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    Clinical Trial Results:
    Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs. Placebo in Combination with Capecitabine and Trastuzumab in Patients with Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma (HER2CLIMB)

    Summary
    EudraCT number
    		 2015-002801-12
    Trial protocol
    		 DE   AT   CZ   BE   DK   FR   PT   GB   IT  
    Global end of trial date
    11 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2023
    First version publication date
    18 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ONT-380-206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02614794
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Seagen Inc.
    Sponsor organisation address
    21823 30th Drive S.E., Bothell, United States, 98021
    Public contact
    Chief Medical Officer, Seagen Inc., 1 8554732436, medinfo@seagen.com
    Scientific contact
    Chief Medical Officer, Seagen Inc., 1 8554732436, medinfo@seagen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab on PFS per RECIST 1.1 based on blinded independent central review (BICR)
    Protection of trial subjects
    This study was conducted in accordance with applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312 and with International Council on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Essential documents will be retained in accordance with ICH GCP.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jan 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 331
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    United Kingdom: 45
    Country: Number of subjects enrolled
    Australia: 39
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Denmark: 20
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Switzerland: 1
    Worldwide total number of subjects
    612
    EEA total number of subjects
    142
    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)
    496
    From 65 to 84 years
    116
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were screened for eligibility prior to enrollment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tuc+Cap+Tra
    Arm description
    		 Tucatinib in combination with capecitabine & trastuzumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tucatinib
    Investigational medicinal product code
    Other name
    TUKYSA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tucatinib 300 mg orally twice daily (PO BID) every day (Days 1–21) of each 21-day cycle

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion, Powder for solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Trastuzumab loading dose 8 mg/kg IV on Day 1, followed by 6 mg/kg on Day 1 of a 21-day cycle. In instances of subcutaneous (SC) trastuzumab use, a fixed dose of 600 mg was administered without a loading dose.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 1000 mg/m2 PO BID on Days 1–14 of each 21-day cycle.

    Arm title
    		 Pbo+Cap+Tra
    Arm description
    		 Placebo in combination with capecitabine & trastuzumab
    Arm type
    		 Placebo-Controlled Active Comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 1000 mg/m2 PO BID on Days 1–14 of each 21-day cycle.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo PO BID for Days 1-21 of a 21-day cycle

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion, Powder for solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Trastuzumab loading dose 8 mg/kg IV on Day 1, followed by 6 mg/kg on Day 1 of a 21-day cycle. In instances of subcutaneous (SC) trastuzumab use, a fixed dose of 600 mg was administered without a loading dose.

    Number of subjects in period 1
    		Tuc+Cap+Tra Pbo+Cap+Tra
    Started
    410
    202
    Completed
    0
    0
    Not completed
    410
    202
         Adverse event, serious fatal
    258
    151
         Consent withdrawn by subject
    24
    5
         Physician decision
    1
    1
         Hospital closure
    1
    -
         Lost to follow-up
    7
    -
         Study closure by Sponsor
    119
    45

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tuc+Cap+Tra
    Reporting group description
    		 Tucatinib in combination with capecitabine & trastuzumab

    Reporting group title
    Pbo+Cap+Tra
    Reporting group description
    		 Placebo in combination with capecitabine & trastuzumab

    Reporting group values
    		 Tuc+Cap+Tra Pbo+Cap+Tra Total
    Number of subjects
    		 410 202 612
    Age Categorical
    Units: participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 328 168 496
        >=65 years
    		 82 34 116
    Age Continuous
    Units: years
        median (full range (min-max))
    		 55 (22 to 80) 54 (25 to 82) -
    Sex: Female, Male
    Units: participants
        Female
    		 407 200 607
        Male
    		 3 2 5
    Region of Enrollment
    Units: Subjects
        United States
    		 220 111 331
        France
    		 29 17 46
        United Kingdom
    		 33 12 45
        Australia
    		 27 12 39
        Canada
    		 26 12 38
        Spain
    		 19 7 26
        Denmark
    		 13 7 20
        Germany
    		 9 8 17
        Israel
    		 13 3 16
        Belgium
    		 4 6 10
        Italy
    		 6 3 9
        Austria
    		 6 1 7
        Portugal
    		 3 1 4
        Czech Republic
    		 2 1 3
        Switzerland
    		 0 1 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 18 5 23
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 41 14 55
        White
    		 287 157 444
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 64 26 90
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 37 14 51
        Not Hispanic or Latino
    		 362 184 546
        Unknown or Not Reported
    		 11 4 15
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    0=Normal activity; 1=Symptoms but ambulatory; 2=In bed <50% of the time; 3= In bed >50% of the time; 4=100% bedridden; 5=Dead
    Units: Subjects
        0: Normal activity
    		 204 94 298
        1: Symptoms, but ambulatory
    		 206 108 314

    End points

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    End points reporting groups
    Reporting group title
    Tuc+Cap+Tra
    Reporting group description
    		 Tucatinib in combination with capecitabine & trastuzumab

    Reporting group title
    Pbo+Cap+Tra
    Reporting group description
    		 Placebo in combination with capecitabine & trastuzumab

    Primary: Progression-free survival (PFS) per RECIST 1.1 as determined by blinded independent central review (BICR)

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    End point title
    		 Progression-free survival (PFS) per RECIST 1.1 as determined by blinded independent central review (BICR)
    End point description
    Defined as the time from the date of randomization to the date of documented disease progression.
    End point type
    Primary
    End point timeframe
    34.6 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    320
    160
    Units: months
        median (inter-quartile range (Q1-Q3))
    7.8 (4.3 to 17.8)
    5.6 (3.0 to 9.7)
    Statistical analysis title
    		 Progression-Free Survival per BICR
    Statistical analysis description
    The two treatment arms were compared using a stratified, log-rank test controlling for the randomization stratification factors. P-value for this test was calculated using a re-randomization based procedure to reflect the dynamic, hierarchical allocation scheme used for the study randomization. Median PFS and its 95% confidence interval (CI) was provided for two treatment arms. A Cox proportional-hazards model was used to estimate the hazard ratio (HR) and its 95% CI.
    Comparison groups
    Tuc+Cap+Tra v Pbo+Cap+Tra
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.00001
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.71

    Secondary: PFS in patients with brain metastases at baseline using RECIST 1.1 as determined by BICR

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    End point title
    		 PFS in patients with brain metastases at baseline using RECIST 1.1 as determined by BICR
    End point description
    Defined as the time from the date of randomization to the date of documented disease progression.
    End point type
    Secondary
    End point timeframe
    34.6 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    198
    93
    Units: months
        median (inter-quartile range (Q1-Q3))
    7.6 (4.2 to 11.8)
    5.4 (3.0 to 7.5)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) per RECIST 1.1 as determined by BICR

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    End point title
    		 Duration of response (DOR) per RECIST 1.1 as determined by BICR
    End point description
    Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    24.6 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    410
    202
    Units: months
        median (inter-quartile range (Q1-Q3))
    8.3 (4.3 to 12.8)
    6.3 (4.2 to 9.0)
    No statistical analyses for this end point

    Secondary: ORR per RECIST 1.1 as determined by investigator assessment

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    End point title
    		 ORR per RECIST 1.1 as determined by investigator assessment
    End point description
    Defined as achieving a best overall response of confirmed CR or confirmed PR.
    End point type
    Secondary
    End point timeframe
    34.6 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    280
    139
    Units: percentage of participants
        number (confidence interval 95%)
    41.4 (35.6 to 47.4)
    23.0 (16.3 to 30.9)
    No statistical analyses for this end point

    Secondary: Confirmed objective response rate (ORR) per RECIST 1.1 as determined by BICR

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    End point title
    		 Confirmed objective response rate (ORR) per RECIST 1.1 as determined by BICR
    End point description
    Defined as achieving a best overall response of confirmed complete response (CR) or confirmed partial response (PR).
    End point type
    Secondary
    End point timeframe
    34.6 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    273
    137
    Units: percentage of participants
        number (confidence interval 95%)
    40.7 (34.8 to 46.7)
    23.4 (16.6 to 31.3)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) at time of primary analysis

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    End point title
    		 Overall Survival (OS) at time of primary analysis
    End point description
    Defined as time from randomization to death from any cause
    End point type
    Secondary
    End point timeframe
    35.9 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    410
    202
    Units: months
        median (confidence interval 95%)
    21.9 (18.3 to 31.0)
    17.4 (13.6 to 19.9)
    No statistical analyses for this end point

    Secondary: PFS per RECIST 1.1 as determined by investigator assessment at time of primary analysis

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    End point title
    		 PFS per RECIST 1.1 as determined by investigator assessment at time of primary analysis
    End point description
    Defined as the time from the date of randomization to the date of documented disease progression
    End point type
    Secondary
    End point timeframe
    34.6 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    320
    160
    Units: months
        median (inter-quartile range (Q1-Q3))
    7.5 (4.1 to 13.1)
    4.3 (2.7 to 8.4)
    No statistical analyses for this end point

    Secondary: DOR per RECIST 1.1 as determined by investigator assessment

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    End point title
    		 DOR per RECIST 1.1 as determined by investigator assessment
    End point description
    Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    33.2 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    410
    202
    Units: months
        median (inter-quartile range (Q1-Q3))
    7.0 (4.3 to 12.9)
    6.9 (4.1 to 9.6)
    No statistical analyses for this end point

    Secondary: CBR per RECIST 1.1 as determined by investigator assessment

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    End point title
    		 CBR per RECIST 1.1 as determined by investigator assessment
    End point description
    Clinical benefit was defined as achieving stable disease (SD) or non-CR/non-PD for at least 6 months or a best overall response of confirmed CR or confirmed PR.
    End point type
    Secondary
    End point timeframe
    34.6 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    410
    202
    Units: percentage of participants
        number (confidence interval 95%)
    58.0 (53.1 to 62.9)
    37.6 (30.9 to 44.7)
    No statistical analyses for this end point

    Secondary: Clinical benefit rate (CBR) as determined by BICR per RECIST 1.1

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    End point title
    		 Clinical benefit rate (CBR) as determined by BICR per RECIST 1.1
    End point description
    Clinical benefit was defined as achieving stable disease (SD) or non-complete response (CR)/non-progressive disease (PD) for at least 6 months or a best overall response of confirmed CR or confirmed partial response (PR).
    End point type
    Secondary
    End point timeframe
    34.6 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    410
    202
    Units: percentage of participants
        number (confidence interval 95%)
    59.8 (54.8 to 64.5)
    38.1 (31.4 to 45.2)
    No statistical analyses for this end point

    Secondary: Incidence of adverse events (AEs) at time of primary analysis

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    End point title
    		 Incidence of adverse events (AEs) at time of primary analysis
    End point description
    As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.
    End point type
    Secondary
    End point timeframe
    36.1 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    404
    197
    Units: Number of Participants
        Any treatment-emergent AE (TEAE)
    401
    191
        Any Grade 3 or higher TEAE
    223
    96
        Any treatment-emergent serious AE
    104
    53
        TEAE leading to death
    8
    6
    No statistical analyses for this end point

    Secondary: Frequency of dose modifications

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    End point title
    		 Frequency of dose modifications
    End point description
    End point type
    Secondary
    End point timeframe
    35.1 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    404
    197
    Units: Number of Participants
        TEAEs resulting in tuc/pbo dose modification
    220
    81
        TEAEs resulting in tucatinib/placebo dose hold
    216
    80
        TEAEs resulting in tuc/pbo dose reduction
    84
    21
        TEAEs resulting capecitabine dose modification
    313
    122
        TEAEs resulting in capecitabine dose hold
    276
    113
        TEAEs resulting in capecitabine dose reduction
    243
    77
        TEAEs resulting trastuzumab dose modification
    104
    38
        TEAEs resulting in trastuzumab dose hold
    104
    38
    No statistical analyses for this end point

    Secondary: Pharmacokinetic measure: Ctrough of tucatinib

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    End point title
    		 Pharmacokinetic measure: Ctrough of tucatinib [1]
    End point description
    Individual plasma tucatinib concentrations at each sampling time
    End point type
    Secondary
    End point timeframe
    3.5 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK outcomes are intended to evaluate the pharmacokinetics of tucatinib and metabolite ONT-993. Participants in the placebo arm are not included in the end point since they did not receive tucatinib.
    End point values
    		 Tuc+Cap+Tra
    Number of subjects analysed
    373
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 2, Day 1 (Pre-dose)
    246.1 ( 260.9 )
        Cycle 3, Day 1 (Pre-dose)
    227.6 ( 210.8 )
        Cycle 3, Day 1 (Post-dose)
    507.1 ( 357.1 )
        Cycle 4, Day 1 (Pre-dose)
    253.2 ( 236.1 )
        Cycle 5, Day 1 (Pre-dose)
    257.6 ( 286.9 )
        Cycle 6, Day 1 (Pre-dose)
    247.8 ( 225.1 )
    No statistical analyses for this end point

    Secondary: Incidence of health resources utilization

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    End point title
    		 Incidence of health resources utilization
    End point description
    Cumulative incidence of health resource utilization, including length of stay, hospitalizations, and ER visits using the EQ-5D-5L questionnaire.
    End point type
    Secondary
    End point timeframe
    36.1 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    404
    197
    Units: hospitalizations
        Total number of hospitalizations
    143
    75
        Hospitalization for AE
    124
    64
        Planned hospitalization (other than AE)
    10
    6
        Ambulatory Surgery
    3
    0
        Other
    6
    5
    No statistical analyses for this end point

    Secondary: Pharmacokinetic measure: ONT-993

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    End point title
    		 Pharmacokinetic measure: ONT-993 [2]
    End point description
    Individual plasma primary metabolite concentrations at each sampling time
    End point type
    Secondary
    End point timeframe
    3.5 months
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK outcomes are intended to evaluate the pharmacokinetics of tucatinib and metabolite ONT-993. Participants in the placebo arm are not included in the end point since they did not receive tucatinib.
    End point values
    		 Tuc+Cap+Tra
    Number of subjects analysed
    373
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 2, Day 1 (Pre-dose)
    25.5 ( 24.4 )
        Cycle 3, Day 1 (Pre-dose)
    22.6 ( 20.6 )
        Cycle 3, Day 1 (Post-dose)
    47.7 ( 47.2 )
        Cycle 4, Day 1 (Pre-dose)
    25.2 ( 24.3 )
        Cycle 5, Day 1 (Pre-dose)
    24.5 ( 30.6 )
        Cycle 6, Day 1 (Pre-dose)
    20.9 ( 18.0 )
    No statistical analyses for this end point

    Secondary: Incidence of adverse events (AEs) at time of final analysis

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    End point title
    		 Incidence of adverse events (AEs) at time of final analysis
    End point description
    As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.
    End point type
    Secondary
    End point timeframe
    Up to 60.1 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    404
    197
    Units: Number of Participants
        Any treatment-emergent AE (TEAE)
    401
    191
        Any Grade 3 or higher TEAE
    248
    101
        Any treatment-emergent serious AE
    123
    58
        TEAE leading to death
    8
    6
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) at time of final analysis

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    End point title
    		 Overall Survival (OS) at time of final analysis
    End point description
    Defined as time from randomization to death from any cause
    End point type
    Secondary
    End point timeframe
    Up to 60.1 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    410
    202
    Units: months
        median (confidence interval 95%)
    24.7 (21.6 to 28.9)
    19.2 (16.4 to 21.4)
    No statistical analyses for this end point

    Secondary: PFS per RECIST 1.1 as determined by investigator assessment at time of final analysis

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    End point title
    		 PFS per RECIST 1.1 as determined by investigator assessment at time of final analysis
    End point description
    Defined as the time from the date of randomization to the date of documented disease progression
    End point type
    Secondary
    End point timeframe
    Up to 58.0 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    410
    202
    Units: months
        median (inter-quartile range (Q1-Q3))
    7.6 (4.1 to 13.8)
    4.9 (2.7 to 9.0)
    No statistical analyses for this end point

    Secondary: Frequency of dose modifications at time of final analysis

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    End point title
    		 Frequency of dose modifications at time of final analysis
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 60.1 months
    End point values
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Number of subjects analysed
    404
    197
    Units: Number of Participants
        TEAEs resulting in tuc/pbo dose modification
    237
    85
        TEAEs resulting in tucatinib/placebo dose hold
    232
    84
        TEAEs resulting in tuc/pbo dose reduction
    92
    21
        TEAEs resulting capecitabine dose modification
    322
    125
        TEAEs resulting in capecitabine dose hold
    288
    117
        TEAEs resulting in capecitabine dose reduction
    251
    79
        TEAEs resulting trastuzumab dose modification
    117
    41
        TEAEs resulting in trastuzumab dose hold
    117
    41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious Adverse Events, Serious Adverse Events, and All-Cause Mortality were followed for up to 60.1 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Tuc+Cap+Tra
    Reporting group description
    		 Tucatinib in combination with capecitabine & trastuzumab

    Reporting group title
    Pbo+Cap+Tra
    Reporting group description
    		 Placebo in combination with capecitabine & trastuzumab

    Serious adverse events
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Total subjects affected by serious adverse events
         subjects affected / exposed
    124 / 404 (30.69%)
    62 / 197 (31.47%)
         number of deaths (all causes)
    262
    152
         number of deaths resulting from adverse events
    8
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acral lentiginous melanoma
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyogenic granuloma
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vena cava thrombosis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Non-cardiac chest pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden death
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    4 / 404 (0.99%)
    3 / 197 (1.52%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    6 / 197 (3.05%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    6 / 404 (1.49%)
    7 / 197 (3.55%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choking
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    6 / 404 (1.49%)
    3 / 197 (1.52%)
         occurrences causally related to treatment / all
    6 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin I increased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (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 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (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 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (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 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haemothorax
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiovascular disorder
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (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 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cauda equina syndrome
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bell's palsy
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system necrosis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    11 / 404 (2.72%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    3 / 197 (1.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuropathy
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enteritis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    4 / 404 (0.99%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    17 / 404 (4.21%)
    7 / 197 (3.55%)
         occurrences causally related to treatment / all
    14 / 18
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    9 / 404 (2.23%)
    4 / 197 (2.03%)
         occurrences causally related to treatment / all
    8 / 10
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (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 24.1
         subjects affected / exposed
    11 / 404 (2.72%)
    5 / 197 (2.54%)
         occurrences causally related to treatment / all
    8 / 12
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatomyositis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture nonunion
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc compression
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (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 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 404 (0.74%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    8 / 404 (1.98%)
    3 / 197 (1.52%)
         occurrences causally related to treatment / all
    1 / 9
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         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 24.1
         subjects affected / exposed
    4 / 404 (0.99%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Septic shock
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Soft tissue infection
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         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 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    4 / 404 (0.99%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypercalcaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 404 (0.25%)
    4 / 197 (2.03%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tuc+Cap+Tra Pbo+Cap+Tra
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    399 / 404 (98.76%)
    188 / 197 (95.43%)
    Vascular disorders
    Hypertension
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    19 / 404 (4.70%)
    10 / 197 (5.08%)
         occurrences all number
    30
    14
    General disorders and administration site conditions
    Asthenia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    34 / 404 (8.42%)
    15 / 197 (7.61%)
         occurrences all number
    46
    19
    Fatigue
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    193 / 404 (47.77%)
    87 / 197 (44.16%)
         occurrences all number
    265
    108
    Influenza like illness
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    24 / 404 (5.94%)
    6 / 197 (3.05%)
         occurrences all number
    31
    6
    Oedema peripheral
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    46 / 404 (11.39%)
    19 / 197 (9.64%)
         occurrences all number
    52
    25
    Pyrexia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    25 / 404 (6.19%)
    8 / 197 (4.06%)
         occurrences all number
    35
    10
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    28 / 404 (6.93%)
    6 / 197 (3.05%)
         occurrences all number
    32
    6
    Oropharyngeal pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    31 / 404 (7.67%)
    9 / 197 (4.57%)
         occurrences all number
    37
    14
    Cough
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    67 / 404 (16.58%)
    24 / 197 (12.18%)
         occurrences all number
    85
    31
    Dyspnoea
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    53 / 404 (13.12%)
    23 / 197 (11.68%)
         occurrences all number
    60
    27
    Epistaxis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    52 / 404 (12.87%)
    10 / 197 (5.08%)
         occurrences all number
    63
    10
    Psychiatric disorders
    Insomnia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    40 / 404 (9.90%)
    17 / 197 (8.63%)
         occurrences all number
    45
    18
    Investigations
    Alanine aminotransferase increased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    87 / 404 (21.53%)
    13 / 197 (6.60%)
         occurrences all number
    115
    15
    Aspartate aminotransferase increased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    92 / 404 (22.77%)
    23 / 197 (11.68%)
         occurrences all number
    137
    32
    Blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    29 / 404 (7.18%)
    6 / 197 (3.05%)
         occurrences all number
    47
    8
    Blood bilirubin increased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    81 / 404 (20.05%)
    21 / 197 (10.66%)
         occurrences all number
    154
    31
    Blood creatinine increased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    65 / 404 (16.09%)
    3 / 197 (1.52%)
         occurrences all number
    108
    3
    Neutrophil count decreased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    21 / 404 (5.20%)
    6 / 197 (3.05%)
         occurrences all number
    48
    7
    Platelet count decreased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    22 / 404 (5.45%)
    5 / 197 (2.54%)
         occurrences all number
    29
    6
    Weight decreased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    62 / 404 (15.35%)
    12 / 197 (6.09%)
         occurrences all number
    66
    13
    White blood cell count decreased
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    21 / 404 (5.20%)
    10 / 197 (5.08%)
         occurrences all number
    57
    10
    Injury, poisoning and procedural complications
    Fall
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    28 / 404 (6.93%)
    9 / 197 (4.57%)
         occurrences all number
    41
    10
    Nervous system disorders
    Dizziness
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    54 / 404 (13.37%)
    27 / 197 (13.71%)
         occurrences all number
    68
    30
    Dysgeusia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    33 / 404 (8.17%)
    6 / 197 (3.05%)
         occurrences all number
    33
    6
    Headache
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    98 / 404 (24.26%)
    38 / 197 (19.29%)
         occurrences all number
    150
    53
    Paraesthesia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    26 / 404 (6.44%)
    10 / 197 (5.08%)
         occurrences all number
    32
    10
    Peripheral sensory neuropathy
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    53 / 404 (13.12%)
    13 / 197 (6.60%)
         occurrences all number
    65
    17
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    89 / 404 (22.03%)
    24 / 197 (12.18%)
         occurrences all number
    146
    32
    Thrombocytopenia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    27 / 404 (6.68%)
    11 / 197 (5.58%)
         occurrences all number
    41
    15
    Neutropenia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    37 / 404 (9.16%)
    17 / 197 (8.63%)
         occurrences all number
    87
    40
    Eye disorders
    Dry eye
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    23 / 404 (5.69%)
    10 / 197 (5.08%)
         occurrences all number
    25
    10
    Gastrointestinal disorders
    Diarrhoea
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    330 / 404 (81.68%)
    106 / 197 (53.81%)
         occurrences all number
    812
    181
    Dry mouth
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    22 / 404 (5.45%)
    5 / 197 (2.54%)
         occurrences all number
    22
    5
    Gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    25 / 404 (6.19%)
    7 / 197 (3.55%)
         occurrences all number
    27
    7
    Nausea
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    243 / 404 (60.15%)
    87 / 197 (44.16%)
         occurrences all number
    382
    120
    Stomatitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    105 / 404 (25.99%)
    28 / 197 (14.21%)
         occurrences all number
    146
    35
    Vomiting
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    155 / 404 (38.37%)
    49 / 197 (24.87%)
         occurrences all number
    276
    80
    Constipation
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    69 / 404 (17.08%)
    40 / 197 (20.30%)
         occurrences all number
    90
    46
    Abdominal pain upper
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    36 / 404 (8.91%)
    17 / 197 (8.63%)
         occurrences all number
    43
    20
    Abdominal pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    66 / 404 (16.34%)
    32 / 197 (16.24%)
         occurrences all number
    98
    40
    Abdominal distension
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    27 / 404 (6.68%)
    10 / 197 (5.08%)
         occurrences all number
    30
    13
    Dyspepsia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    46 / 404 (11.39%)
    19 / 197 (9.64%)
         occurrences all number
    53
    22
    Hepatobiliary disorders
    Hyperbilirubinaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    29 / 404 (7.18%)
    8 / 197 (4.06%)
         occurrences all number
    69
    17
    Skin and subcutaneous tissue disorders
    Dry skin
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    43 / 404 (10.64%)
    18 / 197 (9.14%)
         occurrences all number
    53
    20
    Alopecia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    25 / 404 (6.19%)
    7 / 197 (3.55%)
         occurrences all number
    26
    7
    Rash maculo-papular
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    29 / 404 (7.18%)
    10 / 197 (5.08%)
         occurrences all number
    43
    13
    Pruritus
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    39 / 404 (9.65%)
    15 / 197 (7.61%)
         occurrences all number
    48
    15
    Palmar-plantar erythrodysaesthesia syndrome
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    265 / 404 (65.59%)
    105 / 197 (53.30%)
         occurrences all number
    433
    158
    Skin hyperpigmentation
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    34 / 404 (8.42%)
    11 / 197 (5.58%)
         occurrences all number
    45
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    80 / 404 (19.80%)
    17 / 197 (8.63%)
         occurrences all number
    120
    25
    Back pain
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    58 / 404 (14.36%)
    25 / 197 (12.69%)
         occurrences all number
    73
    27
    Muscle spasms
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    46 / 404 (11.39%)
    6 / 197 (3.05%)
         occurrences all number
    63
    7
    Muscular weakness
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    22 / 404 (5.45%)
    6 / 197 (3.05%)
         occurrences all number
    25
    7
    Myalgia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    34 / 404 (8.42%)
    10 / 197 (5.08%)
         occurrences all number
    43
    11
    Pain in extremity
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    51 / 404 (12.62%)
    18 / 197 (9.14%)
         occurrences all number
    66
    22
    Infections and infestations
    Influenza
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    10 / 404 (2.48%)
    10 / 197 (5.08%)
         occurrences all number
    10
    10
    Nasopharyngitis
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    21 / 404 (5.20%)
    14 / 197 (7.11%)
         occurrences all number
    28
    15
    Paronychia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    23 / 404 (5.69%)
    3 / 197 (1.52%)
         occurrences all number
    30
    4
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    45 / 404 (11.14%)
    15 / 197 (7.61%)
         occurrences all number
    70
    18
    Urinary tract infection
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    45 / 404 (11.14%)
    16 / 197 (8.12%)
         occurrences all number
    76
    24
    Metabolism and nutrition disorders
    Decreased appetite
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    108 / 404 (26.73%)
    41 / 197 (20.81%)
         occurrences all number
    130
    51
    Dehydration
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    31 / 404 (7.67%)
    10 / 197 (5.08%)
         occurrences all number
    40
    13
    Hyperglycaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    26 / 404 (6.44%)
    3 / 197 (1.52%)
         occurrences all number
    40
    5
    Hypokalaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    71 / 404 (17.57%)
    24 / 197 (12.18%)
         occurrences all number
    105
    32
    Hypomagnesaemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    37 / 404 (9.16%)
    10 / 197 (5.08%)
         occurrences all number
    61
    10
    Hypophosphataemia
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    29 / 404 (7.18%)
    10 / 197 (5.08%)
         occurrences all number
    50
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Sep 2015
    A planned interim analysis of PFS as the primary endpoint was removed.
    26 Jan 2016
    Inclusion criteria was amended to remove the numerical size limits on certain CNS metastases.
    21 Mar 2016
    The unblinding procedure in the event of a concerning drug related safety event was revised.
    06 Jul 2016
    The assessment criteria used for the primary endpoint (PFS) was changed from RANO-BM to the validated RECIST 1.1 criteria.
    29 Nov 2016
    Increased the number of subjects from approximately 180 to 480. Changed the order of hierarchical testing of the secondary endpoints PFS in subjects with brain metastases and OS. Updated randomization stratification for region. Cardiac failure was added to the safety plan for cardiotoxicity.
    30 Aug 2017
    Removed the requirement of prior therapy with a taxane. Added HRQoL and health economics objectives. Removed formal interim analyses of the primary endpoint. Added a list of potential sensitive substrates for UGT1A1.
    12 Nov 2018
    Seattle Genetics became the Study Sponsor. Increased the number of subjects from 480 to 600 and the length of enrollment to 48 months. Amended the statistical testing from a hierarchical to parallel structure for key secondary endpoints of PFSBrainMets and OS.
    28 Feb 2019
    Amended to reflect the potential interaction of tucatinib with sensitive CYP3A substrates.
    25 Mar 2019
    Updated the timing of the PFS primary analysis and second interim analysis of OS and PFSBrainMets. Added details to the timing and scope of sponsor unblinding for the primary analysis. Timing of PFS primary endpoint was revised based on events and complete enrollment for the study.

    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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