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    Clinical Trial Results:
    A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Subjects with Type 2 Diabetes Mellitus and Renal Impairment

    Summary
    EudraCT number
    2018-000019-26
    Trial protocol
    GB  
    Global end of trial date
    04 Feb 2019

    Results information
    Results version number
    v3(current)
    This version publication date
    26 Apr 2020
    First version publication date
    28 Feb 2020
    Other versions
    v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D5670C00013
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03550378
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    MedImmune, a wholly owned subsidiary of Astrazeneca
    Sponsor organisation address
    Milstein Building, Granta Park, Cambridge, United Kingdom, CB21 6GH
    Public contact
    Lars Hansen, MedImmune, a wholly owned subsidiary of Astrazeneca, +1 301-398-4563, information.center@astrazeneca.com
    Scientific contact
    Lars Hansen, MedImmune, a wholly owned subsidiary of Astrazeneca, +1 301-398-4563, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    09 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to asses the safety and efficacy of MEDI0382 titrated up to a dose level of 300 µg on glucose control versus Placebo after 32 days of treatment in participants with type 2 diabetes mellitus (T2DM) and renal impairment.
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Germany: 32
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    5
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in the United Kingdom and Germany between 29Jun2018 and 04Feb2019.

    Pre-assignment
    Screening details
    A total of 41 participants were randomized to the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received subcutaneous dose (SC) dose of placebo matched to MEDI0382 once daily for 32 days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous (SC) dose of placebo matched to MEDI0382 once daily for 32 days.

    Arm title
    MEDI0382
    Arm description
    Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
    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
    The SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.

    Number of subjects in period 1
    Placebo MEDI0382
    Started
    20
    21
    Completed
    20
    20
    Not completed
    0
    1
         Adverse event, serious fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received subcutaneous dose (SC) dose of placebo matched to MEDI0382 once daily for 32 days.

    Reporting group title
    MEDI0382
    Reporting group description
    Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.

    Reporting group values
    Placebo MEDI0382 Total
    Number of subjects
    20 21 41
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    1 4 5
        From 65-84 years
    19 17 36
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    70.9 ± 4.7 71.1 ± 7.4 -
    Sex: Female, Male
    Units: Participants
        Female
    11 9 20
        Male
    9 12 21
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 0 0
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Black or African American
    0 0 0
        White
    20 20 40
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0 0
        Not Hispanic or Latino
    20 21 41
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received subcutaneous dose (SC) dose of placebo matched to MEDI0382 once daily for 32 days.

    Reporting group title
    MEDI0382
    Reporting group description
    Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.

    Primary: Percent Change From Baseline in Plasma Glucose Area Under the Concentration Time-curve From Time 0 to 4 hours (AUC0-4 hrs) as Measured by Mixed-meal Tolerance Test (MMTT) to Day 32

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    End point title
    Percent Change From Baseline in Plasma Glucose Area Under the Concentration Time-curve From Time 0 to 4 hours (AUC0-4 hrs) as Measured by Mixed-meal Tolerance Test (MMTT) to Day 32
    End point description
    The MMTT involved the consumption of a standardised liquid meal (a nutritional supplement containing the components of fat, carbohydrate, and protein, which make up a standard MMTT) within 15 minutes, and timed serial blood samples obtained for measurement of glucose and parameters related to glucose metabolism through 240 minutes after consumption of the standardised meal (with no additional food intake during this time). Intent-to-treat (ITT) population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to their randomised treatment group.
    End point type
    Primary
    End point timeframe
    Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised meal on Day -5 (Baseline) and Day 32
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    18
    Units: Percent change in plasma glucose
        least squares mean (confidence interval 90%)
    3.678 (-3.793 to 11.149)
    -26.706 (-34.584 to -18.828)
    Statistical analysis title
    Comparison in percent change of glucose AUC
    Comparison groups
    Placebo v MEDI0382
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -30.384
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -41.27
         upper limit
    -19.498

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

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    End point title
    Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 60
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: Participants
        TEAEs
    13
    20
        TESAEs
    2
    2
    No statistical analyses for this end point

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

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    End point title
    Number of Participants With Abnormal Vital Signs Reported as TEAEs
    End point description
    Number of participants with abnormal vital signs reported as TEAEs is reported. Vital sign measurements were obtained after the participant had rested in the supine position for at least 10 minutes at the recording time. Abnormal vital signs is defined as any abnormal finding in the vital sign parameters (blood pressure, pulse rate, body temperature, and respiratory rate). As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 60
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Postural Blood Pressure

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    End point title
    Change From Baseline in Postural Blood Pressure
    End point description
    The change difference is the change from Day 1 to Day 32 in the difference between systolic blood pressure (SBP) or diastolic blood pressure (DBP) values in standing and supine positions. For this outcome measure, participants with difference (standing-supine) in DBP or SBP on Day 1 and Day 32 were analysed. For few participants either DBP or SBP was recorded eg, standing DBP was not recorded on Day 1 for 2 participants in Placebo arm and 1 participant in MEDI0382 arm; standing SBP was not recorded on Day 32 for a participant in the Placebo arm. As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received. Participants with difference (standing-supine) in DBP or SBP on Day 1 and the participants with difference (standing-supine) in DBP or SBP on Day 32 were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) through Day 32
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    17
    18
    Units: mmHg
    arithmetic mean (standard deviation)
        Systolic Blood Pressure (n = 17, 18)
    0.1 ± 9.3
    8.9 ± 14.2
        Diastolic Blood Pressure (n= 17, 17)
    1.8 ± 6.3
    0.8 ± 5.2
    No statistical analyses for this end point

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

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    End point title
    Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs
    End point description
    Number of participants with abnormal ECGs reported as TEAEs is reported. Abnormal ECGs is defined as any abnormal findings in heart rate, RR interval, PR interval, QRS, axis, ST-T morphology, and QT intervals from the primary lead of the digital 12-lead ECG. As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 60
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: Participants
        Bradyarrhythmia
    1
    0
        Bundle branch block left
    1
    0
        Bundle branch block right
    0
    1
    No statistical analyses for this end point

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

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    End point title
    Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
    End point description
    Number of participants with abnormal clinical laboratory parameters reported as TEAEs is reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of serum chemistry, hematology, and urine. As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 60
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: Participants
        Hypoglycaemia
    1
    3
        Alanine aminotransferase increased
    1
    0
        Aspartate aminotransferase increased
    1
    0
        Glomerular filtration rate decreased
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events of Special Interest (TEAESIs)

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    End point title
    Number of Participants With Treatment-emergent Adverse Events of Special Interest (TEAESIs)
    End point description
    An adverse event of special interest (AESI) was one of scientific and medical interest specific to understanding of the study drug and may require close monitoring and rapid communication by the investigator to the sponsor. As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 60
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean 24-hrs Pulse Rate to the End of Each Dosing Level

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    End point title
    Change From Baseline in Mean 24-hrs Pulse Rate to the End of Each Dosing Level
    End point description
    Change from baseline in mean 24-hrs pulse rate to the end of each dosing levels. End of dosing: Day 5 for 50 μg; Day 12 for 100 μg, Day 19 for 200 μg, and Day 32 for 300 μg. As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received. Here, "n" signifies only the participants with available data were analysed for the specified time points.
    End point type
    Secondary
    End point timeframe
    Day -5 (Baseline) and on Days 5, 12, 19, and 32
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: Beats/min
    arithmetic mean (standard deviation)
        Day 5 (n= 12, 13)
    -0.73 ± 4.13
    6.40 ± 5.53
        Day 12 (n= 11, 12)
    1.04 ± 5.07
    9.01 ± 7.73
        Day 19 (n= 14, 13)
    1.32 ± 5.28
    12.72 ± 8.93
        Day 32 (n= 11, 10)
    -0.92 ± 4.51
    11.85 ± 8.82
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean 24-hrs Systolic and Diastolic Blood Pressure to the end of Each Dosing Level

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    End point title
    Change From Baseline in Mean 24-hrs Systolic and Diastolic Blood Pressure to the end of Each Dosing Level
    End point description
    Change from baseline in mean 24-hrs systolic and diastolic blood pressure to the end of each dosing levels. End of dosing: Day 5 for 50 μg; Day 12 for 100 μg, Day 19 for 200 μg, and Day 32 for 300 μg. As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received. Here, "n" signifies only the participants with available data were analyzed for the specified time points.
    End point type
    Secondary
    End point timeframe
    Day -5 (Baseline) and on Days 5, 12, 19, and 32
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: mmHg
    arithmetic mean (standard deviation)
        Day 5: Systolic Blood Pressure (n=12,13)
    -3.11 ± 9.97
    -1.69 ± 9.06
        Day 12: Systolic Blood Pressure (n=11,12)
    -2.67 ± 12.30
    -4.34 ± 11.46
        Day 19: Systolic Blood Pressure (n=14,13)
    -3.56 ± 10.15
    -4.72 ± 11.65
        Day 32: Systolic Blood Pressure (n=11,10)
    2.21 ± 7.24
    -1.15 ± 18.43
        Day 5: Diastolic Blood Pressure (n=12,13)
    -0.07 ± 3.19
    1.15 ± 3.64
        Day 12: Diastolic Blood Pressure (n=11,12)
    -0.55 ± 5.17
    1.28 ± 5.22
        Day 19: Diastolic Blood Pressure (n=14,13)
    -0.44 ± 3.85
    0.76 ± 3.75
        Day 32: Diastolic Blood Pressure (n=11,10)
    1.84 ± 1.79
    2.54 ± 5.34
    No statistical analyses for this end point

    Secondary: Change From Baseline in Haemoglobin A1c (HbA1c) to Day 32

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    End point title
    Change From Baseline in Haemoglobin A1c (HbA1c) to Day 32
    End point description
    Change from baseline in haemoglobin A1c (HbA1c) is reported. An ITT population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to their randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline) and Day 32
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    19
    Units: Percent
        least squares mean (confidence interval 90%)
    0.01 (-0.15 to 0.17)
    -0.65 (-0.82 to -0.49)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Glucose to Day 32

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    End point title
    Change From Baseline in Fasting Glucose to Day 32
    End point description
    Change from baseline in fasting glucose is reported. An ITT population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to their randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline) and Day 32
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    19
    Units: mg/dL
        least squares mean (confidence interval 90%)
    0.60 (-12.89 to 14.08)
    -19.55 (-33.39 to -5.71)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percentage of Time Spent Within a Target Glucose Range Over a 7-day Period to the Final Week of Treatment

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    End point title
    Change From Baseline in Percentage of Time Spent Within a Target Glucose Range Over a 7-day Period to the Final Week of Treatment
    End point description
    Change from baseline in percentage of time spent within a target glucose range over a 7-day period to the final week of treatment is reported. Target glucose range was considered as 70 mg/dL (3.9 mmol/L) to 180 mg/dL (10 mmol/L). An ITT population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to their randomised treatment group. Here, "n" signifies only the participants with available data were analyzed for the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline (Days -8 to -2), Days 5 to 11, Days 12 to 18, Days 19 to 25, and Days 26 to 32 (final week of treatment)
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: Percentage of time
    least squares mean (confidence interval 90%)
        Days 5 - 11 (n=17,19)
    -10.49 (-20.77 to -0.20)
    12.25 (2.52 to 21.98)
        Days 12 - 18 (n=18,19)
    -5.34 (-12.77 to 2.10)
    15.62 (8.39 to 22.86)
        Days 19 - 25 (n=18,18)
    -16.05 (-25.02 to -7.08)
    19.18 (10.21 to 28.15)
        Days 26 - 32 (n=18,17)
    -21.23 (-33.13 to -9.32)
    14.79 (2.54 to 27.04)
    No statistical analyses for this end point

    Secondary: Percent Change Frome Baseline in Body Weight to Day 33

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    End point title
    Percent Change Frome Baseline in Body Weight to Day 33
    End point description
    Percent change from baseline in body weight is reported. An ITT population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to their randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline) and Day 33
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    19
    Units: Percent change in body weight
        least squares mean (confidence interval 90%)
    -0.21 (-1.05 to 0.62)
    -3.69 (-4.55 to -2.83)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Absolute Body Weight to Day 33

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    End point title
    Change From Baseline in Absolute Body Weight to Day 33
    End point description
    Change from baseline in absolute body weight is reported. An ITT population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to their randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline) and Day 33
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    19
    Units: Kg
        arithmetic mean (standard deviation)
    -0.15 ± 1.84
    -3.39 ± 2.16
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Time Curve Over a Dosing Duration (AUCτ) of MEDI0382 at 300 μg

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    End point title
    Area Under the Plasma Concentration Time Curve Over a Dosing Duration (AUCτ) of MEDI0382 at 300 μg [1]
    End point description
    Area under the plasma concentration time curve over a dosing duration (AUCτ) of MEDI0382 at 300 μg is reported. Pharmacokinetic (PK) population was analysed for this endpoint, which included all participants who received at least 1 dose of study drug and had at least one PK sample collected with a value above the lower limit of quantitation.
    End point type
    Secondary
    End point timeframe
    Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point
    End point values
    MEDI0382
    Number of subjects analysed
    16
    Units: ng.hr/mL
        geometric mean (full range (min-max))
    285.93 (124.08 to 669.17)
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of MEDI0382 at 300 μg

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    End point title
    Maximum Observed Serum Concentration (Cmax) of MEDI0382 at 300 μg [2]
    End point description
    Maximum observed serum concentration (Cmax) of MEDI0382 at 300 μg is reported. The PK population was analysed for this endpoint, which included all participants who received at least 1 dose of study drug and had at least one PK sample collected with a value above the lower limit of quantitation.
    End point type
    Secondary
    End point timeframe
    Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point
    End point values
    MEDI0382
    Number of subjects analysed
    18
    Units: ng/mL
        geometric mean (full range (min-max))
    16.93 (5.17 to 35.4)
    No statistical analyses for this end point

    Secondary: Time to Observed Maximum Serum Concentration (Tmax) of MEDI0382 at 300 μg

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    End point title
    Time to Observed Maximum Serum Concentration (Tmax) of MEDI0382 at 300 μg [3]
    End point description
    Time to observed maximum serum concentration (Tmax) of MEDI0382 at 300 μg is reported. The PK population was analysed for this endpoint, which included all participants who received at least 1 dose of study drug and had at least one PK sample collected with a value above the lower limit of quantitation.
    End point type
    Secondary
    End point timeframe
    Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point
    End point values
    MEDI0382
    Number of subjects analysed
    18
    Units: Hours
        median (full range (min-max))
    5.6 (4 to 24)
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentration (Ctrough) of MEDI0382

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    End point title
    Trough Plasma Concentration (Ctrough) of MEDI0382 [4]
    End point description
    Trough concentration is the lowest concentration reached by a drug before the next dose is administered. Trough plasma concentration (Ctrough) of MEDI0382 reported. The PK population was analysed for this endpoint, which included all participants who received at least 1 dose of study drug and had at least one PK sample collected with a value above the lower limit of quantitation. Here, "n" signifies only the participants with available data were analysed for the specified time points. Here, the arbitrary number "9999" signifies that the data is not reported as no participants were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Days 1, 5, 12, and 19: Predose; and Day 32: Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose (Day 33)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point
    End point values
    MEDI0382
    Number of subjects analysed
    21
    Units: ng/mL
    geometric mean (full range (min-max))
        Day 1 (n=0)
    9999 (9999 to 9999)
        Day 5 (n=19)
    1.44 (0.48 to 2.58)
        Day 12 (n=19)
    2.03 (0.63 to 3.75)
        Day 19 (n=20)
    3.68 (0.59 to 8.86)
        Day 32 (n=17)
    5.86 (1.3 to 19.4)
        Day 33 (n=19)
    5.96 (2.43 to 19.2)
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive Anti-drug antibodies (ADA) Titre to MEDI0382

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    End point title
    Number of Participants With Positive Anti-drug antibodies (ADA) Titre to MEDI0382
    End point description
    Number of participants with positive Anti-drug antibodies (ADA) Titre to MEDI0382 is reported. As-treated population was analysed for this endpoint, which included all participants who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Days 1, 12, and 32 and on Day 60
    End point values
    Placebo MEDI0382
    Number of subjects analysed
    20
    21
    Units: Participants
        Positive at baseline
    0
    0
        Positive post-baseline
    0
    2
        Positive at baseline and post-baseline
    0
    0
        Not detected at baseline; positive post-baseline
    0
    2
        Positive at baseline; not detected post-baseline
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through Day 60
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    MEDI0382
    Reporting group description
    Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.

    Reporting group title
    Placebo
    Reporting group description
    Participants received subcutaneous dose (SC) dose of placebo matched to MEDI0382 once daily for 32 days.

    Serious adverse events
    MEDI0382 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 20 (10.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    MEDI0382 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 21 (90.48%)
    13 / 20 (65.00%)
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Injection site erythema
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Injection site pruritus
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Bradyarrhythmia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Bundle branch block left
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Bundle branch block right
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Headache
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 20 (10.00%)
         occurrences all number
    3
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Vertigo positional
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    5 / 21 (23.81%)
    0 / 20 (0.00%)
         occurrences all number
    5
    0
    Dyspepsia
         subjects affected / exposed
    5 / 21 (23.81%)
    1 / 20 (5.00%)
         occurrences all number
    6
    1
    Eructation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    9 / 21 (42.86%)
    4 / 20 (20.00%)
         occurrences all number
    19
    4
    Vomiting
         subjects affected / exposed
    6 / 21 (28.57%)
    1 / 20 (5.00%)
         occurrences all number
    18
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Skin fissures
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Skin swelling
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Hypoglycaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 20 (5.00%)
         occurrences all number
    8
    1
    Hypoglycaemia unawareness
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 20 (10.00%)
         occurrences all number
    3
    2
    Otitis media
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Pyelonephritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2018
    Addition of weight to schedule of assessments on Day 32. Text modified to state electrocardiogram (ECG) is from lead II on V2. Added a prohibited concomitant medication. Added a prohibited concomitant medication.
    06 Apr 2018
    Changes to discontinuation of study drug criteria. Updated to add a 2-hour post-dose ECG on Days 1 and 32. Added amylase and lipase sampling at Days 5, 12 and 19. Updated that all deaths (including those that are clearly the result of disease progression) reported as a serious adverse event (SAE).
    11 Oct 2018
    Planned interim analysis was removed.
    12 Nov 2018
    “At least” was changed to “Approximately” in regard to eligible participants in the estimated glomerular filtration rate 30 to 45 mL/min/1.73 m^2 category.

    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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