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    Clinical Trial Results:
    Targeting Iatrogenic Cushing’s Syndrome with 11β-hydroxysteroid dehydrogenase type 1 Inhibition

    Summary
    EudraCT number
    		 2016-003060-40
    Trial protocol
    		 GB  
    Global end of trial date
    27 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Nov 2021
    First version publication date
    19 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TICSI
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03111810
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 212634 : IRAS ID
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Churchill Hospital, Oxford, United Kingdom,
    Public contact
    CTRG (via Heather House), University of Oxford, Clinical Trials and Research Governance, ctrg@admin.ox.ac.uk
    Scientific contact
    CTRG (via Heather House), University of Oxford, Clinical Trials and Research Governance, ctrg@admin.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Our main research objectives is… 1. To demonstrate the beneficial effect of the selective 11β-HSD1 inhibitor, AZD4017, upon the prednisolone-induced deterioration in glucose uptake into skeletal muscle and glucose production by the liver.
    Protection of trial subjects
    Potential risks and side effects of the interventions, were explained to participants prior to commencing treatment. AEs were recorded by the investigators as part of the study. All studies were performed in a CRU fully equipped for dealing with emergencies. A physician will be present throughout the studies and the research nurses receive regular training in BLS. Venipuncture for the screening sample may cause momentary discomfort. Insertion of a venous cannula under local anesthetic on the study day normally only causes momentary discomfort because of the 'sting' of the anesthetic. Cannulation sites may bruise and there is a possible risk for clotting or infection. We minimized these risks by the use of good clinical practice and sterile techniques. The potential risk of low blood sugar at the end of the clamp procedure was minimized by ensuring all volunteers are provided with a meal and their blood sugar levels are measured repeatedly to ensure that they are stable at the end of the procedure. At the screening visit we assessed the volunteer’s hemoglobin status to ensure there was no anemia. As a precaution we advised participants to refrain from blood donation for 3 months after the study. During the course of the study day we ensured participants stayed well hydrated and before leaving the CRU at the end of the study we ensured that they had a light meal. We also provided advice regarding the 24-48 hour period after the study to ensure that they consumed sufficient non-alcoholic fluid, food and did not undertake any strenuous exercise or activities. Any stable isotope that we introduced directly into the blood will had been sterility and pyrogenicity tested. The DEXA scans performed on the 2 study days involved exposure to a small radiation dose. There was a small risk of infection and bruising after inserting microdialysis catheters or taking fat and muscle biopsies. This risk was minimized by the use of sterile techniques and applying pressure on wounds.
    Background therapy
    		 Prednisolone is widely used in routine clinical practice (indeed at higher dose and for longer durations) and is generally well tolerated and safe. Possible side effects of the prednisolone treatment that may be anticipated in advance including the possibility of mild fluid retention and ankle swelling and difficulty in sleeping. Volunteers will be warned about these possible effects.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    32
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period: 25/5/2017 to 13/2/2019 Territory: Oxford, UK

    Pre-assignment
    Screening details
    		 Male volunteers without diabetes • BMI 20-30 • Age 18-60 • BP<160/100mmHg or on stable antihypertensive therapy for >3months • No known hypercholesterolaemia or on stable lipid lowering therapy for >3 months • No contraindications to AZD4017 or prednisolone treatment

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    randomization schedule will be drawn up by Almac group who will be providing packaged and labeled AZD4017/placebo on behalf of AstraZeneca. All investigators will remain blinded and a ‘dummy’ randomization schedule will be reviewed and signed off by the investigative team prior to shipment of the study medication (Quality Assurance Agreement in place). Randomization will be in blocks of 4 volunteers (2 AZD4017 and 2 to placebo). Blinding will be by means of scratch cards.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo and prednisolone
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo and prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    placebo; one tablet twice daily and prednisolone; 20mg once daily for 7 days

    Arm title
    		 AZD4017 and prednisolone
    Arm description
    		 AZD4017 and prednisolone given for 7 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4017 and prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AZD4017; 400mg twice daily and prednisolone; 20mg once daily for 7 days.

    Number of subjects in period 1
    		Placebo and prednisolone AZD4017 and prednisolone
    Started
    16
    16
    Completed
    16
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo and prednisolone
    Reporting group description
    		 Placebo

    Reporting group title
    AZD4017 and prednisolone
    Reporting group description
    		 AZD4017 and prednisolone given for 7 days

    Reporting group values
    		 Placebo and prednisolone AZD4017 and prednisolone Total
    Number of subjects
    		 16 16 32
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 16 16 32
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.7 ( 12.4 ) 35.6 ( 11.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 16 16 32
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 25.8 ( 1.9 ) 24.4 ( 2.5 ) -
    Subject analysis sets

    Subject analysis set title
    Subjects included in analysis - Placebo and prednisolone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects included in analysis completed the protocol correctly.

    Subject analysis set title
    Subjects included in analysis - AZD4017 and prednisolone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subject were included in the analysis only if they completed the trial as set out by the protocol.

    Subject analysis sets values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects
    15
    15
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    15
    15
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39 ( 12.7 )
    36.5 ( 11 )
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    15
    15
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    25.8 ( 2 )
    24.5 ( 2.5 )

    End points

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    End points reporting groups
    Reporting group title
    Placebo and prednisolone
    Reporting group description
    		 Placebo

    Reporting group title
    AZD4017 and prednisolone
    Reporting group description
    		 AZD4017 and prednisolone given for 7 days

    Subject analysis set title
    Subjects included in analysis - Placebo and prednisolone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects included in analysis completed the protocol correctly.

    Subject analysis set title
    Subjects included in analysis - AZD4017 and prednisolone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subject were included in the analysis only if they completed the trial as set out by the protocol.

    Primary: Change observed in glucose disposal (Low insulin) from pre-treatment measurement to post-treatment assessment

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    End point title
    		 Change observed in glucose disposal (Low insulin) from pre-treatment measurement to post-treatment assessment
    End point description
    End point type
    Primary
    End point timeframe
    Change from pre-treatment measurement to post-treatment measurement.
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: mg/kg/min
        arithmetic mean (standard deviation)
    4.61 ( 2.28 )
    4.59 ( 1.98 )
    Attachments
    		 Glucose Disposal (Low insulin)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Generalised linear models
    Confidence interval
    Notes
    [1] - Per Protocol
    [2] - 0.17

    Secondary: M/I value (Low insulin)

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    End point title
    		 M/I value (Low insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change from pre-treatment to post-treatment.
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: mg/kg/min per mU/mL
        median (inter-quartile range (Q1-Q3))
    30.98 (18.72 to 35.45)
    28.11 (16.58 to 37.00)
    Statistical analysis title
    		 Generalised liniear model
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.05 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - Change pre-treatment vs post-treatment
    [4] - 0.15

    Secondary: Glucose Disposal (High insulin)

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    End point title
    		 Glucose Disposal (High insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: mg/kg/min
        arithmetic mean (standard deviation)
    -2.88 ( 2.91 )
    -2.16 ( 2.89 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [5]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [5] - 0.26

    Secondary: M/I value (High insulin)

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    End point title
    		 M/I value (High insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: mg/kg/min per mU/ml
        median (inter-quartile range (Q1-Q3))
    -3.72 (-7.25 to -0.98)
    -0.51 (-3.76 to 2.53)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [6]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [6] - 0.17

    Secondary: Ra glucose

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    End point title
    		 Ra glucose
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: mg/kg/min
        median (inter-quartile range (Q1-Q3))
    0.06 (-0.02 to 0.13)
    0.08 (-0.02 to 0.12)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [7]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [7] - 0.55

    Secondary: EGP

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    End point title
    		 EGP
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    14
    Units: mg/kg/min
        median (inter-quartile range (Q1-Q3))
    0.35 (0.12 to 0.49)
    0.16 (-0.03 to 0.29)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [8]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [8] - 0.11

    Secondary: Fasting glucose

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    End point title
    		 Fasting glucose
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: mmol/l
        arithmetic mean (standard deviation)
    0.1 ( 0.5 )
    0.3 ( 0.3 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 generalised linear models
    Confidence interval

    Secondary: Fasting insulin

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    End point title
    		 Fasting insulin
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: mu/l
        arithmetic mean (standard deviation)
    0.48 ( 1.99 )
    -0.2 ( 2.94 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [9]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [9] - 0.63

    Secondary: TAG (Basal)

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    End point title
    		 TAG (Basal)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: umol/l
        arithmetic mean (standard deviation)
    258.2 ( 240.7 )
    -50 ( 198.4 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [10]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [10] - 0.001

    Secondary: TAG (Low Insulin)

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    End point title
    		 TAG (Low Insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: umol/l
        median (inter-quartile range (Q1-Q3))
    125.8 (18 to 155.9)
    -46.9 (-134.9 to 3.5)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [11]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [11] - 0.0014

    Secondary: TAG (High insulin)

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    End point title
    		 TAG (High insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: umol/l
        median (inter-quartile range (Q1-Q3))
    58.1 (-6.9 to 90.2)
    -40.7 (-190.5 to 2.4)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [12]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [12] - 0.0069

    Secondary: Glycerol (Basal)

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    End point title
    		 Glycerol (Basal)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: umol/l
        arithmetic mean (standard deviation)
    8.3 ( 9.9 )
    3.3 ( 10.3 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [13]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [13] - 0.39

    Secondary: Glycerol (Low insulin)

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    End point title
    		 Glycerol (Low insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: umol/l
        median (inter-quartile range (Q1-Q3))
    4.1 (3.3 to 6)
    1.5 (0.4 to 2.7)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [14]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [14] - 0.11

    Secondary: Glycerol (High insulin)

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    End point title
    		 Glycerol (High insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    14
    15
    Units: umol/l
        median (inter-quartile range (Q1-Q3))
    2.8 (1.9 to 4.9)
    0.2 (-1.2 to 1.1)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [15]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [15] - 0.089

    Secondary: Adipose interstitial fluid - Glycerol (Basal)

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    End point title
    		 Adipose interstitial fluid - Glycerol (Basal)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    13
    12
    Units: umol/l/hr
        median (inter-quartile range (Q1-Q3))
    30.3 (-60 to 101.5)
    47.8 (-9.8 to 77.9)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [16]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [16] - 0.3

    Secondary: adipose interstitial fluid - Glycerol (Low insulin)

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    End point title
    		 adipose interstitial fluid - Glycerol (Low insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    13
    11
    Units: umol/l/hr
        arithmetic mean (standard deviation)
    87.3 ( 109.3 )
    36.6 ( 71 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [17]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [17] - 0.38

    Secondary: adipose interstitial fluid - Glycerol (High insulin)

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    End point title
    		 adipose interstitial fluid - Glycerol (High insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    12
    12
    Units: umol/l/hr
        median (inter-quartile range (Q1-Q3))
    71.8 (28.1 to 109.3)
    -3.9 (-15.4 to 46.8)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [18]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [18] - 0.16

    Secondary: NEFA (Basal)

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    End point title
    		 NEFA (Basal)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: umol/l
        median (inter-quartile range (Q1-Q3))
    129.2 (-5.1 to 196.9)
    -4.6 (-93.4 to 241.2)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [19]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [19] - 0.72

    Secondary: NEFA (Low insulin)

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    End point title
    		 NEFA (Low insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: umol/l
        median (inter-quartile range (Q1-Q3))
    33.2 (21.3 to 71.4)
    2.4 (-4.1 to 69.5)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [20]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [20] - 0.25

    Secondary: NEFA (High insulin)

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    End point title
    		 NEFA (High insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: umol/l
        median (inter-quartile range (Q1-Q3))
    16.3 (2.1 to 55.8)
    1.2 (-9.5 to 43.4)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [21]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [21] - 0.66

    Secondary: Ra palmitate (Basal)

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    End point title
    		 Ra palmitate (Basal)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    12
    11
    Units: mg/kg/min
        arithmetic mean (standard deviation)
    -0.12 ( 0.69 )
    0.1 ( 0.86 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [22]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [22] - 0.51

    Secondary: Ra palmitate (Low insulin)

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    End point title
    		 Ra palmitate (Low insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    12
    11
    Units: mg/kg/min
        median (inter-quartile range (Q1-Q3))
    0.16 (-0.15 to 0.32)
    0.1 (-0.05 to 0.41)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [23]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [23] - 0.62

    Secondary: Ra palmitate (High insulin)

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    End point title
    		 Ra palmitate (High insulin)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    12
    11
    Units: mg/kg/min
        median (inter-quartile range (Q1-Q3))
    -0.03 (-0.22 to 0.15)
    -0.17 (-0.44 to -0.03)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [24]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [24] - 0.31

    Secondary: Daytime blood pressure - systolic

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    End point title
    		 Daytime blood pressure - systolic
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    14
    14
    Units: mmhg
        arithmetic mean (standard deviation)
    2.5 ( 6.1 )
    2.4 ( 7 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [25]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [25] - 0.66

    Secondary: Daytime blood pressure - diastolic

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    End point title
    		 Daytime blood pressure - diastolic
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    14
    14
    Units: mmHg
        arithmetic mean (standard deviation)
    0.3 ( 5.8 )
    1.4 ( 6.2 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [26]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [26] - 0.92

    Secondary: Nighttime blood pressure - systolic

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    End point title
    		 Nighttime blood pressure - systolic
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    14
    13
    Units: mmHg
        arithmetic mean (standard deviation)
    4.6 ( 10.6 )
    1 ( 11.5 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [27]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [27] - 0.19

    Secondary: Nighttime blood pressure - diastolic

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    End point title
    		 Nighttime blood pressure - diastolic
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    14
    13
    Units: mmHg
        arithmetic mean (standard deviation)
    4.6 ( 8.6 )
    0.7 ( 8.1 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [28]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [28] - 0.03

    Secondary: Osteocalcin

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    End point title
    		 Osteocalcin
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    -3.86 (-5.78 to -2.74)
    0 (-3.46 to 2.18)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [29]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [29] - <0.0001

    Secondary: VZV OX40

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    End point title
    		 VZV OX40
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: %
        median (inter-quartile range (Q1-Q3))
    -0.3 (-1.85 to 0)
    -0.4 (-0.55 to -0.1)
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [30]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [30] - 0.81

    Secondary: PHA OX40

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    End point title
    		 PHA OX40
    End point description
    End point type
    Secondary
    End point timeframe
    Change in measurement of pre Vs post-treatment
    End point values
    		 Subjects included in analysis - Placebo and prednisolone Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects analysed
    15
    15
    Units: %
        arithmetic mean (standard deviation)
    -21.7 ( 14 )
    -10.2 ( 14.4 )
    Statistical analysis title
    		 Generalised linear models
    Comparison groups
    Subjects included in analysis - Placebo and prednisolone v Subjects included in analysis - AZD4017 and prednisolone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [31]
    Method
    		 generalised linear models
    Confidence interval
    Notes
    [31] - 0.046

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall trial up to 30 days post treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Non-serious adverse events
    Reporting group description
    		 -

    Serious adverse events
    		 Non-serious adverse events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Non-serious adverse events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 32 (15.63%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Irritability
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Endocrine disorders
    Thyroid disorder
    Additional description: Elevated TSH which normalised after 14 days.
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2018
    We changed the poster advertisement to make it more noteworthy by changing some of the wording and by making it more pictorial. We drafted 5 new posters which were reviewed by the ethics committee. Protocol: The original wording was not clear on who was eligible to participate and needed to be changed. Patient Information Leaflet: There was a typographical error. It should read 8 weeks instead of 4-5 weeks.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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