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    Clinical Trial Results:
    A Phase 3 Clinical Study to Investigate the Prevention of Relapse in Lymphoma Using Daily Enzastaurin

    Summary
    EudraCT number
    		 2005-004630-41
    Trial protocol
    		 SE   HU   ES   DK   BE   PT   DE   GR   IT   GB   CZ   FI  
    Global end of trial date
    31 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jun 2018
    First version publication date
    15 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H6Q-MC-JCBJ
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00332202
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number : 9823
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-CTLilly,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-285-4559,
    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
    31 Jul 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objective: To compare maintenance therapy with enzastaurin versus placebo, in terms of the overall disease-free survival (DFS) time in patients with DLBCL in first remission with high risk of relapse (initial IPI score ≥3) following R-CHOP using a 14- or 21-day
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 May 2006
    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
    Portugal: 8
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Sweden: 24
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Denmark: 13
    Country: Number of subjects enrolled
    Finland: 16
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Australia: 29
    Country: Number of subjects enrolled
    Brazil: 18
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    China: 25
    Country: Number of subjects enrolled
    India: 33
    Country: Number of subjects enrolled
    Korea, Republic of: 58
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Puerto Rico: 4
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Taiwan: 32
    Country: Number of subjects enrolled
    United States: 186
    Country: Number of subjects enrolled
    Japan: 87
    Worldwide total number of subjects
    758
    EEA total number of subjects
    224
    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)
    404
    From 65 to 84 years
    348
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 No text entered

    Pre-assignment
    Screening details
    		 No text entered

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Enzastaurin: Arm A - Experimental
    Arm description
    		 Enzastaurin 500 milligram (mg) administered orally (PO) each day (QD) after an initial loading dose of 1125 mg on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enzastaurin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1125 mg enzastaurin loading dose given oral (PO on Day 1), then 500 mg enzastaurin given PO daily (QD) until disease progression or maximum of 3 years.

    Arm title
    		 Placebo: Arm B - Control
    Arm description
    		 Placebo administered PO QD after an initial loading dose of placebo on Day 1.
    Arm type
    		 Control

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered PO QD after an initial loading dose of placebo on Day 1.

    Number of subjects in period 1
    		Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Started
    504
    254
    Received At Least One Dose of Study Drug
    493
    249
    Completed
    263
    129
    Not completed
    241
    125
         Physician decision
    6
    8
         Protocol entry criteria not met
    6
    5
         Consent withdrawn by subject
    36
    17
         Adverse event, non-fatal
    72
    28
         Protocol violation
    7
    2
         Death
    5
    2
         Lost to follow-up
    2
    1
         Sponsor decision
    1
    2
         Progressive disease
    106
    60

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enzastaurin: Arm A - Experimental
    Reporting group description
    		 Enzastaurin 500 milligram (mg) administered orally (PO) each day (QD) after an initial loading dose of 1125 mg on Day 1.

    Reporting group title
    Placebo: Arm B - Control
    Reporting group description
    		 Placebo administered PO QD after an initial loading dose of placebo on Day 1.

    Reporting group values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control Total
    Number of subjects
    		 504 254 758
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.19 ( 13.13 ) 62.65 ( 12.09 ) -
    Gender categorical
    Units: Subjects
        Female
    		 245 105 350
        Male
    		 259 149 408
    Region of Enrollment
    Units: Subjects
        Australia
    		 20 9 29
        Belgium
    		 10 4 14
        Brazil
    		 13 5 18
        Canada
    		 24 16 40
        China
    		 18 7 25
        Czech Republic
    		 6 2 8
        Germany
    		 15 10 25
        Denmark
    		 9 4 13
        Spain
    		 20 5 25
        Finland
    		 11 5 16
        France
    		 22 10 32
        Greece
    		 2 2 4
        Hungary
    		 4 2 6
        India
    		 22 11 33
        Italy
    		 15 10 25
        Japan
    		 54 33 87
        Korea, Republic of
    		 37 21 58
        Mexico
    		 13 9 22
        Poland
    		 9 7 16
        Puerto Rico
    		 3 1 4
        Portugal
    		 5 3 8
        Sweden
    		 19 5 24
        Taiwan
    		 24 8 32
        United Kingdom
    		 4 4 8
        United States
    		 125 61 186
    Race/Ethnicity, Customized
    Units: Subjects
        African
    		 5 2 7
        Caucasian
    		 309 155 464
        East Asian
    		 144 73 217
        Hispanic
    		 24 13 37
        Native American
    		 1 0 1
        West Asian (Indian sub-continent)
    		 21 11 32

    End points

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    End points reporting groups
    Reporting group title
    Enzastaurin: Arm A - Experimental
    Reporting group description
    		 Enzastaurin 500 milligram (mg) administered orally (PO) each day (QD) after an initial loading dose of 1125 mg on Day 1.

    Reporting group title
    Placebo: Arm B - Control
    Reporting group description
    		 Placebo administered PO QD after an initial loading dose of placebo on Day 1.

    Subject analysis set title
    Germinal-center B-cells
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Reported are the DFS based on DLBCL molecular subtypes. DLBCL molecular subtypes of GCB/non-GCB using Hans' algorithm were determined by protein expression by immunohistochemistry (IHC) of cluster differentiation 10 (CD10), B-cell/lymphoma 6 (BCL6) and multiple myeloma oncogene 1 (MUM1) for percent of tumor cells stained, and using 30% positive staining as the cutoff for positive/negative. Analysis Population Description: All randomized participants for which a pre-treatment tumor tissue was provided and had evaluable samples.

    Subject analysis set title
    Non-germinal-center B-cells
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Reported are the DFS based on DLBCL molecular subtypes. DLBCL molecular subtypes of GCB/non-GCB using Hans' algorithm were determined by protein expression by immunohistochemistry (IHC) of cluster differentiation 10 (CD10), B-cell/lymphoma 6 (BCL6) and multiple myeloma oncogene 1 (MUM1) for percent of tumor cells stained, and using 30% positive staining as the cutoff for positive/negative. Analysis Population Description: All randomized participants for which a pre-treatment tumor tissue was provided and had evaluable samples.

    Subject analysis set title
    PKC-β2 Cytoplasm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Reported are the DFS based on PKC-β2 protein expression. Immunohistochemistry (IHC) staining was performed to assess protein expression of PKC-β2 in cytoplasm scored for percent of tumor cells stained, and using 50% positive staining as the cutoff for high/low expression (high expression: >=50% staining, low expression: <50% staining). Analysis Population Definition: All randomized participants for which a pre-treatment tumor tissue was provided and had evaluable samples.

    Subject analysis set title
    Total Enzastaurin Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Analysis Population Description: All participants who received at least one dose of the study drug and had evaluable PK data.

    Primary: Overall Disease-Free Survival

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    End point title
    		 Overall Disease-Free Survival
    End point description
    Overall Disease-Free Survival (DFS) time is defined as the time from the date of study enrollment to the first date of objectively determined disease recurrence (progressive disease) or death from any cause. DFS was assessed according to International Working Group recommendations (Cheson et al. 1999). Progressive disease (PD) is defined as a ≥ 50% increase from the lowest point in the sum of the product of the diameters (SPD) of any previously identified abnormal node for partial or nonresponders, or the appearance of any new lesion during or at the end of therapy. Analysis Population Description: All randomized participants. DFS is censored at the last assessable disease free assessment for participants who are alive or have not progressed. The number of censored participant data for enzastaurin and placebo is 369 (73.2%) and 180 (70.9%), respectively.
    End point type
    Primary
    End point timeframe
    Baseline to Measured Progressive Disease or Death from Any Cause (up to 80.30 months)
    End point values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Number of subjects analysed
    504 [1]
    254 [2]
    Units: Month
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [1] - Median, the upper & lower 95% confidence interval were not estimable due to high rate of censoring.
    [2] - Median, the upper & lower 95% confidence interval were not estimable due to high rate of censoring.
    Statistical analysis title
    		 Overall Disease-Free Survival
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.541
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.689
         upper limit
    		 1.216

    Secondary: Disease Free Survival at 2 Years

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    End point title
    		 Disease Free Survival at 2 Years
    End point description
    Disease-free survival at 2 years (DFS2) is defined as the rate of DFS at 2 years from the date of study enrollment and is determined using the distribution of overall DFS times. Disease-free survival rates at 2 years will be estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Baseline to 2 Years
    End point values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Number of subjects analysed
    504 [3]
    254 [4]
    Units: Rate
        number (confidence interval 95%)
    0.785 (0.745 to 0.819)
    0.748 (0.687 to 0.798)
    Notes
    [3] - All randomized participants.
    [4] - All randomized participants.
    No statistical analyses for this end point

    Secondary: Event-Free Survival

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    End point title
    		 Event-Free Survival
    End point description
    Overall Event-Free Survival (EFS) time is defined as the time from the date of study enrollment to the first date of objectively determined disease recurrence (progressive disease), institution of a new anti-cancer treatment, or death from any cause. Progressive disease (PD) is defined as a ≥ 50% increase from the lowest point in the sum of the product of the diameters (SPD) of any previously identified abnormal node for partial or nonresponders, or the appearance of any new lesion during or at the end of therapy. Analysis Population Description: All randomized participants. EFS is censored at the last assessable disease-free assessment for participants who are alive, have not progressed or started new anticancer treatment. The number of censored participant data for enzastaurin and placebo is 364 (72.2%) and 176 (69.3%), respectively.
    End point type
    Secondary
    End point timeframe
    Baseline to Objective PD, Start of New Therapy or Death From Any Cause (up to 76.81 months)
    End point values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Number of subjects analysed
    504 [5]
    254 [6]
    Units: Month
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [5] - Median, the upper & lower 95% confidence interval were not estimable due to high rate of censoring.
    [6] - Median, the upper & lower 95% confidence interval were not estimable due to high rate of censoring.
    Statistical analysis title
    		 Event-Free Survival
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.683
         upper limit
    		 1.188

    Secondary: Event-Free Survival at 2 Years

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    End point title
    		 Event-Free Survival at 2 Years
    End point description
    Event-Free Survival at 2 years (EFS2) is defined as the rate of EFS at 2 years from the date of study enrollment and is determined using the distribution of overall EFS times. Event-free survival rates at 2 years will be estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Baseline to 2 Years
    End point values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Number of subjects analysed
    504 [7]
    254 [8]
    Units: Rate
        number (confidence interval 95%)
    0.781 (0.741 to 0.816)
    0.734 (0.673 to 0.785)
    Notes
    [7] - All randomized participants.
    [8] - All randomized participants.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival (OS) time is defined as the time from the date of study enrollment to the date of death from any cause. Analysis Population Description: All randomized participants. Overall survival is censored at the last date of contact for participants who have no reported death. The number of censored participant data for enzastaurin and placebo is 404 (80.2%) and 205 (80.7%), respectively.
    End point type
    Secondary
    End point timeframe
    Baseline to Date of Death from Any Cause (up to 80.30 months)
    End point values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Number of subjects analysed
    504 [9]
    254 [10]
    Units: Month
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [9] - Median, the upper & lower 95% confidence interval were not estimable due to high rate of censoring.
    [10] - Median, the upper & lower 95% confidence interval were not estimable due to high rate of censoring.
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    Placebo: Arm B - Control v Enzastaurin: Arm A - Experimental
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.807
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.741
         upper limit
    		 1.468

    Secondary: Number of Participants With Treatment-Emergent Adverse Events

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events
    End point description
    Number of treatment-emergent adverse events occurring in at least 10% of participants regardless of causality.
    End point type
    Secondary
    End point timeframe
    First dose through 30 days post-study treatment discontinuation (up to 81.30 months)
    End point values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Number of subjects analysed
    493 [11]
    249 [12]
    Units: Participants
        number (not applicable)
    459
    230
    Notes
    [11] - All randomized participants who received at least one dose of study drug.
    [12] - All randomized participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Quality of Life: Change From Baseline in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Score

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    End point title
    		 Quality of Life: Change From Baseline in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Score
    End point description
    The FACT-Lym (Cella et al. 2005) assesses health-related quality of life (HRQoL) in participants with non-Hodgkin lymphoma. It includes the 27-item cancer-specific FACT-G (General), which assesses physical, social/family, emotional and functional well-being, plus a 15-item subscale that assesses concerns specific to lymphoma. Each item is scored on a scale from 0 (not at all) to 4 (very much), yielding a possible score of 0-168, with higher scores representing better HRQoL. This analysis utilized mixed-effect model repeated measure (MMRM) analysis of change from baseline adjusting for baseline covariates. Analysis Population Description: All randomized participants who completed at least one FACT-Lym assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2; Baseline, Month 4; Baseline, Month 6; Baseline, Month 12; Baseline, Month 18; Baseline, Month 24; Baseline, Month 36
    End point values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Number of subjects analysed
    348
    189
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Month 2
    2.45 ( 0.67 )
    1.86 ( 0.93 )
        Month 4
    2.56 ( 0.8 )
    2.51 ( 1.06 )
        Month 6
    2.04 ( 0.87 )
    2.82 ( 1.1 )
        Month 12
    3.85 ( 0.87 )
    2.11 ( 1.29 )
        Month 18
    2.87 ( 0.89 )
    1.73 ( 1.26 )
        Month 24
    2.72 ( 0.99 )
    3.96 ( 1.26 )
        Month 36
    2.54 ( 1.13 )
    4.22 ( 1.43 )
    Statistical analysis title
    		 FACT-Lym Score Month 2
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.606
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 FACT-Lym Score Month 4
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.971
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Fact-Lym Score Month 6
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 FACT-Lym Score Month 12
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.265
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 FACT-Lym Score Month 18
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 FACT-Lym Score Month 24
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.441
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 FACT-Lym Score Month 36
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.357
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change From Baseline in EuroQol-5D (EQ-5D) Score

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    End point title
    		 Change From Baseline in EuroQol-5D (EQ-5D) Score
    End point description
    The EQ-5D instrument is a participant-rated questionnaire used to evaluate health status. The EQ-5D assesses five dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression) that participants rate using three levels (no problem, some problem, or extreme problem), as well as overall health status. The five dimensions can be combined using country-specific weights to create an estimate of overall health status. This analysis utilized mixed-effect model repeated measure (MMRM) analysis of change from baseline in the EQ-5D for the United Kingdom population-based index score adjusting for baseline covariates.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6; Baseline, Month 24; Baseline, Month 33
    End point values
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Number of subjects analysed
    346 [13]
    187 [14]
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Month 6
    0.02 ( 0.01 )
    0 ( 0.01 )
        Month 24
    0.02 ( 0.01 )
    0.03 ( 0.02 )
        Month 33
    0.03 ( 0.01 )
    0.03 ( 0.01 )
    Notes
    [13] - All randomized participants who completed at least one EQ-5D assessment.
    [14] - All randomized participants who completed at least one EQ-5D assessment.
    Statistical analysis title
    		 EuroQol-5D Score Month 6
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.267
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 EuroQol-5D Score Month 24
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.807
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 EuroQol-5D Score Month 33
    Comparison groups
    Enzastaurin: Arm A - Experimental v Placebo: Arm B - Control
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.864
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Translational Research: DFS of Participants With Diffuse Large B-cell Lymphoma (DLBCL) Germinal-center B-cells (GCB) Versus Non-GCB Molecular Subtypes

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    End point title
    		 Translational Research: DFS of Participants With Diffuse Large B-cell Lymphoma (DLBCL) Germinal-center B-cells (GCB) Versus Non-GCB Molecular Subtypes
    End point description
    Reported are the DFS based on DLBCL molecular subtypes. DLBCL molecular subtypes of GCB/non-GCB using Hans' algorithm were determined by protein expression by immunohistochemistry (IHC) of cluster differentiation 10 (CD10), B-cell/lymphoma 6 (BCL6) and multiple myeloma oncogene 1 (MUM1) for percent of tumor cells stained, and using 30% positive staining as the cutoff for positive/negative. Analysis Population Description: All randomized participants for which a pre-treatment tumor tissue was provided and had evaluable samples.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Germinal-center B-cells Non-germinal-center B-cells
    Number of subjects analysed
    109
    106
    Units: Participants
        number (not applicable)
    109
    106
    Statistical analysis title
    		 Germinal-center versus Non-germinal-center B-cells
    Comparison groups
    Germinal-center B-cells v Non-germinal-center B-cells
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.74
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.52
    Notes
    [15] - Cox regression of DFS (for the combined treatment arm) for DLBCL molecular subtypes as a function of molecular subtype, treatment, adjusting for covariates of International Prognostic Index (IPI) score (<=3 vs. >3), age (<=60 vs. > 60) and Prior Radiation (yes vs. no).

    Secondary: Translational Research: DFS of Participants With Diffuse Large B-cell Lymphoma (DLBCL) Protein Kinase C-β2 (PKC-β2) Expression

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    End point title
    		 Translational Research: DFS of Participants With Diffuse Large B-cell Lymphoma (DLBCL) Protein Kinase C-β2 (PKC-β2) Expression
    End point description
    Reported are the DFS based on PKC-β2 protein expression. Immunohistochemistry (IHC) staining was performed to assess protein expression of PKC-β2 in cytoplasm scored for percent of tumor cells stained, and using 50% positive staining as the cutoff for high/low expression (high expression: >=50% staining, low expression: <50% staining). Analysis Population Description: All randomized participants for which a pre-treatment tumor tissue was provided and had evaluable samples. Statistical Analysis: The PKC-β2 Cytoplasm expression summary statistics is reported as the combined Enzastaurin and Placebo reporting groups for which an evaluable pre-treatment tumor tissue sample was provided. Although the statistical analysis has been performed, it is not reported here as at least two comparison groups are required.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 PKC-β2 Cytoplasm
    Number of subjects analysed
    227 [16]
    Units: Participants
    number (not applicable)
        High Cytoplasmic Expression
    60
        Low Cytoplasmic Expression
    167
    Notes
    [16] - PKC-B2 stats analysis performed on combined tx arms, however requires 2 comparison groups to report.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Average Steady-State Concentration (Cavg,ss) for Total Analyte

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    End point title
    		 Pharmacokinetics: Average Steady-State Concentration (Cavg,ss) for Total Analyte
    End point description
    Analysis Population Description: All participants who received at least one dose of the study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Month 2, Month 4
    End point values
    		 Total Enzastaurin Population
    Number of subjects analysed
    328
    Units: Nanomole/liter (nmol/L)
        geometric mean (geometric coefficient of variation)
    2370 ( 59.9 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    H6Q-MC-JCBJ
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Enzastaurin: Arm A - Experimental
    Reporting group description
    		 Enzastaurin 500 mg administered orally PO QD after an initial loading dose of 1125 mg on Day 1.

    Reporting group title
    Placebo: Arm B - Control
    Reporting group description
    		 Placebo administered PO QD after an initial loading dose of placebo on Day 1.

    Serious adverse events
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    135 / 493 (27.38%)
    72 / 249 (28.92%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    acute myeloid leukaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    basal cell carcinoma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    breast cancer in situ
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebellar tumour
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colon adenoma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colon cancer
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diffuse large b-cell lymphoma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric cancer
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    hepatic cancer metastatic
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypopharyngeal cancer
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    large intestine carcinoma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung neoplasm
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung neoplasm malignant
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multiple myeloma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myelodysplastic syndrome
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ovarian neoplasm
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed [1]
    1 / 239 (0.42%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatic neoplasm
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    prostate cancer
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed [2]
    1 / 254 (0.39%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectal cancer
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    salivary gland adenoma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    squamous cell carcinoma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thyroid neoplasm
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    aortic aneurysm
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    deep vein thrombosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 493 (0.81%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    3 / 21
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    abdominal hernia repair
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anal fissure excision
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    meniscus removal
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal fusion surgery
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chest pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    death
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multi-organ failure
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    multi-organ disorder
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    allergy to arthropod sting
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    contrast media allergy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    prostatic obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed [3]
    1 / 254 (0.39%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    prostatitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed [4]
    1 / 254 (0.39%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute pulmonary oedema
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    asthma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    interstitial lung disease
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung infiltration
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleurisy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 493 (0.61%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    8 / 493 (1.62%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    4 / 23
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    delirium
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    depression
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ejection fraction decreased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    electrocardiogram abnormal
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    electrocardiogram qt prolonged
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 493 (0.61%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    12 / 12
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    acetabulum fracture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ankle fracture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cervical vertebral fracture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    concussion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fall
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hip fracture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lumbar vertebral fracture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    maternal exposure during pregnancy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed [5]
    2 / 239 (0.84%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    radius fracture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    road traffic accident
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal compression fracture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subdural haematoma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tendon rupture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tibia fracture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    acute coronary syndrome
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    angina pectoris
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    angina unstable
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    arrhythmia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial flutter
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrioventricular block complete
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    bradycardia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac arrest
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    cardiac failure
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 493 (0.61%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 16
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac failure chronic
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac failure congestive
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    cardio-respiratory arrest
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cardiomyopathy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 493 (0.61%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    10 / 25
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coronary artery disease
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coronary artery stenosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    left ventricular dysfunction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial ischaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    sick sinus syndrome
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sinus bradycardia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    torsade de pointes
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ventricular fibrillation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ventricular tachycardia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    basal ganglia infarction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebral haemorrhage
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    convulsion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cranial nerve paralysis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysaesthesia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    epilepsy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    grand mal convulsion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoaesthesia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoxic-ischaemic encephalopathy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ischaemic stroke
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    nerve root compression
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neuropathy peripheral
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    posterior reversible encephalopathy syndrome
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sciatica
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 493 (1.22%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tongue paralysis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tonic convulsion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vith nerve paralysis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vocal cord paralysis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 493 (1.01%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    8 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 493 (1.22%)
    3 / 249 (1.20%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    leukopenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lymphadenopathy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 493 (0.61%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    cataract
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    conjunctival haemorrhage
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    eyelid ptosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ophthalmoplegia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    retinal detachment
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    retinal vein occlusion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vision blurred
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain upper
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anal prolapse
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colonic polyp
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 493 (0.61%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysphagia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    food poisoning
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastritis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gingivitis ulcerative
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhoids
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus paralytic
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    inguinal hernia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    jejunal perforation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oral lichen planus
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    11 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatitis acute
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pseudopolyposis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subileus
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    umbilical hernia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    volvulus of small bowel
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholecystitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 493 (0.61%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholecystitis acute
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholelithiasis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 493 (0.81%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic cirrhosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic function abnormal
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    hepatotoxicity
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    dermal cyst
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin fibrosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin ulcer
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    calculus ureteric
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hydronephrosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    incontinence
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oliguria
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure acute
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary retention
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemarthrosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intervertebral disc protrusion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myalgia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neck pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteoarthritis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteolysis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain in extremity
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    plantar fasciitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    abdominal sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    arthritis infective
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    beta haemolytic streptococcal infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchopulmonary aspergillosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchopneumonia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cellulitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cervicitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed [6]
    1 / 239 (0.42%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    clostridium difficile colitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enterocolitis infectious
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enteritis infectious
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    escherichia sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    escherichia urinary tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    helicobacter gastritis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    2 / 249 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic cyst infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatitis b
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    3 / 249 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    hepatitis c
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    herpes zoster
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infectious peritonitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intervertebral discitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lobar pneumonia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myelitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    necrotising fasciitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    neutropenic infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    periodontitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 493 (1.22%)
    7 / 249 (2.81%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    pseudomembranous colitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pseudomonal bacteraemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyelonephritis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    scrub typhus
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 493 (1.01%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    septic shock
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    staphylococcal infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 493 (0.61%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    urosepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    viral upper respiratory tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wound infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 493 (0.00%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 493 (0.20%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoglycaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 493 (0.41%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Enzastaurin: Arm A - Experimental Placebo: Arm B - Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    447 / 493 (90.67%)
    221 / 249 (88.76%)
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    8 / 493 (1.62%)
    13 / 249 (5.22%)
         occurrences all number
    64
    127
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    91 / 493 (18.46%)
    45 / 249 (18.07%)
         occurrences all number
    628
    304
    oedema peripheral
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    63 / 493 (12.78%)
    16 / 249 (6.43%)
         occurrences all number
    370
    84
    pyrexia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    34 / 493 (6.90%)
    16 / 249 (6.43%)
         occurrences all number
    60
    21
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    76 / 493 (15.42%)
    30 / 249 (12.05%)
         occurrences all number
    283
    130
    oropharyngeal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    26 / 493 (5.27%)
    7 / 249 (2.81%)
         occurrences all number
    84
    14
    Psychiatric disorders
    insomnia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    40 / 493 (8.11%)
    13 / 249 (5.22%)
         occurrences all number
    327
    107
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    27 / 493 (5.48%)
    12 / 249 (4.82%)
         occurrences all number
    148
    73
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    29 / 493 (5.88%)
    12 / 249 (4.82%)
         occurrences all number
    191
    52
    electrocardiogram qt prolonged
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    54 / 493 (10.95%)
    11 / 249 (4.42%)
         occurrences all number
    317
    44
    weight increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    24 / 493 (4.87%)
    19 / 249 (7.63%)
         occurrences all number
    194
    149
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    53 / 493 (10.75%)
    21 / 249 (8.43%)
         occurrences all number
    238
    129
    headache
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    49 / 493 (9.94%)
    32 / 249 (12.85%)
         occurrences all number
    295
    189
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    33 / 493 (6.69%)
    13 / 249 (5.22%)
         occurrences all number
    221
    79
    leukopenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    27 / 493 (5.48%)
    11 / 249 (4.42%)
         occurrences all number
    87
    45
    neutropenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    52 / 493 (10.55%)
    26 / 249 (10.44%)
         occurrences all number
    143
    66
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    40 / 493 (8.11%)
    12 / 249 (4.82%)
         occurrences all number
    140
    20
    constipation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    49 / 493 (9.94%)
    20 / 249 (8.03%)
         occurrences all number
    256
    101
    diarrhoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    97 / 493 (19.68%)
    33 / 249 (13.25%)
         occurrences all number
    387
    115
    dry mouth
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    25 / 493 (5.07%)
    5 / 249 (2.01%)
         occurrences all number
    177
    44
    faeces discoloured
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    39 / 493 (7.91%)
    0 / 249 (0.00%)
         occurrences all number
    340
    0
    nausea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    73 / 493 (14.81%)
    38 / 249 (15.26%)
         occurrences all number
    195
    150
    vomiting
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    47 / 493 (9.53%)
    26 / 249 (10.44%)
         occurrences all number
    64
    44
    Skin and subcutaneous tissue disorders
    pruritus
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    51 / 493 (10.34%)
    21 / 249 (8.43%)
         occurrences all number
    329
    104
    rash
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    56 / 493 (11.36%)
    27 / 249 (10.84%)
         occurrences all number
    323
    120
    Renal and urinary disorders
    chromaturia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    96 / 493 (19.47%)
    1 / 249 (0.40%)
         occurrences all number
    916
    13
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    43 / 493 (8.72%)
    28 / 249 (11.24%)
         occurrences all number
    368
    238
    back pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    52 / 493 (10.55%)
    24 / 249 (9.64%)
         occurrences all number
    353
    213
    musculoskeletal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    32 / 493 (6.49%)
    15 / 249 (6.02%)
         occurrences all number
    263
    107
    pain in extremity
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    36 / 493 (7.30%)
    17 / 249 (6.83%)
         occurrences all number
    173
    71
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    37 / 493 (7.51%)
    13 / 249 (5.22%)
         occurrences all number
    112
    34
    upper respiratory tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    42 / 493 (8.52%)
    15 / 249 (6.02%)
         occurrences all number
    80
    47
    urinary tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    27 / 493 (5.48%)
    7 / 249 (2.81%)
         occurrences all number
    93
    13
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    34 / 493 (6.90%)
    14 / 249 (5.62%)
         occurrences all number
    151
    56

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2009
    Amendment E: Protocol has been amended to modify ECG monitoring in response to the US FDA’s recommendation, based on enzastaurin-associated QTc prolongation.
    24 Sep 2012
    Amendment G: Revised database lock, based on agreement from the United States Food and Drug Administration (FDA), to change the primary endpoint from a pre-specified number of events (event-driven) to a fixed cut-off date (time-driven). Due to a slower than originally expected pooled event rate in this study, the protocol has been revised so that the primary analysis of the DFS endpoint will occur at LPET+3 years.

    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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