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    Clinical Trial Results:
    A Phase I/II, Multicentre, Study Comprising a Safety Run-In of AZD5363 when Combined with Paclitaxel in Patients with Advanced or Metastatic Breast Cancer; Followed by a Randomised Expansion of AZD5363 when Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA Mutation Status (BEECH).

    Summary
    EudraCT number
    		 2011-006312-31
    Trial protocol
    		 GB   CZ  
    Global end of trial date
    03 Oct 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Jul 2023
    First version publication date
    08 Jan 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D3610C00002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01625286
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Forskargatan, Sodertalje, Sweden, SE-151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A: To assess the safety and tolerability of AZD5363 when combined with weekly paclitaxel in patients with advanced or metastatic breast cancer, and to recommend, by assessment of dose-limiting toxicities (DLTs) and other safety, tolerability, PK, and PDc data, a dose and schedule of AZD5363 for further study when combined with weekly paclitaxel. Part B: To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel compared with weekly paclitaxel plus placebo by assessment of PFS in the overall advanced or metastatic ER-positive breast cancer population
    Protection of trial subjects
    After each dose level during Part A of the study, the SRC evaluated the safety and tolerability and pharmacokinetics of AZD5363 to decide the next dose. During the Part B Randomised Phase of the study, an independent SRC (ISRC) monitored safety and tolerability in the study by means of reviews of safety data at approximately 3 to 6 monthly intervals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2012
    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: 29
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Peru: 26
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Singapore: 4
    Worldwide total number of subjects
    148
    EEA total number of subjects
    46
    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)
    115
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Part A: Patients were recruited at 9 study centres in 3 countries; 44 patients were enrolled in this part of the study. Part B: Patients were recruited in 40 study centres in 11 countries; 194 patients were enrolled in this part of the study, of which 51 patients had a tumour detectable as carrying a PIK3CA mutation.

    Pre-assignment
    Screening details
    		 Female patients aged ≥18 years, with histological or cytological confirmation of ER-positive and HER2-negative breast cancer, with evidence of relapsed advanced or metastatic disease.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Part A was an open-label phase, Part B double-blind

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A Schedule 1 560 mg bd
    Arm description
    		 Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    An intermittent dosing schedule of 560 mg bd (1120 mg daily)

    Arm title
    		 Part A Schedule 1 640 mg bd
    Arm description
    		 Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    An intermittent dosing schedule of 640 mg bd

    Arm title
    		 Part A Schedule 2 360 mg bd
    Arm description
    		 Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    An intermittent dosing schedule of 360 mg bd

    Arm title
    		 Part A Schedule 2 400 mg bd
    Arm description
    		 Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    An intermittent dosing schedule of 400 mg bd

    Arm title
    		 Part A Schedule 2 480 mg bd
    Arm description
    		 Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    An intermittent dosing schedule of 480 mg bd

    Arm title
    		 Part B AZD5363
    Arm description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    An intermittent dosing schedule of 400 mg bd (4 days on / 3 days off) administered in combination with paclitaxel

    Arm title
    		 Part B Placebo
    Arm description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    An intermittent dosing schedule of 400 mg bd (4 days on / 3 days off) placebo administered in combination with paclitaxel

    Number of subjects in period 1
    		Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Started
    12
    8
    5
    7
    6
    54
    56
    Received AZD5363/Placebo treatment
    12
    8
    5
    7
    6
    54
    55
    Did not receive AZD5363/Placebo trt
    0 [1]
    0 [2]
    0
    0
    0
    0 [3]
    1 [4]
    Completed
    6
    4
    0
    0
    0
    40
    37
    Not completed
    6
    4
    5
    7
    6
    14
    19
         Adverse event, serious fatal
    -
    -
    1
    1
    -
    11
    16
         Consent withdrawn by subject
    -
    1
    -
    1
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    -
    -
    1
    2
    1
         Any reason not specifically recorded
    -
    -
    -
    -
    -
    1
    -
         Progressive disease
    6
    3
    4
    5
    5
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected the number of subjects will be greater than, or equal to the number that completed minus those that left.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected the number of subjects will be greater than, or equal to the number that completed minus those that left.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected the number of subjects will be greater than, or equal to the number that completed minus those that left.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected the number of subjects will be greater than, or equal to the number that completed minus those that left.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A Schedule 1 560 mg bd
    Reporting group description
    		 Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part A Schedule 1 640 mg bd
    Reporting group description
    		 Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part A Schedule 2 360 mg bd
    Reporting group description
    		 Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part A Schedule 2 400 mg bd
    Reporting group description
    		 Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part A Schedule 2 480 mg bd
    Reporting group description
    		 Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part B AZD5363
    Reporting group description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly

    Reporting group title
    Part B Placebo
    Reporting group description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly

    Reporting group values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo Total
    Number of subjects
    		 12 8 5 7 6 54 56 148
    Age, Customized
    Units: Subjects
        <50
    		 5 3 1 4 2 19 16 50
        >=50 - <65
    		 5 2 3 3 3 23 26 65
        >=65
    		 2 3 1 0 1 12 14 33
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 52.2 ( 9.92 ) 58.8 ( 12.78 ) 56.6 ( 10.26 ) 47.1 ( 9.41 ) 49.8 ( 13.12 ) 54.3 ( 10.01 ) 57.4 ( 11.38 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 12 8 5 7 6 54 56 148
        Male
    		 0 0 0 0 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian|
    		 1 0 0 0 0 12 15 28
        Black Or African American|
    		 1 0 0 0 0 0 0 1
        White|
    		 10 8 5 7 6 24 18 78
        American Indian or Alaska Native|
    		 0 0 0 0 0 15 16 31
        Other|
    		 0 0 0 0 0 3 7 10

    End points

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    End points reporting groups
    Reporting group title
    Part A Schedule 1 560 mg bd
    Reporting group description
    		 Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part A Schedule 1 640 mg bd
    Reporting group description
    		 Schedule 1 - AZD5363 640 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part A Schedule 2 360 mg bd
    Reporting group description
    		 Schedule 2 - AZD5363 360 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part A Schedule 2 400 mg bd
    Reporting group description
    		 Schedule 2 - AZD5363 400 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part A Schedule 2 480 mg bd
    Reporting group description
    		 Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part B AZD5363
    Reporting group description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly

    Reporting group title
    Part B Placebo
    Reporting group description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly

    Primary: Dose-limiting toxicity (DLT) Events - Part A

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    End point title
    		 Dose-limiting toxicity (DLT) Events - Part A [1]
    End point description
    An Adverse Event (AE) or laboratory abnormality considered to be related to study drug, that starts at any time during the DLT evaluation period (Cycle 1) and is dose limiting
    End point type
    Primary
    End point timeframe
    During Part A DLT evaluation period (Cycle 1, up to 28 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed. This was the safety run-in part of the study, where the primary purpose was to assess DLTs rather than to compare treatment groups, so no comparative analyses were conducted.
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    11
    6
    5
    7
    6
    0 [2]
    0 [3]
    Units: participants
    0
    2
    0
    0
    2
    Notes
    [2] - DLTs were not assessed in Part B (the randomized part of the study)
    [3] - DLTs were not assessed in Part B (the randomized part of the study)
    No statistical analyses for this end point

    Primary: Progression Free Survival (PFS) - Part B

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    End point title
    		 Progression Free Survival (PFS) - Part B
    End point description
    Time from randomisation to date of objective disease progression or death (by any cause in the absence of progression). Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a >= 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, and an absolute increase of >=5mm, or progression of non-target lesions or the appearance of new lesions.
    End point type
    Primary
    End point timeframe
    From randomisation date to date of objective disease progression or death (by any cause) whichever came first, assessed every 12 wks (median total treatment duration AZD5363=325.5 days; Placebo=245 days)
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    54
    56
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    10.9 (8.3 to 12.4)
    8.4 (8.2 to 10.8)
    Notes
    [4] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [5] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [6] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [7] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [8] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    Statistical analysis title
    		 PFS - Part B
    Comparison groups
    Part B AZD5363 v Part B Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.308 [10]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.06
    Notes
    [9] - A hazard ratio < 1 favours AZD5363
    [10] - 2-sided p-value

    Secondary: Change in tumour size at 12 weeks

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    End point title
    		 Change in tumour size at 12 weeks
    End point description
    Percentage change from baseline to week 12 in sum of longest diameters of target lesions as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1). Based on patients with measurable disease who had sufficient data available to either calculate or impute a change at 12 weeks
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments every 12 weeks
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    10
    7
    5
    5
    4
    53
    55
    Units: % change from baseline
        arithmetic mean (standard deviation)
    -11.0 ( 33.42 )
    -15.7 ( 13.33 )
    -19.1 ( 17.73 )
    -18.3 ( 37.74 )
    -10.2 ( 24.84 )
    -34.2 ( 28.91 )
    -25.4 ( 35.87 )
    Statistical analysis title
    		 Percentage change in tumour size at Week 12
    Comparison groups
    Part B AZD5363 v Part B Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.081 [11]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.9
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -17.1
         upper limit
    		 -0.8
    Notes
    [11] - 1-sided p-value

    Secondary: Objective Response Rate (ORR) at week 12

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    End point title
    		 Objective Response Rate (ORR) at week 12
    End point description
    Number of patients who have at least one visit response of Complete Response or Partial Response prior to any evidence of progression at week 12 as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments every 12 weeks
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    12
    8
    5
    7
    6
    54
    56
    Units: Number of participants
    5
    1
    0
    0
    0
    27
    24
    No statistical analyses for this end point

    Secondary: Best Objective Response (BOR)

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    End point title
    		 Best Objective Response (BOR)
    End point description
    Number of patients, taking their BOR, which is their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
    End point type
    Secondary
    End point timeframe
    From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    12
    8
    5
    7
    6
    54
    56
    Units: Participants
        Complete Response (CR)
    0
    0
    0
    0
    0
    3
    4
        Partial Response (PR)
    0
    2
    1
    1
    0
    29
    28
        Stable Disease (SD)
    7
    4
    3
    4
    3
    14
    14
        Progression
    4
    1
    1
    1
    2
    6
    8
        Not Evaluable (NE)
    1
    1
    0
    1
    1
    2
    2
    No statistical analyses for this end point

    Secondary: Overall Objective Response Rate

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    End point title
    		 Overall Objective Response Rate
    End point description
    Number of patients, taking their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. Overall Response Rate (ORR) = CR + PR
    End point type
    Secondary
    End point timeframe
    From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    12
    8
    5
    7
    6
    54
    56
    Units: Number of participants
    0
    2
    1
    1
    0
    32
    32
    No statistical analyses for this end point

    Secondary: Number of subjects Without Progressive Disease at Week 12 - Part A

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    End point title
    		 Number of subjects Without Progressive Disease at Week 12 - Part A
    End point description
    Number of patients with a 12 week visit response of CR, PR or SD (as defined by RECIST 1.1) with no evidence of previous progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
    End point type
    Secondary
    End point timeframe
    up to 12 weeks
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    12
    8
    5
    7
    6
    0 [12]
    0 [13]
    Units: Participants
    6
    5
    3
    4
    2
    Notes
    [12] - The endpoint was not assessed in Part B (the randomized part of the study)
    [13] - The endpoint was not assessed in Part B (the randomized part of the study)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) - Part B

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    End point title
    		 Duration of Response (DOR) - Part B
    End point description
    Date of first documentation of response (Complete Response/Partial Response) until the date of disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.. If a subject does not progress following a response, then their DOR will use the PFS censoring time.
    End point type
    Secondary
    End point timeframe
    From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    54
    56
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    8.3 (6 to 11.3)
    8.2 (5.6 to 10.6)
    Notes
    [14] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [15] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [16] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [17] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [18] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    No statistical analyses for this end point

    Secondary: Durable Response Rate (DRR) - Part B

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    End point title
    		 Durable Response Rate (DRR) - Part B
    End point description
    Number of patients who have a Complete Response (CR) or Partial Response (PR) lasting continuously for at least 24 weeks as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: PR, >=30% decrease in the sum of the longest diameter of target lesions; CR, disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.
    End point type
    Secondary
    End point timeframe
    From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    54
    56
    Units: Number of participants
    26
    21
    Notes
    [19] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [20] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [21] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [22] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [23] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    Statistical analysis title
    		 Durable response rate (Part B)
    Comparison groups
    Part B AZD5363 v Part B Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.139 [24]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.53
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 2.54
    Notes
    [24] - 1-sided p-value

    Secondary: Overall Survival - Part B

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    End point title
    		 Overall Survival - Part B
    End point description
    The interval between the date of randomisation and the date of patient death due to any cause. All Part B patients were analysed, number of deaths is presented.
    End point type
    Secondary
    End point timeframe
    From date of randomisation, assessed every 12 weeks, up until the time of final statistical analysis. (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
    End point values
    		 Part A Schedule 1 560 mg bd Part A Schedule 1 640 mg bd Part A Schedule 2 360 mg bd Part A Schedule 2 400 mg bd Part A Schedule 2 480 mg bd Part B AZD5363 Part B Placebo
    Number of subjects analysed
    0 [25]
    0 [26]
    0 [27]
    0 [28]
    0 [29]
    54
    56
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    32.8 (21.3 to 32.8)
    999 (20.9 to 999)
    Notes
    [25] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [26] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [27] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [28] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    [29] - The endpoint was not assessed in Part A (the safety run-in part of the study)
    Statistical analysis title
    		 Analysis of overall survival (Part B)
    Comparison groups
    Part B AZD5363 v Part B Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 [30]
    P-value
    		 = 0.482 [31]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.24
    Notes
    [30] - A hazard ratio < 1 favours AZD5363
    [31] - 2-sided p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time of signature of informed consent throughout the treatment period up to and including the follow-up period (median follow-up AZD5363 16.9 months; Placebo 15.2 months)
    Adverse event reporting additional description
    The 5% threshold is applied to trt schedule in Part A. Part A AEs were coded with MedDRA v20.0 (schedule 1) or v18.1 (schedule 2). The 5% threshold is applied to each Part B trt arm and Part B AEs were coded with MedDRA v19.1. 1 patient in the placebo arm did not receive placebo trt (hence n=56 for All Cause Mortality, n=55 for SAEs/AEs)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1819.120
    Reporting groups
    Reporting group title
    Part A Schedule 1 560 mg bd
    Reporting group description
    		 Schedule 1 - AZD5363 560 mg bd (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Sched 2 - AZD5363 360 mg bd
    Reporting group description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part B Placebo
    Reporting group description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly

    Reporting group title
    Part A Schedule 2 480 mg bd
    Reporting group description
    		 Schedule 2 - AZD5363 480 mg bd (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Part B AZD5363
    Reporting group description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly

    Reporting group title
    Sched 1 - AZD5363 640 mg bd
    Reporting group description
    		 (2 days on/5 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Reporting group title
    Sched 2 - AZD5363 400 mg bd
    Reporting group description
    		 (4 days on/3 days off) with Paclitaxel 90 mg/m2 once weekly. 3/4 weeks.

    Serious adverse events
    		 Part A Schedule 1 560 mg bd Sched 2 - AZD5363 360 mg bd Part B Placebo Part A Schedule 2 480 mg bd Part B AZD5363 Sched 1 - AZD5363 640 mg bd Sched 2 - AZD5363 400 mg bd
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 5 (0.00%)
    8 / 55 (14.55%)
    4 / 6 (66.67%)
    13 / 54 (24.07%)
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         number of deaths (all causes)
    0
    1
    15
    0
    13
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Salivary gland cancer
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    1 / 6 (16.67%)
    4 / 54 (7.41%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    2 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A Schedule 1 560 mg bd Sched 2 - AZD5363 360 mg bd Part B Placebo Part A Schedule 2 480 mg bd Part B AZD5363 Sched 1 - AZD5363 640 mg bd Sched 2 - AZD5363 400 mg bd
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    5 / 5 (100.00%)
    48 / 55 (87.27%)
    6 / 6 (100.00%)
    50 / 54 (92.59%)
    8 / 8 (100.00%)
    7 / 7 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    0
    Hypertension
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    10
    0
    3
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    1 / 6 (16.67%)
    2 / 54 (3.70%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    1
    2
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 12 (50.00%)
    1 / 5 (20.00%)
    7 / 55 (12.73%)
    3 / 6 (50.00%)
    7 / 54 (12.96%)
    5 / 8 (62.50%)
    6 / 7 (85.71%)
         occurrences all number
    12
    4
    16
    3
    8
    22
    11
    Device breakage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 5 (40.00%)
    11 / 55 (20.00%)
    0 / 6 (0.00%)
    16 / 54 (29.63%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    4
    14
    0
    20
    0
    0
    Malaise
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    4 / 55 (7.27%)
    0 / 6 (0.00%)
    4 / 54 (7.41%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    8
    0
    4
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    8 / 55 (14.55%)
    2 / 6 (33.33%)
    8 / 54 (14.81%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    1
    11
    2
    10
    0
    3
    Peripheral swelling
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    2
    0
    3
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 5 (40.00%)
    3 / 55 (5.45%)
    2 / 6 (33.33%)
    14 / 54 (25.93%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    3
    3
    15
    3
    0
    Influenza like illness
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    3
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    Suprapubic pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Catheter site related reaction
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Face oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Hyperthermia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    4 / 54 (7.41%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    3
    0
    5
    0
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Breast discharge
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Vaginal discharge
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Menorrhagia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 12 (41.67%)
    1 / 5 (20.00%)
    8 / 55 (14.55%)
    2 / 6 (33.33%)
    11 / 54 (20.37%)
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    6
    1
    11
    2
    13
    4
    1
    Dysphonia
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 5 (40.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    5 / 54 (9.26%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    2
    0
    5
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    2
    0
    3
    0
    0
    Dyspnoea
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    9 / 55 (16.36%)
    1 / 6 (16.67%)
    6 / 54 (11.11%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    3
    0
    14
    1
    6
    1
    2
    Epistaxis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    2 / 6 (33.33%)
    5 / 54 (9.26%)
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    1
    3
    5
    3
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    6 / 55 (10.91%)
    1 / 6 (16.67%)
    4 / 54 (7.41%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    6
    1
    6
    0
    0
    Nasal obstruction
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Nasal dryness
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    2 / 6 (33.33%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 5 (20.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    3 / 8 (37.50%)
    2 / 7 (28.57%)
         occurrences all number
    4
    1
    2
    0
    1
    4
    2
    Rhinitis allergic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    3
    0
    3
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    2
    0
    2
    2
    2
    Sleep disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    2 / 54 (3.70%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    1
    0
    Hallucination
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    0 / 6 (0.00%)
    13 / 54 (24.07%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    5
    0
    22
    3
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    0 / 6 (0.00%)
    11 / 54 (20.37%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    6
    0
    19
    9
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    5
    0
    2
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    2
    0
    6
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    0
    0
    3
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    4
    0
    3
    3
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    1 / 6 (16.67%)
    4 / 54 (7.41%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    5
    1
    8
    5
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    18
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    5 / 54 (9.26%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    3
    0
    5
    0
    0
    Blood glucose increased
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    1
    0
    2
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    2
    0
    2
    0
    0
    Thyroxine decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    Liver palpable
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    1
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Wound
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    1
    0
    1
    0
    0
    Pericardial effusion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 5 (40.00%)
    7 / 55 (12.73%)
    1 / 6 (16.67%)
    11 / 54 (20.37%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    8
    1
    13
    2
    4
    Lethargy
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    2 / 55 (3.64%)
    2 / 6 (33.33%)
    2 / 54 (3.70%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    6
    2
    3
    5
    1
    0
    Headache
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 5 (20.00%)
    10 / 55 (18.18%)
    1 / 6 (16.67%)
    8 / 54 (14.81%)
    4 / 8 (50.00%)
    2 / 7 (28.57%)
         occurrences all number
    7
    1
    12
    1
    14
    4
    2
    Neuropathy peripheral
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 5 (20.00%)
    18 / 55 (32.73%)
    1 / 6 (16.67%)
    13 / 54 (24.07%)
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    13
    2
    26
    1
    22
    7
    3
    Neurotoxicity
         subjects affected / exposed
    5 / 12 (41.67%)
    1 / 5 (20.00%)
    3 / 55 (5.45%)
    2 / 6 (33.33%)
    5 / 54 (9.26%)
    3 / 8 (37.50%)
    3 / 7 (42.86%)
         occurrences all number
    6
    1
    3
    3
    9
    3
    3
    Paraesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    2 / 55 (3.64%)
    2 / 6 (33.33%)
    6 / 54 (11.11%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    2
    2
    8
    3
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    10 / 55 (18.18%)
    0 / 6 (0.00%)
    14 / 54 (25.93%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    11
    0
    17
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    2 / 6 (33.33%)
    1 / 54 (1.85%)
    5 / 8 (62.50%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    5
    3
    1
    7
    0
    Migraine
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Radicular pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    1 / 6 (16.67%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    0
    Myoclonus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Parosmia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    1
    0
    Ageusia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Visual field defect
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 12 (50.00%)
    1 / 5 (20.00%)
    15 / 55 (27.27%)
    2 / 6 (33.33%)
    18 / 54 (33.33%)
    4 / 8 (50.00%)
    0 / 7 (0.00%)
         occurrences all number
    17
    1
    20
    2
    32
    16
    0
    Neutropenia
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 5 (40.00%)
    7 / 55 (12.73%)
    0 / 6 (0.00%)
    7 / 54 (12.96%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
         occurrences all number
    20
    4
    26
    0
    21
    23
    0
    Leukopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    5 / 54 (9.26%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    2
    0
    16
    3
    0
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Febrile neutropenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    2
    0
    Tinnitus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    8
    2
    0
    Vertigo
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    0
    Ear canal erythema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hypoacusis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    2
    Dry eye
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    1 / 6 (16.67%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    1
    2
    2
    0
    0
    Photopsia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Conjunctival pallor
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Vitreous detachment
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 5 (40.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    3
    0
    2
    0
    0
    Constipation
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 5 (40.00%)
    7 / 55 (12.73%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    5
    4
    8
    0
    1
    1
    1
    Diarrhoea
         subjects affected / exposed
    11 / 12 (91.67%)
    5 / 5 (100.00%)
    15 / 55 (27.27%)
    6 / 6 (100.00%)
    41 / 54 (75.93%)
    7 / 8 (87.50%)
    6 / 7 (85.71%)
         occurrences all number
    66
    31
    32
    101
    228
    57
    34
    Dry mouth
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 5 (40.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    0
    1
    1
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    8 / 55 (14.55%)
    1 / 6 (16.67%)
    5 / 54 (9.26%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    8
    1
    6
    2
    1
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    0
    0
    0
    0
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    4 / 54 (7.41%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    1
    0
    5
    2
    0
    Nausea
         subjects affected / exposed
    8 / 12 (66.67%)
    3 / 5 (60.00%)
    13 / 55 (23.64%)
    5 / 6 (83.33%)
    21 / 54 (38.89%)
    5 / 8 (62.50%)
    2 / 7 (28.57%)
         occurrences all number
    23
    8
    19
    15
    33
    6
    5
    Odynophagia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    2
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 5 (40.00%)
    8 / 55 (14.55%)
    4 / 6 (66.67%)
    14 / 54 (25.93%)
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    17
    3
    10
    9
    20
    6
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    1
    0
    Toothache
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    4 / 54 (7.41%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    6
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    5 / 55 (9.09%)
    2 / 6 (33.33%)
    2 / 54 (3.70%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    6
    2
    4
    4
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    5 / 54 (9.26%)
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    3
    0
    0
    0
    6
    4
    2
    Gastrointestinal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    2
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    3 / 6 (50.00%)
    15 / 54 (27.78%)
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    3
    0
    4
    10
    26
    5
    2
    Colitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Rectal tenesmus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    0
    Hepatic pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Hepatocellular injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 5 (40.00%)
    1 / 55 (1.82%)
    1 / 6 (16.67%)
    4 / 54 (7.41%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    2
    2
    1
    5
    0
    0
    Alopecia
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 5 (60.00%)
    27 / 55 (49.09%)
    0 / 6 (0.00%)
    28 / 54 (51.85%)
    4 / 8 (50.00%)
    2 / 7 (28.57%)
         occurrences all number
    6
    3
    30
    0
    28
    4
    2
    Rash erythematous
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 5 (60.00%)
    2 / 55 (3.64%)
    3 / 6 (50.00%)
    3 / 54 (5.56%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    5
    4
    3
    5
    3
    3
    0
    Pruritus
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 5 (20.00%)
    5 / 55 (9.09%)
    2 / 6 (33.33%)
    2 / 54 (3.70%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    1
    7
    3
    2
    2
    0
    Nail disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    3
    0
    4
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 5 (40.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    14 / 54 (25.93%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    3
    2
    2
    0
    18
    0
    2
    Rash macular
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    4 / 54 (7.41%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    1
    8
    1
    0
    Swelling face
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    Nail discolouration
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    5 / 55 (9.09%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    5
    0
    1
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    1 / 6 (16.67%)
    4 / 54 (7.41%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    4
    1
    4
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    1
    Rash papular
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    0
    0
    8
    0
    0
    Skin reaction
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    0
    Erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    1 / 6 (16.67%)
    2 / 54 (3.70%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    4
    1
    4
    2
    1
    Melanoderma
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Nail dystrophy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    Onycholysis
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    5 / 55 (9.09%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    7
    0
    2
    2
    2
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    1
    2
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    0 / 6 (0.00%)
    8 / 54 (14.81%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    8
    0
    8
    5
    1
    Dermatitis acneiform
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    0
    3
    1
    Eczema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Generalised erythema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    2
    0
    4
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    Renal failure
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    2 / 6 (33.33%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    2
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 5 (40.00%)
    5 / 55 (9.09%)
    1 / 6 (16.67%)
    8 / 54 (14.81%)
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    5
    2
    5
    1
    10
    4
    1
    Muscle spasms
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    2 / 55 (3.64%)
    1 / 6 (16.67%)
    3 / 54 (5.56%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    3
    1
    6
    5
    0
    Joint swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 5 (20.00%)
    5 / 55 (9.09%)
    1 / 6 (16.67%)
    6 / 54 (11.11%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    5
    1
    7
    1
    7
    2
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    1
    Bone pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    3
    0
    0
    2
    1
    Arthralgia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    5 / 55 (9.09%)
    2 / 6 (33.33%)
    7 / 54 (12.96%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    3
    0
    12
    2
    8
    1
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    12 / 55 (21.82%)
    0 / 6 (0.00%)
    5 / 54 (9.26%)
    2 / 8 (25.00%)
    3 / 7 (42.86%)
         occurrences all number
    2
    0
    24
    0
    6
    3
    5
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    5
    0
    1
    2
    1
    Spinal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 5 (40.00%)
    5 / 55 (9.09%)
    0 / 6 (0.00%)
    7 / 54 (12.96%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    7
    0
    11
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 5 (60.00%)
    5 / 55 (9.09%)
    1 / 6 (16.67%)
    7 / 54 (12.96%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    3
    5
    1
    13
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    0
    2
    1
    0
    2
    Cystitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    4
    1
    0
    Cellulitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    3
    0
    1
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    4 / 54 (7.41%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    5
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    3
    0
    6
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    5 / 55 (9.09%)
    0 / 6 (0.00%)
    8 / 54 (14.81%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    6
    0
    12
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    4 / 54 (7.41%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Fungal infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 5 (0.00%)
    2 / 55 (3.64%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    4
    0
    2
    0
    2
    0
    1
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    2 / 6 (33.33%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    4
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Vaginal infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Varicella
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    Bacterial infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    2 / 54 (3.70%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    Folliculitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    1
    Herpes virus infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    1 / 6 (16.67%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 12 (41.67%)
    2 / 5 (40.00%)
    6 / 55 (10.91%)
    0 / 6 (0.00%)
    15 / 54 (27.78%)
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    39
    2
    13
    0
    48
    15
    1
    Decreased appetite
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 5 (40.00%)
    3 / 55 (5.45%)
    3 / 6 (50.00%)
    10 / 54 (18.52%)
    3 / 8 (37.50%)
    2 / 7 (28.57%)
         occurrences all number
    8
    2
    4
    3
    11
    3
    2
    Hypocalcaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    3 / 55 (5.45%)
    0 / 6 (0.00%)
    1 / 54 (1.85%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    4
    0
    1
    3
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    5 / 55 (9.09%)
    0 / 6 (0.00%)
    6 / 54 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    5
    0
    8
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    1 / 6 (16.67%)
    3 / 54 (5.56%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    11
    1
    3
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    4 / 55 (7.27%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    6
    0
    0
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 55 (1.82%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Calcium deficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Cell death
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 55 (0.00%)
    0 / 6 (0.00%)
    0 / 54 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    8
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2012
    Reporting time of an SAE was updated from “within 1 day ie, immediately but no later than the end of the next business day” to “immediately or no later than 24 hours of when investigator became aware of it”.
    24 Apr 2013
    Replacement of AZD5363 continuous dosing schedule with an intermittent dosing schedule. The total number of patients to be enrolled was changed from 60 to 100 and primary endpoint changed to PFS. Addition of OS as a secondary endpoint. Extension of WHO PS evaluations. Introduction of an independent SRC Provision for a change in AZD5363/placebo formulation: During Part A, patients could receive AZD5363 in capsule form only. During Part B, patients could receive AZD5363/placebo as capsules or as dose-equivalent tablets. A tablet formulation could be applied in all sites or in selected sites only. Inclusion of Japanese patient population in the study.
    09 May 2013
    Part B inclusion criteria: Requirement for patients to be negative for presence of HER2 was added for entry to Part B of this study Part B inclusion criteria: Removal of requirement for patients to have received prior endocrine therapy for entry to Part B Updated exclusion criteria 9 Part B patient stratification updated Efficacy variable: DRR added as a new efficacy variable Part B patient assessments: Reduction in the number of patient assessments and the number of days on which patients were required to attend for evaluation Data Monitoring Committee: Inclusion of an AstraZeneca internal Data Monitoring Committee
    29 Apr 2015
    Doses and treatment regimens: changes were made to the text to permit the use of dose-equivalent tablets in Part A of the study, as the previous wording specified capsules only Part B Patient Assessments: changes made to, and an overall reduction in, the number of patient assessments and the number of days on which patients were required to attend clinic for evaluation Exclusion criteria: updated exclusion criterion 4 and removal of exclusion criterion 11 Part A and B secondary objectives: addition of the secondary objective to assess the toxicity burden associated with diarrhoea Update to exploratory objectives Update to the Asian patient evaluation Update to Part B inclusion criterion 1 Update to exclusion criterion 20 Treatment description updated

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    QoL, PK/PD & efficacy response modelling were considered non-key secondary endpoints and not disclosed at this time. QoL data was limited and considered exploratory, PK/PD and modelling were not reported in CSR. Diarrhoea burden is reported with AEs.
    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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