increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    3
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Extrasystoles
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    7
    1
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    3
    0
    1
    1
    0
    0
    0
    0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Arrhythmia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    0
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Nasal mucosal ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    5 / 26 (19.23%)
    4 / 25 (16.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    6
    0
    2
    0
    2
    Dizziness postural
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    4 / 7 (57.14%)
    2 / 26 (7.69%)
    9 / 25 (36.00%)
    1 / 5 (20.00%)
    3 / 11 (27.27%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    6
    3
    6
    6
    10
    1
    3
    1
    1
    Paraesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    3 / 25 (12.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    6 / 25 (24.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    1
    0
    9
    0
    2
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    4
    0
    0
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    3 / 26 (11.54%)
    6 / 25 (24.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    5
    7
    1
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    3 / 26 (11.54%)
    4 / 25 (16.00%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    8
    0
    2
    4
    6
    1
    2
    0
    2
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 7 (42.86%)
    1 / 26 (3.85%)
    7 / 25 (28.00%)
    0 / 5 (0.00%)
    4 / 11 (36.36%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    0
    0
    0
    3
    1
    7
    0
    7
    0
    2
    Eructation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    4 / 25 (16.00%)
    0 / 5 (0.00%)
    3 / 11 (27.27%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    4
    0
    3
    0
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Faeces hard
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Faeces soft
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 26 (7.69%)
    2 / 25 (8.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    2
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Infrequent bowel movements
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    3 / 7 (42.86%)
    5 / 26 (19.23%)
    13 / 25 (52.00%)
    1 / 5 (20.00%)
    3 / 11 (27.27%)
    0 / 5 (0.00%)
    5 / 12 (41.67%)
         occurrences all number
    0
    0
    0
    0
    7
    4
    7
    39
    2
    6
    0
    7
    Pancreatolithiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Regurgitation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    0 / 26 (0.00%)
    8 / 25 (32.00%)
    0 / 5 (0.00%)
    3 / 11 (27.27%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    2
    8
    0
    40
    0
    9
    0
    2
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    2
    0
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    1
    1
    0
    4
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    2
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    3 / 25 (12.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    3
    0
    0
    0
    0
    Skin reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Ankle deformity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    1
    2
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    6 / 7 (85.71%)
    0 / 26 (0.00%)
    5 / 25 (20.00%)
    1 / 5 (20.00%)
    4 / 11 (36.36%)
    0 / 5 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    0
    1
    2
    6
    0
    5
    1
    4
    0
    3
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    1
    0
    0
    0
    1
    Increased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    6 / 26 (23.08%)
    4 / 25 (16.00%)
    1 / 5 (20.00%)
    2 / 11 (18.18%)
    1 / 5 (20.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    7
    4
    1
    2
    1
    3
    Tonsillitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2015
    Number of anticipated study sites was changed from approximately 3 to 5 to “up to 8” (Section 9.1) • Data for progression from single-ascending dose (SAD) study to Cohort 1 of this multiple-ascending dose (MAD) study were updated (Section 9.4.3.1) • Provision that relevant data for progression from SAD study to the MAD study will be summarized and provided to appropriate regulatory body and central ethics committee was added. Additionally, approval to proceed with MAD study will be obtained from the appropriate regulatory body prior to initiating enrollment was added (Section 9.4.3.1) • Text were added for subject safety (Section 9.4.3.1) • The following text was added for clarification: the decision for progression from Cohort 1 to Cohort 2, and from Cohort 2 to Cohort 3 will be made by Dose Escalation Committee (DEC); relevant data will be summarized and provided to appropriate regulatory body and central ethics committee. And, approval to proceed with Cohort 4 will be obtained from the appropriate regulatory body prior to initiating enrollment (Section 9.4.3.1) • DEC recommendations were updated (Section 9.4.3.1) • Significant vomiting was clarified as “3 or more episodes of vomiting on a single day or across 2 consecutive days, despite adjustment to diet having been made” (Section 9.4.5)• Starting dose reported for SAD study was updated from 30 µg/day to 5 µg/day. Dose rationale was updated. A new table was added (Section 9.2) • A note was added to clarify Inclusion Criterion 9 (about contraception) (Section 9.3.1) • The exclusion criterion “Concurrent participation in another study of any kind is prohibited” was added (Section 9.3.2) • Text was modified to add that an individual subject will not receive any further study drug if that subject has more than 2 symptomatic hypoglycemic events; or persistent hyperglycemia, Section 9.3.3).
    14 Aug 2015
    Updated and modified text to include a summary of the safety information and statement regarding the current status from the SAD study (D5670C00001) • Changed text to specify change from baseline in glucose and body weight was to be evaluated (Sections 8 and 9.5.1.1) • Objective 1/endpoint 1 were changed to specify change from baseline to be used to evaluate glucose control, blood sample collection parameters at Day 1 were rationalized (Sections 8 and 9.5.1.1) • Clarified that subjects should be treated with a daily dose of statin at baseline. Amended text to include measurement of metformin concentration (Sections 9.5.1.1 and 9.7.1.4) • Analysis of non-esterified fatty acids and beta-hydroxybutyrate were added to the lipid endpoints (Sections 9.5.1.1 and 9.7.1.5) • Number of anticipated clinical sites was increased from 8 to 10. In addition, the inclusion of overweight as well as obese subjects was reflected due to the increased range for body weight eligibility (Section 9.1) • Amended text to lengthen the screening period from 28 days to 42 days • Edited text to clarify that subjects were admitted to the clinic 2 evenings before the receipt of study drug • The Day 1 assessment of MMT and blood samples for glucose metabolism panel were removed from the protocol (Section 9.5.1.2) • Data form SAD study wad added (Section 9.2) • Amended the dose escalation stopping decision and cardiac stopping criteria (Section 9.4.3.1) • Inclusion, exclusion and removal of subjects from therapy or assessment sections were amended (Section 9.3.1, Section 9.3.2, Section 9.3.3) • Schedule of screening procedures (GFR, glucose) and a predose blood sample (Section 9.5.1.2) • Identity of study drug text was modified (Section 9.4.2) • Dose preparation steps were modified • Process of SAE reporting by the Sponsor and the implementation of electronic SAE reporting were modified • Appendix 6 was added • References were updated • Appendix 2 was revised.
    10 Oct 2015
    Text was amended to reflect a reduction in the maximum dose that was to administered in this study from 400 to 300 µg/day (Section 9.4.3.1) • Amended text to provide the predicted safety margins for the 300 µg/day dose (Section 9.2) • An exclusion criterion excluding subjects with a history of lactic acidosis or ketoacidosis was added (Section 9.3.2) • Text was amended to include collection of finger prick glucose samples 15 minutes prior to and 2 hours after breakfast and before going to bed in addition to the measures taken before and after the mid-day and evening meals to increase glucose monitoring (Section 9.5.1.2) • The footnotes describing the timing of ECG capture were corrected to be consistent with the measurements indicated in the tables (Section 9.5.1.2) • The volume of injection was reduced consistent with the reduction in dose from 400 to 300 µg • The needle gauge was amended from 27G to 29G.
    18 Mar 2016
    Texts were modified to be consistent with the updated results from SAD study (Section 9.2) • Inclusion criteria related to statin therapy was removed (Sections 9.3.1 and 9.4.7.1) • Exploratory objectives/endpoints and their assessment methods were added (Sections 8.3, 9.5.1.1, 9.5.1.2, 9.7.1.3, and 9.7.1.5) • Study design was changed related to telemetry and return home for subjects in Cohorts 3 and 4 (Sections 9.1 and 9.5.1.2) • Screening window was changed from 42 days to 60 days • Requirement that regulatory approval be obtained “prior to initiating enrollment” in order to proceed with Cohort 4 was changed to “prior to initiating dosing” • Age range for inclusion criteria, upper and lower range of screening HbA1c, and inclusion criterion for HbA1c were changed (Section 9.1 and 9.3.1) • Exclusion criteria for fasting blood glucose was removed; upper range of abnormal systolic and diastolic BP was increased and text was added to note for vital signs criteria and exclusion criteria concerning QRS duration; exclusion criteria regarding subject’s use of weight loss diets/agents, and conditions where MRI is contraindicated were added for Cohort 4 only if site has access to an MRI (Section 9.3.2) • Exclusion criterion of “history of cancer, with exception of non-melanoma skin cancer” was changed to “history of cancer within the last 10 years, with the exception of non-melanoma skin cancer (Section 9.3.2).
    27 Apr 2016
    The text was changed from “up to 10 study sites” to “approximately 10 study sites” (Section 9.1) • The study design was reverted to state that subjects will be admitted to and remain in the unit for all doses and all dose levels during the up-titration period. Relevant text was modified to reflect the reversion in study design (Section 9.5.1.2) • The age range for inclusion in the study was changed from 18 through <= 69 years to 18 through <= 65 years and relevant text was modified to reflect this change (Sections 9.1 and 9.3.1) • The upper range of screening HbA1c was changed from 9.0% to 8.5% (Sections 9.1 and 9.3.1) • The exclusion criterion of “fasting blood glucose >= 200 mg/dL (11.11 mmol/L)” was reinstated (Section 9.3.2) • The upper range of abnormal systolic BP was decreased by 10 mm Hg for both age groups (< 60 years old, >= 60 years old), and the upper range of abnormal diastolic BP was decreased by 10 mm Hg (Section 9.3.2).
    21 Jul 2016
    Exploratory endpoint 7 was updated (Sections 9.5.1.1)• Text was changed from “approximately 10 study sites” to “approximately 12 study sites”; “48 subjects” to “approximately 48 subjects” (Section 9.1) • Text was revised to clarify maximum dose in the study (Section 9.1); widen window of pre-dose MRI scan (Table 9.5.1.2-4); criteria of MRI scan (Table 9.5.1.1-1 and Table 9.5.1.2-4); clarification for post dose MRI scan (Table 9.5.1.1-1 and Table 9.5.1.2-4); subjects may be rescreened more than once; subjects will wear the accelerometer on the nondominant wrist continuously for approximately 7 days (Section 9.5.1.3); diluent is not required for Cohort 4 and that a 0.3 mL insulin syringe will be utilized during the in clinic and at-home treatment periods • summary of SAD Study D5670C00001 was revised and Cohort 1-3 safety data from this MAD study was included • Exclusion criteria 35 was revised • Serum chemistries panel note, daily diary training, dose preparation steps were updated.
    25 Aug 2016
    Text was reverted to specify that subjects may be rescreened only once (Section 9.4.3) • Text was reverted to state that additional subjects may be screened and available to ensure that a sufficient number of subjects are randomized into each cohort (Section 9.4.3).
    23 Sep 2016
    Text was added/updated to: include Part C of the study and to describe the details of Cohorts 5 and 6 (Sections 9.1, 9.2, and 9.4.1, and Figure 9.1-1); provide rationale for using the 300 μg dose in Part C; add study endpoints related to the addition of Part C, including Cohorts 5 and 6, to the study (Section 9.5.1.1); describe the inpatient periods and clinic visits for Cohorts 5 and 6; concerning the timing of the MMT procedures for Cohorts 5 and 6; to make clear that, for Cohorts 4, 5, and 6, the last PK sample was collected 24 hours after the last dose; provide details of the sample size calculation resulting in 32 subjects in total in Cohorts 5 and 6 (Section 9.7.2); specify 24-hour ABPM was applicable to Cohorts 5 and 6, in addition to Cohort 4 (Section 9.3.2); add Cohorts 5 and 6 to the measuring of body weight during the outpatient periods, and at the 28-day End of Study Visit; describe the sentinel dosing approach for Cohorts 5 and 6 (Section 9.4.3.1); modify description of hypertension; clarify randomization ratio for Cohorts 5 and 6; include 5-day up-titration periods for Cohorts 5 and 6; • 300 μg results were added to the table, and human PK parameters were updated (Section 9.2 and Table 9.2-1) • Number of subjects was increased from 75 to 107 (Sections 9.1 and 9.2) • ‘Cohort 4’ was removed from description of analysis of efficacy endpoints • Updated the inclusion and exclusion criteria; and safety criteria related to the addition of Part C, including Cohorts 5 and 6, to the study • Modified the C SSRS assessment Cohort 4 table (Table 9.5.1.2-4) and 24-hour ABPM assessment • Procedures for Cohorts 5 and 6, were added (Table 9.5.1.2-6 and Table 9.5.1.2-7).

    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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