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    Clinical Trial Results:
    A Phase II, Double-blind, Placebo-controlled, Randomized Study of GDC-0941 (Pictilisib) or GDC-0980 (Apitolisib) with Fulvestrant versus Fulvestrant in Advanced or Metastatic Breast Cancer in Patients Resistant to Aromatase Inhibitor Therapy

    Summary
    EudraCT number
    		 2010-023763-17
    Trial protocol
    		 BE   CZ   GB   DK   HU   DE   IT  
    Global end of trial date
    07 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Apr 2017
    First version publication date
    21 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GDC4950g
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01437566
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Secondary ID: GO00769
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    15 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objectives were to evaluate the efficacy and safety of fulvestrant + pictilisib in all treated subjects and subjects with PIK3CA-mutant tumors and mutations; and to evaluate the safety of fulvestrant + apitolisib all treated subjects.
    Protection of trial subjects
    Each subject, or the subject's representative, signed an informed consent form prior to study participation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    United States: 87
    Worldwide total number of subjects
    261
    EEA total number of subjects
    103
    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)
    170
    From 65 to 84 years
    90
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 261 subjects were enrolled in the study.

    Pre-assignment
    Screening details
    		 Subjects with estrogen receptor (ER)-positive locally advanced breast cancer or metastatic breast cancer (MBC) were screened for study; Part 1: recurrent or progressive disease while receiving treatment with an aromatase inhibitor (AI) as the most recent treatment; Part 2: PIK3CA mutant tumor progression during or after treatment with an AI.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GDC-0941 (340 mg) + Fulvestrant
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    GDC-0941
    Investigational medicinal product code
    Other name
    Pictilisib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GDC-0941, 340 mg, once daily, starting on Day 15 of Cycle 1 (28-day cycle), after the fulvestrant “run-in” period (Cycle 1, Day 1 to Cycle 1, Day 14)

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant, 500 mg, on Day 1 and Day 15 of Cycle 1 and Day 1 of each subsequent 28-day cycle.

    Arm title
    		 GDC-0941-Matching Placebo (340 mg) + Fulvestrant
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    GDC-0941-Matching Placebo (340 mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered similarly to GDC-0941 (340 mg) treatment.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant, 500 mg, on Day 1 and Day 15 of Cycle 1 and Day 1 of each subsequent 28-day cycle.

    Arm title
    		 GDC−0980 + Fulvestrant
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    GDC−0980
    Investigational medicinal product code
    Other name
    Apitolisib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GDC−0980, 30 mg, once daily, starting on Day 15 of Cycle 1 (28-day cycle), after the fulvestrant “run-in” period (Cycle 1, Day 1 to Cycle 1, Day 14)

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant, 500 mg, on Day 1 and Day 15 of Cycle 1 and Day 1 of each subsequent 28-day cycle.

    Arm title
    		 GDC−0980-Matching Placebo + Fulvestrant
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    GDC−0980-Matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered similarly to GDC-0980 treatment.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant, 500 mg, on Day 1 and Day 15 of Cycle 1 and Day 1 of each subsequent 28-day cycle.

    Arm title
    		 GDC-0941 (260 mg) + Fulvestrant
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    GDC-0941
    Investigational medicinal product code
    Other name
    Pictilisib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GDC-0941, 260 mg, once daily, starting on Day 15 of Cycle 1 (28-day cycle), after the fulvestrant “run-in” period (Cycle 1, Day 1 to Cycle 1, Day 14)

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant, 500 mg, on Day 1 and Day 15 of Cycle 1 and Day 1 of each subsequent 28-day cycle.

    Arm title
    		 GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    GDC−0941-Matching Placebo (260 mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered similarly to GDC-0941 (260 mg) treatment.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant, 500 mg, on Day 1 and Day 15 of Cycle 1 and Day 1 of each subsequent 28-day cycle.

    Number of subjects in period 1
    		GDC-0941 (340 mg) + Fulvestrant GDC-0941-Matching Placebo (340 mg) + Fulvestrant GDC−0980 + Fulvestrant GDC−0980-Matching Placebo + Fulvestrant GDC-0941 (260 mg) + Fulvestrant GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Started
    89
    79
    21
    11
    41
    20
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    89
    79
    21
    11
    41
    20
         Physician decision
    -
    1
    -
    -
    -
    -
         Withdrawal By Subject
    4
    6
    3
    1
    5
    3
         Study Terminated By Sponsor
    35
    30
    5
    6
    23
    10
         Adverse event, non-fatal
    -
    -
    1
    -
    1
    -
         Death
    47
    39
    12
    3
    11
    5
         Reason Not Specified
    -
    1
    -
    -
    -
    -
         Progressive Disease
    1
    -
    -
    -
    1
    1
         Lost to follow-up
    2
    2
    -
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GDC-0941 (340 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC-0941-Matching Placebo (340 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0980 + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0980-Matching Placebo + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC-0941 (260 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group values
    		 GDC-0941 (340 mg) + Fulvestrant GDC-0941-Matching Placebo (340 mg) + Fulvestrant GDC−0980 + Fulvestrant GDC−0980-Matching Placebo + Fulvestrant GDC-0941 (260 mg) + Fulvestrant GDC−0941-Matching Placebo (260 mg) + Fulvestrant Total
    Number of subjects
    		 89 79 21 11 41 20 261
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 60 50 14 7 28 11 170
        Elderly (From 65-84 years)
    		 28 29 7 4 13 9 90
        Elderly 85 years and over
    		 1 0 0 0 0 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60 ( 10.9 ) 61.1 ( 10.1 ) 61.2 ( 10.5 ) 60.3 ( 10.3 ) 58.3 ( 10.2 ) 62.7 ( 11.3 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 89 79 21 11 41 20 261
        Male
    		 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    GDC-0941 (340 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC-0941-Matching Placebo (340 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0980 + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0980-Matching Placebo + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC-0941 (260 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Reporting group description
    		 -

    Subject analysis set title
    GDC-0941 (340 mg) + Fulvestrant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis

    Subject analysis set title
    GDC-0941-Matching Placebo (340 mg) + Fulvestrant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis

    Subject analysis set title
    GDC−0980 + Fulvestrant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis

    Subject analysis set title
    GDC−0980-Matching Placebo + Fulvestrant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis

    Subject analysis set title
    GDC-0941 (260 mg) + Fulvestrant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis. This analysis set includes one subject who crossed over from placebo treatment.

    Subject analysis set title
    GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis

    Primary: Progression Free Survival (PFS, 10 April 2013 Data Cut-Off)

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    End point title
    		 Progression Free Survival (PFS, 10 April 2013 Data Cut-Off) [1]
    End point description
    PFS was assessed by the investigator, per Modified Response Evaluation Criteria In Solid Tumors (RECIST), v 1.1, criteria, and defined as the start date of any treatment to first disease progression or death from any cause within 30 days after the last dose of any study treatment. The intent-to-treat (ITT) population included all randomized subjects according to their randomized treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 1 year, 8 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analyzed in the reported arms only.
    End point values
    		 GDC-0941 (340 mg) + Fulvestrant GDC-0941-Matching Placebo (340 mg) + Fulvestrant
    Number of subjects analysed
    89
    79
    Units: months
        median (confidence interval 95%)
    6.5 (3.9 to 8.2)
    3.8 (3.6 to 6)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    GDC-0941 (340 mg) + Fulvestrant v GDC-0941-Matching Placebo (340 mg) + Fulvestrant
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.2505
    Method
    		 Logrank
    Confidence interval

    Primary: Progression Free Survival (PFS, 12 September 2014 Data Cut-Off)

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    End point title
    		 Progression Free Survival (PFS, 12 September 2014 Data Cut-Off) [2]
    End point description
    PFS was assessed by the investigator, per Modified Response Evaluation Criteria In Solid Tumors (RECIST), v 1.1, criteria, and defined as the start date of any treatment to first disease progression or death from any cause within 30 days after the last dose of any study treatment. The intent-to-treat (ITT) population included all randomized subjects according to their randomized treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 2 years, 11 months
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analyzed in the reported arms only.
    End point values
    		 GDC-0941 (260 mg) + Fulvestrant GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Number of subjects analysed
    41
    20
    Units: months
        median (confidence interval 95%)
    5.4 (3.8 to 8.3)
    10 (3.6 to 12.8)
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    GDC-0941 (260 mg) + Fulvestrant v GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.842
    Method
    		 Logrank
    Confidence interval

    Primary: Percentage of Subjects with Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects with Adverse Events (AEs) [3]
    End point description
    An adverse event can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. The safety-evaluable population included all subjects who were randomized and received at least one dose of fulvestrant, pictilisib, apitolisib, or placebo, with subjects allocated to the treatment arm associated with the regimen actually received.
    End point type
    Primary
    End point timeframe
    4 years, 8 months
    Notes
    [3] - 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: Descriptive analysis only.
    End point values
    		 GDC-0941 (340 mg) + Fulvestrant GDC-0941-Matching Placebo (340 mg) + Fulvestrant GDC−0980 + Fulvestrant GDC−0980-Matching Placebo + Fulvestrant GDC-0941 (260 mg) + Fulvestrant GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Number of subjects analysed
    89
    79
    21
    11
    42
    19
    Units: percentage of subjects
        number (not applicable)
    98.9
    93.7
    100
    90.9
    97.6
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 years, 8 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    GDC-0941 (340 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC-0941-Matching Placebo (340 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0980 + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0980-Matching Placebo + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC-0941 (260 mg) + Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Reporting group description
    		 -

    Serious adverse events
    		 GDC-0941 (340 mg) + Fulvestrant GDC-0941-Matching Placebo (340 mg) + Fulvestrant GDC−0980 + Fulvestrant GDC−0980-Matching Placebo + Fulvestrant GDC-0941 (260 mg) + Fulvestrant GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 89 (30.34%)
    11 / 79 (13.92%)
    5 / 21 (23.81%)
    1 / 11 (9.09%)
    5 / 42 (11.90%)
    3 / 19 (15.79%)
         number of deaths (all causes)
    3
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Meningioma
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Transcatheter aortic valve implantation
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Chest pain
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    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
    Fatigue
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Mucosal inflammation
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    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
    Pneumonitis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    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
    Pulmonary embolism
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Pleural effusion
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Cardiac disorders
    Cardiac tamponade
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Palpitations
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Dystonia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    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
    Headache
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    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
    Neutropenia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Tinnitus
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    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
    Colitis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    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
    Diarrhoea
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Ascites
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 89 (3.37%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    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
    Rash generalised
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo−papular
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Osteoarthritis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    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
    Infectious colitis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paratyphoid fever
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Sinusitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Viral infection
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    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
    Dehydration
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypokalaemia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GDC-0941 (340 mg) + Fulvestrant GDC-0941-Matching Placebo (340 mg) + Fulvestrant GDC−0980 + Fulvestrant GDC−0980-Matching Placebo + Fulvestrant GDC-0941 (260 mg) + Fulvestrant GDC−0941-Matching Placebo (260 mg) + Fulvestrant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    88 / 89 (98.88%)
    72 / 79 (91.14%)
    21 / 21 (100.00%)
    10 / 11 (90.91%)
    40 / 42 (95.24%)
    19 / 19 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    11 / 89 (12.36%)
    11 / 79 (13.92%)
    3 / 21 (14.29%)
    2 / 11 (18.18%)
    4 / 42 (9.52%)
    2 / 19 (10.53%)
         occurrences all number
    14
    14
    4
    3
    4
    2
    Hypertension
         subjects affected / exposed
    6 / 89 (6.74%)
    3 / 79 (3.80%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    8
    3
    1
    0
    0
    1
    Lymphoedema
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    5
    3
    0
    0
    1
    2
    Peripheral coldness
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Poor peripheral circulation
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    37 / 89 (41.57%)
    25 / 79 (31.65%)
    10 / 21 (47.62%)
    6 / 11 (54.55%)
    12 / 42 (28.57%)
    6 / 19 (31.58%)
         occurrences all number
    69
    36
    20
    7
    21
    6
    Injection site pain
         subjects affected / exposed
    10 / 89 (11.24%)
    10 / 79 (12.66%)
    3 / 21 (14.29%)
    3 / 11 (27.27%)
    4 / 42 (9.52%)
    2 / 19 (10.53%)
         occurrences all number
    10
    11
    3
    6
    4
    3
    Pyrexia
         subjects affected / exposed
    13 / 89 (14.61%)
    2 / 79 (2.53%)
    4 / 21 (19.05%)
    0 / 11 (0.00%)
    5 / 42 (11.90%)
    1 / 19 (5.26%)
         occurrences all number
    18
    3
    4
    0
    6
    2
    Mucosal inflammation
         subjects affected / exposed
    9 / 89 (10.11%)
    2 / 79 (2.53%)
    4 / 21 (19.05%)
    0 / 11 (0.00%)
    6 / 42 (14.29%)
    1 / 19 (5.26%)
         occurrences all number
    14
    2
    6
    0
    9
    1
    Oedema peripheral
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 79 (5.06%)
    6 / 21 (28.57%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    0 / 19 (0.00%)
         occurrences all number
    7
    5
    7
    0
    3
    0
    Chest pain
         subjects affected / exposed
    2 / 89 (2.25%)
    7 / 79 (8.86%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    3 / 19 (15.79%)
         occurrences all number
    2
    8
    0
    0
    2
    3
    Asthenia
         subjects affected / exposed
    4 / 89 (4.49%)
    4 / 79 (5.06%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    2 / 19 (10.53%)
         occurrences all number
    4
    5
    1
    0
    2
    2
    Pain
         subjects affected / exposed
    4 / 89 (4.49%)
    4 / 79 (5.06%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    2 / 42 (4.76%)
    0 / 19 (0.00%)
         occurrences all number
    4
    4
    2
    2
    3
    0
    Chills
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 79 (1.27%)
    3 / 21 (14.29%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 19 (0.00%)
         occurrences all number
    3
    1
    4
    0
    2
    0
    Injection site bruising
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Cyst
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 89 (2.25%)
    4 / 79 (5.06%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    4
    1
    0
    0
    0
    Breast discomfort
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 89 (16.85%)
    12 / 79 (15.19%)
    4 / 21 (19.05%)
    3 / 11 (27.27%)
    6 / 42 (14.29%)
    2 / 19 (10.53%)
         occurrences all number
    20
    18
    5
    3
    6
    2
    Dyspnoea
         subjects affected / exposed
    9 / 89 (10.11%)
    8 / 79 (10.13%)
    4 / 21 (19.05%)
    1 / 11 (9.09%)
    6 / 42 (14.29%)
    2 / 19 (10.53%)
         occurrences all number
    18
    10
    5
    2
    7
    5
    Oropharyngeal pain
         subjects affected / exposed
    8 / 89 (8.99%)
    4 / 79 (5.06%)
    3 / 21 (14.29%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences all number
    11
    4
    3
    0
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    5 / 89 (5.62%)
    3 / 79 (3.80%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    6
    4
    0
    0
    0
    0
    Pneumonitis
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences all number
    6
    2
    0
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    0
    1
    3
    Hypoxia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 89 (8.99%)
    7 / 79 (8.86%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    2 / 42 (4.76%)
    2 / 19 (10.53%)
         occurrences all number
    16
    9
    1
    1
    2
    4
    Anxiety
         subjects affected / exposed
    3 / 89 (3.37%)
    4 / 79 (5.06%)
    1 / 21 (4.76%)
    2 / 11 (18.18%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    4
    5
    1
    2
    0
    2
    Depression
         subjects affected / exposed
    6 / 89 (6.74%)
    2 / 79 (2.53%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    6
    2
    1
    0
    0
    1
    Depressed mood
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    0
    1
    1
    0
    Mood swings
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 89 (12.36%)
    11 / 79 (13.92%)
    1 / 21 (4.76%)
    2 / 11 (18.18%)
    10 / 42 (23.81%)
    3 / 19 (15.79%)
         occurrences all number
    16
    15
    1
    2
    12
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 89 (8.99%)
    6 / 79 (7.59%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    8 / 42 (19.05%)
    2 / 19 (10.53%)
         occurrences all number
    18
    8
    1
    1
    9
    5
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 89 (6.74%)
    8 / 79 (10.13%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    0 / 19 (0.00%)
         occurrences all number
    9
    16
    0
    0
    3
    0
    Weight decreased
         subjects affected / exposed
    7 / 89 (7.87%)
    3 / 79 (3.80%)
    3 / 21 (14.29%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    8
    6
    4
    0
    3
    1
    Blood cholesterol increased
         subjects affected / exposed
    1 / 89 (1.12%)
    4 / 79 (5.06%)
    0 / 21 (0.00%)
    2 / 11 (18.18%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    2
    5
    0
    3
    2
    1
    Lipase increased
         subjects affected / exposed
    3 / 89 (3.37%)
    3 / 79 (3.80%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    4
    0
    1
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    3 / 89 (3.37%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    5
    0
    2
    0
    1
    2
    Blood creatinine increased
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 79 (1.27%)
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    5
    0
    0
    0
    1
    1
    Weight increased
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    0
    2
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Blood triglycerides increased
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    5
    0
    0
    0
    0
    1
    Blood alkaline phosphatase
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 89 (2.25%)
    3 / 79 (3.80%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    4
    3
    0
    0
    2
    1
    Tooth fracture
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Excoriation
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    36 / 89 (40.45%)
    3 / 79 (3.80%)
    3 / 21 (14.29%)
    2 / 11 (18.18%)
    13 / 42 (30.95%)
    3 / 19 (15.79%)
         occurrences all number
    46
    6
    4
    2
    13
    3
    Headache
         subjects affected / exposed
    16 / 89 (17.98%)
    10 / 79 (12.66%)
    7 / 21 (33.33%)
    5 / 11 (45.45%)
    9 / 42 (21.43%)
    3 / 19 (15.79%)
         occurrences all number
    21
    13
    12
    6
    12
    4
    Dizziness
         subjects affected / exposed
    8 / 89 (8.99%)
    7 / 79 (8.86%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    5 / 42 (11.90%)
    1 / 19 (5.26%)
         occurrences all number
    10
    10
    1
    2
    6
    1
    Paraesthesia
         subjects affected / exposed
    3 / 89 (3.37%)
    3 / 79 (3.80%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    1 / 19 (5.26%)
         occurrences all number
    4
    4
    2
    1
    5
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    1
    3
    0
    0
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    Lethargy
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Memory impairment
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    Hyperaesthesia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hypokinesia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 89 (6.74%)
    7 / 79 (8.86%)
    1 / 21 (4.76%)
    2 / 11 (18.18%)
    1 / 42 (2.38%)
    2 / 19 (10.53%)
         occurrences all number
    8
    10
    1
    5
    3
    3
    Thrombocytopenia
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    4
    0
    1
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 89 (1.12%)
    5 / 79 (6.33%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences all number
    2
    7
    0
    0
    1
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 79 (3.80%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    5
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    1
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 89 (0.00%)
    4 / 79 (5.06%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    Eye irritation
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Eye disorder
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    59 / 89 (66.29%)
    12 / 79 (15.19%)
    14 / 21 (66.67%)
    2 / 11 (18.18%)
    29 / 42 (69.05%)
    8 / 19 (42.11%)
         occurrences all number
    119
    17
    23
    3
    104
    9
    Nausea
         subjects affected / exposed
    50 / 89 (56.18%)
    23 / 79 (29.11%)
    17 / 21 (80.95%)
    4 / 11 (36.36%)
    19 / 42 (45.24%)
    6 / 19 (31.58%)
         occurrences all number
    87
    27
    23
    6
    26
    11
    Vomiting
         subjects affected / exposed
    25 / 89 (28.09%)
    11 / 79 (13.92%)
    6 / 21 (28.57%)
    1 / 11 (9.09%)
    10 / 42 (23.81%)
    2 / 19 (10.53%)
         occurrences all number
    34
    15
    8
    1
    13
    8
    Constipation
         subjects affected / exposed
    14 / 89 (15.73%)
    12 / 79 (15.19%)
    6 / 21 (28.57%)
    2 / 11 (18.18%)
    3 / 42 (7.14%)
    6 / 19 (31.58%)
         occurrences all number
    18
    14
    7
    2
    3
    7
    Stomatitis
         subjects affected / exposed
    17 / 89 (19.10%)
    2 / 79 (2.53%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    5 / 42 (11.90%)
    0 / 19 (0.00%)
         occurrences all number
    22
    2
    2
    1
    7
    0
    Abdominal pain
         subjects affected / exposed
    10 / 89 (11.24%)
    6 / 79 (7.59%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    3 / 19 (15.79%)
         occurrences all number
    13
    6
    2
    1
    5
    6
    Dyspepsia
         subjects affected / exposed
    11 / 89 (12.36%)
    2 / 79 (2.53%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    2 / 19 (10.53%)
         occurrences all number
    14
    4
    1
    1
    4
    2
    Dry mouth
         subjects affected / exposed
    8 / 89 (8.99%)
    6 / 79 (7.59%)
    3 / 21 (14.29%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 19 (0.00%)
         occurrences all number
    8
    6
    4
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 89 (3.37%)
    6 / 79 (7.59%)
    3 / 21 (14.29%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    1 / 19 (5.26%)
         occurrences all number
    5
    7
    5
    0
    3
    2
    Abdominal pain upper
         subjects affected / exposed
    7 / 89 (7.87%)
    5 / 79 (6.33%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    8
    6
    0
    0
    3
    1
    Mouth ulceration
         subjects affected / exposed
    6 / 89 (6.74%)
    1 / 79 (1.27%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    4 / 42 (9.52%)
    1 / 19 (5.26%)
         occurrences all number
    6
    1
    1
    0
    4
    1
    Abdominal distension
         subjects affected / exposed
    4 / 89 (4.49%)
    3 / 79 (3.80%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    5
    3
    0
    0
    0
    4
    Flatulence
         subjects affected / exposed
    2 / 89 (2.25%)
    3 / 79 (3.80%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    3
    3
    1
    0
    1
    1
    Gingival pain
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    Oral pain
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 79 (1.27%)
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    Ascites
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Eructation
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Gingival bleeding
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tongue ulceration
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    22 / 89 (24.72%)
    8 / 79 (10.13%)
    14 / 21 (66.67%)
    1 / 11 (9.09%)
    16 / 42 (38.10%)
    1 / 19 (5.26%)
         occurrences all number
    68
    8
    29
    1
    31
    1
    Pruritus
         subjects affected / exposed
    9 / 89 (10.11%)
    8 / 79 (10.13%)
    7 / 21 (33.33%)
    0 / 11 (0.00%)
    7 / 42 (16.67%)
    3 / 19 (15.79%)
         occurrences all number
    22
    12
    13
    0
    9
    3
    Rash maculo−papular
         subjects affected / exposed
    14 / 89 (15.73%)
    2 / 79 (2.53%)
    4 / 21 (19.05%)
    0 / 11 (0.00%)
    6 / 42 (14.29%)
    0 / 19 (0.00%)
         occurrences all number
    24
    2
    13
    0
    19
    0
    Dry skin
         subjects affected / exposed
    9 / 89 (10.11%)
    3 / 79 (3.80%)
    4 / 21 (19.05%)
    0 / 11 (0.00%)
    6 / 42 (14.29%)
    0 / 19 (0.00%)
         occurrences all number
    11
    4
    4
    0
    6
    0
    Alopecia
         subjects affected / exposed
    10 / 89 (11.24%)
    3 / 79 (3.80%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    4 / 42 (9.52%)
    0 / 19 (0.00%)
         occurrences all number
    12
    3
    0
    0
    4
    0
    Erythema
         subjects affected / exposed
    3 / 89 (3.37%)
    2 / 79 (2.53%)
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    2
    2
    0
    0
    0
    Night sweats
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    7
    0
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    0
    0
    1
    2
    Pain of skin
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    0
    1
    0
    1
    Pruritus generalised
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    0
    Skin mass
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Trichorrhexis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 89 (13.48%)
    22 / 79 (27.85%)
    3 / 21 (14.29%)
    2 / 11 (18.18%)
    9 / 42 (21.43%)
    4 / 19 (21.05%)
         occurrences all number
    13
    28
    5
    2
    12
    7
    Back pain
         subjects affected / exposed
    10 / 89 (11.24%)
    15 / 79 (18.99%)
    2 / 21 (9.52%)
    2 / 11 (18.18%)
    7 / 42 (16.67%)
    3 / 19 (15.79%)
         occurrences all number
    18
    18
    2
    3
    11
    4
    Pain in extremity
         subjects affected / exposed
    6 / 89 (6.74%)
    16 / 79 (20.25%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    3 / 42 (7.14%)
    4 / 19 (21.05%)
         occurrences all number
    8
    21
    2
    2
    5
    6
    Bone pain
         subjects affected / exposed
    12 / 89 (13.48%)
    10 / 79 (12.66%)
    1 / 21 (4.76%)
    2 / 11 (18.18%)
    2 / 42 (4.76%)
    4 / 19 (21.05%)
         occurrences all number
    15
    14
    1
    3
    3
    4
    Myalgia
         subjects affected / exposed
    8 / 89 (8.99%)
    7 / 79 (8.86%)
    3 / 21 (14.29%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    2 / 19 (10.53%)
         occurrences all number
    12
    8
    3
    1
    4
    2
    Muscle spasms
         subjects affected / exposed
    12 / 89 (13.48%)
    4 / 79 (5.06%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    1 / 19 (5.26%)
         occurrences all number
    17
    4
    0
    1
    6
    3
    Musculoskeletal pain
         subjects affected / exposed
    3 / 89 (3.37%)
    8 / 79 (10.13%)
    0 / 21 (0.00%)
    2 / 11 (18.18%)
    3 / 42 (7.14%)
    3 / 19 (15.79%)
         occurrences all number
    3
    10
    0
    2
    3
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 89 (5.62%)
    5 / 79 (6.33%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    6
    7
    0
    1
    1
    1
    Neck pain
         subjects affected / exposed
    4 / 89 (4.49%)
    1 / 79 (1.27%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    2 / 19 (10.53%)
         occurrences all number
    5
    1
    1
    1
    2
    3
    Muscular weakness
         subjects affected / exposed
    2 / 89 (2.25%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences all number
    2
    2
    0
    1
    1
    0
    Flank pain
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    8
    1
    0
    0
    0
    1
    Arthritis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Muscle twitching
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    11 / 89 (12.36%)
    5 / 79 (6.33%)
    3 / 21 (14.29%)
    2 / 11 (18.18%)
    3 / 42 (7.14%)
    1 / 19 (5.26%)
         occurrences all number
    13
    6
    3
    2
    3
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 79 (6.33%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    3 / 19 (15.79%)
         occurrences all number
    3
    6
    7
    2
    2
    4
    Nasopharyngitis
         subjects affected / exposed
    4 / 89 (4.49%)
    5 / 79 (6.33%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    5 / 42 (11.90%)
    0 / 19 (0.00%)
         occurrences all number
    5
    7
    0
    0
    5
    0
    Sinusitis
         subjects affected / exposed
    2 / 89 (2.25%)
    4 / 79 (5.06%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    2
    8
    0
    0
    3
    1
    Bronchitis
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 79 (2.53%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    2 / 42 (4.76%)
    0 / 19 (0.00%)
         occurrences all number
    1
    2
    2
    1
    2
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 79 (1.27%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    4
    2
    1
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    0
    2
    1
    Rhinitis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 79 (1.27%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 89 (25.84%)
    11 / 79 (13.92%)
    7 / 21 (33.33%)
    2 / 11 (18.18%)
    11 / 42 (26.19%)
    4 / 19 (21.05%)
         occurrences all number
    33
    12
    12
    2
    12
    4
    Hyperglycaemia
         subjects affected / exposed
    15 / 89 (16.85%)
    6 / 79 (7.59%)
    3 / 21 (14.29%)
    0 / 11 (0.00%)
    12 / 42 (28.57%)
    0 / 19 (0.00%)
         occurrences all number
    33
    17
    3
    0
    25
    0
    Hypokalaemia
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 79 (5.06%)
    3 / 21 (14.29%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    5
    5
    3
    0
    1
    1
    Dehydration
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 79 (1.27%)
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    5
    1
    2
    0
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    4 / 79 (5.06%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 19 (5.26%)
         occurrences all number
    0
    8
    1
    0
    1
    2
    Hypercalcaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    3 / 79 (3.80%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 19 (5.26%)
         occurrences all number
    0
    3
    0
    0
    2
    3
    Hypocalcaemia
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 79 (0.00%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    4
    0
    1
    1
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    2 / 19 (10.53%)
         occurrences all number
    0
    5
    0
    0
    2
    3
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 79 (2.53%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 42 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 79 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2012
    Protocol Amendment 2 included the following changes: halted enrollment in the apitolisib /matching placebo arm of the study due to an unacceptably high rate of Grade 3 rash; added two additional study arms to examine the safety and tolerability and to estimate the effect of pictilisib at a dose of 260 mg, once daily, in combination with fulvestrant versus fulvestrant + placebo in subjects who received prior treatment with an aromatase inhibitor and whose tumors had a PIK3CA mutation.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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