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    Clinical Trial Results:
    The short term effects of an AKT inhibitor (AZD5363) on biomarkers of the AKT pathway and anti-tumour activity in a breast cancer paired biopsy study (STAKT Trial)

    Summary
    EudraCT number
    		 2012-005019-14
    Trial protocol
    		 GB  
    Global end of trial date
    30 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Oct 2018
    First version publication date
    19 Oct 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    12076
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02077569
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    University Park, nottingham, United Kingdom, NG7 2RD
    Public contact
    Professor J F R Robertson, University of Nottingham, +44 01332724881, John.robertson@nottingham.ac.uk
    Scientific contact
    Professor J F R Robertson, University of Nottingham, +44 01332724881, John.robertson@nottingham.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
    14 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    PRIMARY OBJECTIVE To compare the effect of three different dose levels of AZD5363 versus a placebo (dummy drug)on the reduction in the growth of cancer cells and the direct effect on selected biological markers of the AKT pathway of four and a half days treatment in oestrogen receptor positive breast cancers by measuring the biological changes in the tumour using the biomarkers outlined below: • pPRAS40 • pGSK3b • Ki67 Stage 1 will compare 480mg BD versus placebo. Stage 2 will compare 360mg BD versus 240mg BD. Secondary: 1) To assess the tolerability of four and a half days treatment of AZD5363. 2) To assess the effect of four and a half days treatment of a range of doses of AZD5363 on alternative biological markers which relate to anti-tumour activity of the AKT pathway
    Protection of trial subjects
    patients were encouraged to report all side affects during their time on the study. Diaries were provided for patients to record dates and severity of any side affects experienced, emergency contact numbers were also included.
    Background therapy
    		 none
    Evidence for comparator
    		 none
    Actual start date of recruitment
    01 Apr 2013
    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: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    42
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Double blind randomised, placebo controlled, multicentre trial in terms of treatment allocation, performed in two stages, in females with breast cancer (Stage 2 will not be placebo controlled but will be double blind due to the different doses of AZD5363 being allocated).

    Pre-assignment
    Screening details
    		 Women, aged 18 years and over, able to give written informed consent. No evidence of dementia, altered mental status or any psychiatric condition that would prohibit understanding, or rendering, of informed consent. WHO performance status 0-1 with histological confirmation of ER positive invasive breast carcinoma Stage 1/2/3 or Stage 4 with pr

    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, Assessor
    Blinding implementation details
    Randomisation, treatment allocation, delivery of pre-packaged drug and enabling emergency unblinding via IWRS will be the responsibility of Fisher Clinical Services and Cenduit. The randomisation schemes will be produced by computer software which incorporates a standard procedure for generating random numbers. The patients will be allocated to treatment in balanced blocks. Medications will be allocated unique numerical identifiers.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Stage 1 IMP
    Arm description
    		 480mg BD for 4.5 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    AKT inhibitor
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    480mg BD capsule

    Arm title
    		 Stage 1 placebo
    Arm description
    		 placebo given over 4.5 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matched to IMP

    Arm title
    		 Stage 2 240mg IMP
    Arm description
    		 240 mg BD for 4.5 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363 240mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg for 4.5 days

    Arm title
    		 Stage 2 360mg IMP
    Arm description
    		 360mg IMP BD for 4.5 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363 360mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    360mg IMP BD for 4.5 days

    Number of subjects in period 1
    		Stage 1 IMP Stage 1 placebo Stage 2 240mg IMP Stage 2 360mg IMP
    Started
    19
    17
    7
    5
    Completed
    19
    17
    7
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Stage 1 IMP
    Reporting group description
    		 480mg BD for 4.5 days

    Reporting group title
    Stage 1 placebo
    Reporting group description
    		 placebo given over 4.5 days

    Reporting group title
    Stage 2 240mg IMP
    Reporting group description
    		 240 mg BD for 4.5 days

    Reporting group title
    Stage 2 360mg IMP
    Reporting group description
    		 360mg IMP BD for 4.5 days

    Reporting group values
    		 Stage 1 IMP Stage 1 placebo Stage 2 240mg IMP Stage 2 360mg IMP Total
    Number of subjects
    		 19 17 7 5 48
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 17 16 5 4 42
        From 65-84 years
    		 2 1 2 1 6
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 19 17 7 5 48
    Subject analysis sets

    Subject analysis set title
    stage 1 IMP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who completed IMP dosage of 4.5 days.

    Subject analysis set title
    stage 1 placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all subjects who completed 4.5 days of placebo

    Subject analysis set title
    Stage 2 240mg IMP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    stage 2 240mg IMP

    Subject analysis set title
    Stage 2 360mg IMP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Stage 2 360mg AZD5363

    Subject analysis sets values
    		 stage 1 IMP stage 1 placebo Stage 2 240mg IMP Stage 2 360mg IMP
    Number of subjects
    19
    17
    7
    5
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    17
    16
    5
    16
        From 65-84 years
    2
    1
    2
    1
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    19
    19
    7
    5

    End points

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    End points reporting groups
    Reporting group title
    Stage 1 IMP
    Reporting group description
    		 480mg BD for 4.5 days

    Reporting group title
    Stage 1 placebo
    Reporting group description
    		 placebo given over 4.5 days

    Reporting group title
    Stage 2 240mg IMP
    Reporting group description
    		 240 mg BD for 4.5 days

    Reporting group title
    Stage 2 360mg IMP
    Reporting group description
    		 360mg IMP BD for 4.5 days

    Subject analysis set title
    stage 1 IMP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who completed IMP dosage of 4.5 days.

    Subject analysis set title
    stage 1 placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all subjects who completed 4.5 days of placebo

    Subject analysis set title
    Stage 2 240mg IMP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    stage 2 240mg IMP

    Subject analysis set title
    Stage 2 360mg IMP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Stage 2 360mg AZD5363

    Primary: Primary endpoints: changes in biomarkers

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    End point title
    		 Primary endpoints: changes in biomarkers
    End point description
    primary endpoint: pharmocodynamic biomarker analysis in tumour tissue, to assess the the biological effect of AZD5363 on markers of anti proliferation and the AKT pathway • pPRAS40 • pGSK3b • Ki67
    End point type
    Primary
    End point timeframe
    analysis of tumour biomarker immediately following study biopsy compared to diagnostic biopsy.
    End point values
    		 stage 1 IMP stage 1 placebo Stage 2 240mg IMP Stage 2 360mg IMP
    Number of subjects analysed
    19
    17
    7
    5
    Units: Percentage change pre and post op tumour
    arithmetic mean (confidence interval 95%)
        pPRAS40
    -43.68 (-56.71 to -30.65)
    6.55 (-5.39 to 18.49)
    350.65 (-587.61 to 1288.91)
    -46.94 (-86.58 to -7.29)
        pGSK3b
    -41.63 (-57.46 to -25.80)
    -0.87 (-22.08 to 20.33)
    194.43 (-308.76 to 697.62)
    -27.1 (-74.19 to 19.98)
        Ki67
    -38.3 (-57.56 to -19.08)
    -12.1 (-36.00 to 11.78)
    25.09 (-6.12 to 56.30)
    -0.33 (-30.25 to 29.60)
    Statistical analysis title
    		 Stage 1 Primary o/c biomarker pPRAS40
    Statistical analysis description
    Data analysis performed in SAS 9.3. All data in the study summarized by group and time point and reported accordingly. Continuous data reported using mean (SD), while categorical data will be reported as N (%).
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -50.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -68.89
         upper limit
    		 -31.73
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Primary o/c biomarker pGSK3b
    Comparison groups
    stage 1 placebo v stage 1 IMP
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0057
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -41.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.48
         upper limit
    		 -12.46
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 primary o/c biomarker Ki67
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0521
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    -23.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -59.09
         upper limit
    		 0.29
    Variability estimate
    Standard error of the mean

    Secondary: Secondary endpoints: changes in alternative biomarkers

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    End point title
    		 Secondary endpoints: changes in alternative biomarkers
    End point description
    To compare the anti-proliferative effect and the direct effect on selected markers of the AKT pathway of four and a half days treatment at three different dose levels of AZD5363 versus placebo in oestrogen receptor positive breast cancers by measuring the biological changes in the tumour and circulation via measurement of: Tumour pAKT, caspase 3000, caspase 500, pS6, FOXO3a
    End point type
    Secondary
    End point timeframe
    analysis of tumour biomarkers immediately following study biopsy compared to baseline/diagnostic biopsy
    End point values
    		 stage 1 IMP stage 1 placebo Stage 2 240mg IMP Stage 2 360mg IMP
    Number of subjects analysed
    19
    17
    7
    5
    Units: Percentage change pre and post op tumour
    arithmetic mean (confidence interval 95%)
        Tumour pAKT
    107.01 (25.16 to 188.86)
    5.91 (-24.94 to 36.77)
    133.5 (21.79 to 245.21)
    71.26 (-19.88 to 162.39)
        Tumour pS6
    -38.83 (-48.80 to 28.86)
    -8.18 (-25.84 to 9.47)
    -21.22 (-92.25 to 49.81)
    -40.51 (-83.30 to 2.27)
        Tumour FOX03a
    12.01 (-13.52 to 37.55)
    1.04 (-44.54 to 46.62)
    79.04 (-17.18 to 275.27)
    55.03 (-56.64 to 166.7)
        Tumour caspase 3000
    17.20 (-22.77 to 57.20)
    5.33 (-36.35 to 47.01)
    -42.83 (-78.61 to -7.05)
    122.65 (-336.23 to 581.53)
        Tumour caspase 500
    64.74 (-45.42 to 174.95)
    4.84 (-32.31 to 42.00)
    -42.83 (-78.61 to -7.05)
    122.65 (-336.23 to 581)
    Statistical analysis title
    		 Stage 1 secondary outcome tumour pAKT
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.011
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    116.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29.3
         upper limit
    		 204.56
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 secondary outcome tumour pS6
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0031
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -29.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.84
         upper limit
    		 -11.12
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 secondary outcome tumour FOX03a
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3376
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.42
         upper limit
    		 60.22
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 secondary outcome tumour caspase 500
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.365
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    63.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -78
         upper limit
    		 204.61
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 secondary outcome caspase 3000
    Comparison groups
    stage 1 placebo v stage 1 IMP
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5702
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.076
         upper limit
    		 0.135
    Variability estimate
    Standard error of the mean

    Other pre-specified: Exploratory endpoints: changes in biomarkers

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    End point title
    		 Exploratory endpoints: changes in biomarkers
    End point description
    Exploratory Endpoints: Assessment of molecular aberrations of the AKT pathway and changes in blood and tissue based markers related to other cellular pathways Platelet-rich plasma: pPRAS40, pGSK3b, P70S6K, pAKT, pAKT/AKT , PRP biomarker, PRP GSK-3b Eyebrow hair: pPRAS40
    End point type
    Other pre-specified
    End point timeframe
    Analysis of tumour biomarkers immediately following study biopsy compared to baseline/diagnostic biopsy
    End point values
    		 stage 1 IMP stage 1 placebo Stage 2 240mg IMP Stage 2 360mg IMP
    Number of subjects analysed
    17
    11
    7
    5
    Units: percentage
    arithmetic mean (confidence interval 95%)
        EH pPRAS 40
    7.56 (-13.77 to 28.88)
    23.56 (-30.86 to 77.98)
    0 (0 to 0)
    0 (0 to 0)
        PRP Biomarker AKT
    33.54 (-33.14 to 100.23)
    206.58 (-288.46 to 701.61)
    0 (0 to 0)
    3.29 (-5.84 to 12.43)
        PRP Biomarker GSK-3b
    183.06 (-13.73 to 379.85)
    502.13 (-695.51 to 1699.77)
    31.19 (1.21 to 61.18)
    7.61 (-27.20 to 42.42)
        PRP Biomarker PRAS 40
    87.85 (-67.43 to 243.05)
    -10.38 (-34.54 to 13.78)
    0 (0 to 0)
    0 (0 to 0)
        PRP Biomarker p70S6K
    73.19 (-19.91 to 166.28)
    983.53 (-1388.33 to 3355.39)
    -2.01 (-37.74 to 33.73)
    -10.56 (-27.47 to 6.35)
        PRP Biomarker pAKT
    -0.89 (-94.24 to 92.46)
    155.18 (-33.28 to 343.63)
    0 (0 to 0)
    3.29 (-5.84 to 12.43)
        PRP Biomarker pAKT/AKT
    -40.04 (-63.75 to 16.33)
    48.93 (-102.70 to 200.56)
    0 (0 to 0)
    0 (0 to 0)
        PRP Biomarker pGSK 3b
    17.98 (-144.09 to 180.05)
    5.27 (-26.23 to 36.77)
    -37.68 (-57.84 to -17.51)
    -55.37 (-85.83 to -28.11)
        PRP Biomarker pPRAS 40
    -18.62 (-31.83 to 5.40)
    7.18 (-11.18 to 25.55)
    -4.37 (-14.14 to 5.40)
    -7.85 (-20.65 to 4.95)
        PRP Biomarker pp70S6K
    -13.32 (-33.8 to 7.16)
    14.56 (-11.68 to 40.79)
    -4.66 (-25.31 to 34.63)
    -6.13 (-25.57 to 13.32)
    Statistical analysis title
    		 Stage 1 Exploratory outcomes EH pPRAS40
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6608
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.83
         upper limit
    		 36.18
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Exploratory outcomes PRP GSK-3b
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4184
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -327.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1169.56
         upper limit
    		 514.81
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Exploratory outcomes PRP AKT
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3169
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -168.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -517.17
         upper limit
    		 180.88
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Exploratory outome PRP PRAS 40
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.157
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.43
         upper limit
    		 274.92
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Exploratory outome PRP p70S6K
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2864
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -831.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2441.28
         upper limit
    		 777.8
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Exploratory outcome PRP pAKT
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1653
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -111.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -272.06
         upper limit
    		 50.45
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Exploratpry outcome PRP pAKT/AKT
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1175
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -81.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -188.03
         upper limit
    		 25.01
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Staage 1 Exploratory outome PRP pGSK 3b
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9848
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.492
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -160.14
         upper limit
    		 163.13
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Exploratory outcome PRP pPRAS 40
    Comparison groups
    stage 1 IMP v stage 1 placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0153
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -27.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.51
         upper limit
    		 5.79
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Stage 1 Exploratory outome PRP pp70S6K
    Comparison groups
    stage 1 placebo v stage 1 IMP
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1146
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.72
         upper limit
    		 5.51
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events will be recorded and closely monitored until resolution, stabilisation, or until it has been shown that the study medication or treatment is not the cause.
    Adverse event reporting additional description
    For the purpose of this trial, any detrimental change in a patient’s condition, subsequent to their entering the trial and during the 30-day follow-up period after the last AZD5363/placebo capsule or tablet, should be considered an AE
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    stage 1 IMP
    Reporting group description
    		 AZD5363

    Reporting group title
    stage 1 placebo
    Reporting group description
    		 240mg/360mg AZD5363

    Reporting group title
    Stage 2 240mg IMP
    Reporting group description
    		 STAGE 2 240mg AZD5363

    Reporting group title
    Stage 2 360mg IMP
    Reporting group description
    		 Stage 2 360mg AZD5363

    Serious adverse events
    		 stage 1 IMP stage 1 placebo Stage 2 240mg IMP Stage 2 360mg IMP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 19 (15.79%)
    3 / 17 (17.65%)
    2 / 7 (28.57%)
    2 / 5 (40.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Delayed recovery from anaesthesia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Migraine without aura
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 stage 1 IMP stage 1 placebo Stage 2 240mg IMP Stage 2 360mg IMP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 19 (94.74%)
    12 / 17 (70.59%)
    7 / 7 (100.00%)
    5 / 5 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    hypotension
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Abdominal pain and/or distension
         subjects affected / exposed
    7 / 19 (36.84%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    7
    1
    0
    0
    Blood creatine increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood urea increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    chills
         subjects affected / exposed
    3 / 19 (15.79%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Fatigue
         subjects affected / exposed
    7 / 19 (36.84%)
    3 / 17 (17.65%)
    2 / 7 (28.57%)
    5 / 5 (100.00%)
         occurrences all number
    7
    3
    2
    7
    impaired healing
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injection site rash
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Puncture site swelling
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Vulval disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Early satiety
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infusion site extravasation
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    breast pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vulvovaginal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    cough
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    0
    1
    Depression
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Irritability
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    restlessness
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Delayed recovery from anaesthesia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    procedural pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    1
    Seroma
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    2 / 7 (28.57%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    2
    2
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    palpitations
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 19 (31.58%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    6
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Headache
         subjects affected / exposed
    10 / 19 (52.63%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    5 / 5 (100.00%)
         occurrences all number
    10
    2
    1
    5
    Hot flush
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    1
    Hyperaesthesia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Migraine without aura
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    neuralgia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Parosmia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    3 / 5 (60.00%)
         occurrences all number
    0
    0
    0
    3
    Blood and lymphatic system disorders
    Blood bilirubin increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    0
    1
    Neutropenic sepsis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Face oedema
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    ear pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    External ear pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Mydriasis
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    blurred vision
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye pruritus
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hordeolum
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    3 / 19 (15.79%)
    3 / 17 (17.65%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    3
    3
    0
    2
    Diarrhoea
         subjects affected / exposed
    18 / 19 (94.74%)
    4 / 17 (23.53%)
    1 / 7 (14.29%)
    2 / 5 (40.00%)
         occurrences all number
    25
    4
    1
    2
    dyspepsia
         subjects affected / exposed
    4 / 19 (21.05%)
    3 / 17 (17.65%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    4
    3
    2
    0
    Faeces discoloured
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Glossodynia
         subjects affected / exposed
    3 / 19 (15.79%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Mouth ulceration
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nausea
         subjects affected / exposed
    10 / 19 (52.63%)
    4 / 17 (23.53%)
    3 / 7 (42.86%)
    5 / 5 (100.00%)
         occurrences all number
    10
    4
    3
    5
    Oral pain
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    orophayangeal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 17 (17.65%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Toothache
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    vomiting
         subjects affected / exposed
    4 / 19 (21.05%)
    1 / 17 (5.88%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
         occurrences all number
    4
    1
    2
    0
    Eructation
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    alopecia
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Acne
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    rash
         subjects affected / exposed
    5 / 19 (26.32%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    5 / 19 (26.32%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    5
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    back pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    0
    0
    2
    Joint swelling
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Febrile neutropenia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    post operative wound infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    bacterial infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    2
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2013
    patient pathway clarifications and typographical errors corrected.SA/01/13 documents changed: protocol V2.0 participant consent form v3.0 participant information sheet v3.0 GP letter v2.0 patient information and diary: stage1 day 1-5 v1.0 patient information and diary: stage2 day 1-5 v1.0 patient information and diary: day 5-34 v1.0
    16 Jan 2014
    SA/02/14 Appendix 12: change to concomitant medications re antidepressants and statins ( reverted to advisory) Appendix 13 added, typographical error corrected, updated information re sites and dates, anaesthetic advisory added, poster added. GP letter amended to provide Appendix 12 and 13 updated information. Protocol v3.0 11/01/14 poster v1 added GP letter 2.1
    17 Apr 2014
    Trial/study personnel and contact details updated: Edinburgh PI details changed: Coventry removed as a participating site. protocol v 4.0
    11 Jul 2014
    change to eligibility criteria to include pre-menopausal women; Increase in the number of participating sites; Reduction in minimum age to 18 years; Addition of pregnancy testing and contraception requirements for pre-menopausal women; mandatory 8 hr PK/PRP samples replaced with optional 6hr samples; removal of exclusion criterion 2 regarding HRT; addition of new information in Appendix 12 as supplied by AZ. Protocol v 5.0 consent pre-menopausal v1.0 consent post-menopausa v4.0 participant information sheet pre-menopausal v4.0 patient letter v1.0 summary information leaflet v1.0 GP letter v3.0
    14 Sep 2015
    Change of AZD5363 formulation from capsules to tablets;addition of information on new causally associated AZ of hypersensitivity and update to details on other causally assosciated AEs; addition of detail around visit 3 pre-dose blood glucose serum samples; inclusion of patient ID and name of participant on all pages of consent forms and patient information and diary booklets; clarification that tumour total AKT and PTEN are exploratory endpoints; new eligibility criteria allowing patients with new primary breast tumours despite prior endocrine treatment for an earlier breast tumour to considered eligible: definition of what constitutes an evaluable patient included; clarification around numbers of patients require in both stages. protocol V6.0 participant information sheet pre-menopausal V2.0 patient information sheet post-menopausal V5.0 consent pre-menopausal V1.1 consent post-menopausal V4.1 GP letter V4.0 patient info and diary stage 1 day 1-5 V2.0 patient info and diary stage 2 day 1-5 V2.0 patient info and diary day 5-34 V2.0 summary information leaflet V2.0 investigator brochure edition 6
    02 Dec 2015
    Removal of placebo arm in stage 2; Removal of eyebrow hair sampling in stage2; Removal of Tayside and Lincolnshire sites. Protocol V7.0 30/10/15 Participant information sheet pre-menopausal V3 30-10-15 Consent form post-menopausal V6 30-10-2015 consent form pre-menopausal V2 30-10-2015 consent form post menopausal V5 30-10-15 GP letter V5 30-10-15 summary information leaflet V3.3 30-10-15
    21 Jul 2016
    DMC,TSC, trial statistician, the funder and CI request and support the substantial amendment 08. This amendment requires to un-blind stage 1 for scientific not safety reasons. in addition to the substantial amendment the following minor amendments were submitted. clarification of trial staff since the last amendment these changes are in management staff only. Clarification that signed ICF will be filed in site File during the study p70. clarification of monitoring scheduling as per monitoring plan p73 clarification of IMP supply appendix 1- study drug manufacture. addition of text: note for stage2 placebo will not be manufactured, shipped or dispensed.

    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.
    There were no pre-planned analyses as Phase 1 & 2 were separate, sequential phases and therefore non-randomised comparisons. In addition the number of patients per group in Phase 2 were only half that of the groups in Phase 1. The data are presented
    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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