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    Clinical Trial Results:
    A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PARALLEL-GROUP, PHASE III STUDY OF THE EFFICACY AND SAFETY OF HERCULES PLUS TAXANE VERSUS HERCEPTIN® PLUS TAXANE AS FIRST LINE THERAPY IN PATIENTS WITH HER2-POSITIVE METASTATIC BREAST CANCER

    Summary
    EudraCT number
    		 2011-001965-42
    Trial protocol
    		 DE   HU   BG   CZ   SK   LV   ES   GR   AT  
    Global end of trial date
    03 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2020
    First version publication date
    01 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MYL-Her-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02472964
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mylan GmbH
    Sponsor organisation address
    Thurgauerstrasse 40, Zurich, Switzerland, 8050
    Public contact
    Senior Clinical Project Manager, Gail Tribble, Mylan Inc. 1000 Mylan Boulevard Canonsburg, PA, 15317 USA, 1 7244856124 , gail.tribble@mylan.com
    Scientific contact
    Deputy General Manager Clinical, Tazeen Aamena Idris, Mylan Pharmaceuticals Private Limited Plot No.1-60/35/A, 500032 Hyderabad, India, TazeenAamena.Idris@mylan.in
    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
    03 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1: To compare the independently assessed best overall response rate (ORR) (according to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 criteria) at Week 24 with MYL-1402O plus taxane versus Herceptin® plus taxane in patients who have not received previous first line treatment for HER2+ MBC. Part 2: To continue to evaluate the safety and tolerability profile of MYL-1402O and Herceptin® given as a single agent. And to compare the immunogenicity of MYL-1402O and Herceptin® by examining clinical immunogenic response. To compare the clinical activity at Week 48 between treatment arms by measuring PFS, OS and duration of response (DR), and OS at 36 months or after 240 deaths, whichever occurs first, as observed from the time of randomization of the last patient.
    Protection of trial subjects
    Monitoring of adverse events and serious adverse events. Regularly scheduled IDMC review.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 151
    Country: Number of subjects enrolled
    Philippines: 51
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    South Africa: 15
    Country: Number of subjects enrolled
    Thailand: 47
    Country: Number of subjects enrolled
    Ukraine: 55
    Country: Number of subjects enrolled
    Chile: 5
    Country: Number of subjects enrolled
    Georgia: 62
    Country: Number of subjects enrolled
    India: 55
    Worldwide total number of subjects
    500
    EEA total number of subjects
    54
    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)
    415
    From 65 to 84 years
    85
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 500 subjects enrolled at 95 sites across Eastern Europe, Russia, Asia Pacific, Africa aand South America. The intent-to-treat1 (ITT1) population of 458 was used to determine Primary Outcome of Overall Response Rate.

    Pre-assignment
    Screening details
    		 The primary efficacy analysis was derived from ITT1 population 230 (MYL-1401O) + 228 (Herceptin) = 458. Safety analysis was derived from the Safety Population 247(MYL-1401O) + 246 (Herceptin) = 493. Total Randomized population 249 (MYL-1401O) + 251 (Herceptin) = 500.

    Period 1
    Period 1 title
    Part I (up to week 24)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Herceptin® + Taxane
    Arm description
    		 Part 1: Herceptin® (trastuzumab) intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Herceptin®
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab 8mg/kg IV over 90 minutes x 1 then Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80mg/m2 IV over 60 minutes weekly.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle

    Arm title
    		 MYL-1401O + Taxane
    Arm description
    		 Part 1: MYL-1401O Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigator's choice) for 8 cycles then evaluate for primary endpoint.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MYL-1401O
    Investigational medicinal product code
    trastuzumab
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MYL-1401O 8mg/kg Iv over 90 minutes x 1 then MYL-1401O Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80mg/m2 IV over 60 minutes weekly.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle

    Number of subjects in period 1
    		Herceptin® + Taxane MYL-1401O + Taxane
    Started
    251
    249
    Protocol Amendment 2
    228
    230
    Completed
    171
    185
    Not completed
    80
    64
         Adverse event, serious fatal
    3
    6
         Physician decision
    5
    1
         Consent withdrawn by subject
    9
    2
         Disease progression
    58
    49
         unknown
    2
    1
         Adverse event, non-fatal
    2
    4
         Death before treatment start
    1
    -
         Lost to follow-up
    -
    1
    Period 2
    Period 2 title
    Part 2 (Week 24-week 48)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Herceptin®
    Arm description
    		 Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin® (trastuzumab) alone once every 3 weeks until DP or subject withdrawal .
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Herceptin®
    Investigational medicinal product code
    trastuzumab
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks

    Arm title
    		 Myl-1401O
    Arm description
    		 Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O alone once every 3 weeks until DP or subject withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MYL-1401O
    Investigational medicinal product code
    trastuzumab
    Other name
    Hercules
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MYL-1401O Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks

    Number of subjects in period 2 [1]
    		Herceptin® Myl-1401O
    Started
    163
    179
    Completed
    98
    116
    Not completed
    65
    63
         Adverse event, serious fatal
    -
    1
         Physician decision
    1
    1
         Consent withdrawn by subject
    3
    1
         Disease progression
    52
    56
         Adverse event, non-fatal
    4
    2
         Other
    3
    -
         Lost to follow-up
    2
    1
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 14 patients who completed Part 1 of the study did not enter Part 2 (MYL-1401O 6 patients, Herceptin 8 patients). Reasons for not entering Part 2 monotherapy were disease progression (MYL-1401O 4 patients/Herceptin 4 patients), withdrawal of consent (2/1), death (0/1), AE not due to disease progression (0/1), no reason (0/1).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Herceptin® + Taxane
    Reporting group description
    		 Part 1: Herceptin® (trastuzumab) intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint.

    Reporting group title
    MYL-1401O + Taxane
    Reporting group description
    		 Part 1: MYL-1401O Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigator's choice) for 8 cycles then evaluate for primary endpoint.

    Reporting group values
    		 Herceptin® + Taxane MYL-1401O + Taxane Total
    Number of subjects
    		 251 249 500
    Age categorical
    The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
    Units: Subjects
        18-49 years
    		 93 80 173
        >/= 50 years
    		 158 169 327
    Gender categorical
    Units: Subjects
        Female
    		 251 249 500
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Herceptin® + Taxane
    Reporting group description
    		 Part 1: Herceptin® (trastuzumab) intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint.

    Reporting group title
    MYL-1401O + Taxane
    Reporting group description
    		 Part 1: MYL-1401O Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigator's choice) for 8 cycles then evaluate for primary endpoint.
    Reporting group title
    Herceptin®
    Reporting group description
    		 Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin® (trastuzumab) alone once every 3 weeks until DP or subject withdrawal .

    Reporting group title
    Myl-1401O
    Reporting group description
    		 Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O alone once every 3 weeks until DP or subject withdrawal.

    Primary: Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population

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    End point title
    		 Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population
    End point description
    Tumor measurements were performed by centralized blinded reviewers using RECIST 1.1 criteria. Per RECIST 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to <10 mm.Partial Response (PR): >/= 30% decrease sum of the diameters of target lesions from baseline sum diameters. Progressive Disease (PD): </= 20% increase in the sum of the diameters of target lesions, from the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions* denotes disease progression. Stable Disease (SD): Neither sufficient decrease or increase. Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions. Non-complete Response/Non-Progressive Disease: Persistence of one or more non-target lesions. Progressive Disease (PD): Substantial, unequivocal progression of existing non-target lesions.
    End point type
    Primary
    End point timeframe
    from time of First treatment to week 24
    End point values
    		 Herceptin® + Taxane MYL-1401O + Taxane
    Number of subjects analysed
    228 [1]
    230 [2]
    Units: participants
        Complete Response
    0
    3
        Partial Response
    146
    157
        Stable Disease
    49
    48
        Progressive Disease
    20
    9
        Not Evaluable
    13
    13
    Notes
    [1] - ITT1
    [2] - ITT1
    Statistical analysis title
    		 Difference of Best ORR* at week 24
    Statistical analysis description
    *ORR = Overall Response Rate The following hypotheses were set up with the EMA’s equivalence margin of (-15%, 15%): H0: (RT - RC ≤ -15%) or (RT - RC ≥ 15%) H1: -15% < (RT - RC) < 15%, where, RT and RC were the best ORR of test (MYL-1401O) and control (Herceptin®), respectively. A two-sided 95% CI for the difference of the best ORRs at Week 24 was calculated. Equivalence was declared if the CI was completely within the equivalence range of (-15%, 15%)
    Comparison groups
    Herceptin® + Taxane v MYL-1401O + Taxane
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.08
         upper limit
    		 14.04

    Secondary: PFS (Progression-Free-Survival) at week 48

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    End point title
    		 PFS (Progression-Free-Survival) at week 48
    End point description
    To compare the clinical activity at Week 48 between treatment arms by measuring PFS, as observed from the time of randomization.
    End point type
    Secondary
    End point timeframe
    week 48
    End point values
    		 Herceptin® + Taxane MYL-1401O + Taxane
    Number of subjects analysed
    228
    230
    Units: Months
        median (confidence interval 95%)
    11.1 (8.60 to 11.20)
    11.1 (8.81 to 11.20)
    No statistical analyses for this end point

    Secondary: DR (duration of response) at week 48

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    End point title
    		 DR (duration of response) at week 48
    End point description
    To compare the clinical activity at Week 48 between treatment arms by measuring duration of response (DR), as observed from the time of randomization.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Herceptin® + Taxane MYL-1401O + Taxane
    Number of subjects analysed
    228 [3]
    230 [4]
    Units: months
        median (confidence interval 95%)
    9.7 (7.68 to 9.87)
    9.7 (7.38 to 9.89)
    Notes
    [3] - number of patients with data available: 182
    [4] - number of patients with data available: 191
    No statistical analyses for this end point

    Secondary: OS (Overall Survival) at month 36

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    End point title
    		 OS (Overall Survival) at month 36
    End point description
    To compare the clinical activity between treatment arms by measuring OS at 36 months as observed from the time of randomization of the last patient.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 Herceptin® + Taxane MYL-1401O + Taxane
    Number of subjects analysed
    228
    230
    Units: months
        median (confidence interval 95%)
    30.2 (25.00 to 39.86)
    35.0 (26.75 to 39.88)
    No statistical analyses for this end point

    Secondary: TTP (Time to Tumor Progression) at week 48

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    End point title
    		 TTP (Time to Tumor Progression) at week 48
    End point description
    To compare the clinical activity at Week 48 between treatment arms by measuring TTP, as observed from the time of randomization.
    End point type
    Secondary
    End point timeframe
    week 48
    End point values
    		 Herceptin® + Taxane MYL-1401O + Taxane
    Number of subjects analysed
    228
    230
    Units: months
        median (confidence interval 95%)
    11.1 (8.88 to 11.20)
    11.1 (8.83 to 11.20)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Active AE reporting period is from first dose until 28 days (+/- 7 days) after last administered dose of IMP per patient. SAEs should be reported any time after the active reporting period when SAE is considered related to study drug.
    Adverse event reporting additional description
    Investigator is responsible for detection and documentation of events meeting the criteria of an AE/SAE. At each visit, the patient will be allowed time to report any issues since the last evaluation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Herceptin® + Taxane (up to wk 24)
    Reporting group description
    		 Part 1: Herceptin® (trastuzumab) intravenously+ paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Timeframe: up to week 24

    Reporting group title
    MYL-1401O + Taxane (up to wk 24)
    Reporting group description
    		 Part 1: MYL-1401O intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigator's choice) for 8 cycles then evaluate for primary endpoint. Timeframe: up to week 24

    Reporting group title
    Herceptin® (wk 25 up to 36 months)
    Reporting group description
    		 Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin® (trastuzumab) alone once every 3 weeks until DP or subject withdrawal. Timeframe: week 25 up to 36 months

    Reporting group title
    MYL-1401O (wk 25 up to 36 months)
    Reporting group description
    		 Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O alone once every 3 weeks until DP or subject withdrawal. Timeframe: week 25 up to 36 months

    Serious adverse events
    		 Herceptin® + Taxane (up to wk 24) MYL-1401O + Taxane (up to wk 24) Herceptin® (wk 25 up to 36 months) MYL-1401O (wk 25 up to 36 months)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 246 (36.59%)
    95 / 247 (38.46%)
    10 / 164 (6.10%)
    10 / 179 (5.59%)
         number of deaths (all causes)
    4
    4
    0
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ disorder
    Additional description: Multi-organ failure
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
    1 / 164 (0.61%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 247 (0.81%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood uric acid increased
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
    1 / 164 (0.61%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Carditis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    10 / 246 (4.07%)
    11 / 247 (4.45%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 13
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    12 / 246 (4.88%)
    5 / 247 (2.02%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    62 / 246 (25.20%)
    68 / 247 (27.53%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 78
    0 / 92
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 246 (1.63%)
    3 / 247 (1.21%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 247 (0.40%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 246 (0.41%)
    3 / 247 (1.21%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 246 (2.03%)
    4 / 247 (1.62%)
    0 / 164 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 246 (1.22%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 247 (0.00%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 247 (0.81%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 247 (0.81%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
    0 / 164 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Herceptin® + Taxane (up to wk 24) MYL-1401O + Taxane (up to wk 24) Herceptin® (wk 25 up to 36 months) MYL-1401O (wk 25 up to 36 months)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    231 / 246 (93.90%)
    235 / 247 (95.14%)
    119 / 164 (72.56%)
    121 / 179 (67.60%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 246 (8.54%)
    18 / 247 (7.29%)
    7 / 164 (4.27%)
    11 / 179 (6.15%)
         occurrences all number
    36
    26
    12
    17
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 246 (8.94%)
    13 / 247 (5.26%)
    7 / 164 (4.27%)
    9 / 179 (5.03%)
         occurrences all number
    38
    20
    10
    13
    Ejection fraction decreased
         subjects affected / exposed
    3 / 246 (1.22%)
    5 / 247 (2.02%)
    6 / 164 (3.66%)
    10 / 179 (5.59%)
         occurrences all number
    3
    6
    8
    13
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    10 / 246 (4.07%)
    17 / 247 (6.88%)
    1 / 164 (0.61%)
    0 / 179 (0.00%)
         occurrences all number
    18
    30
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 246 (3.25%)
    7 / 247 (2.83%)
    9 / 164 (5.49%)
    12 / 179 (6.70%)
         occurrences all number
    10
    7
    25
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 246 (5.69%)
    15 / 247 (6.07%)
    23 / 164 (14.02%)
    19 / 179 (10.61%)
         occurrences all number
    18
    15
    31
    25
    Neuropathy peripheral
         subjects affected / exposed
    28 / 246 (11.38%)
    28 / 247 (11.34%)
    9 / 164 (5.49%)
    5 / 179 (2.79%)
         occurrences all number
    43
    36
    10
    5
    Peripheral sensory neuropathy
         subjects affected / exposed
    34 / 246 (13.82%)
    29 / 247 (11.74%)
    2 / 164 (1.22%)
    5 / 179 (2.79%)
         occurrences all number
    39
    38
    2
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    40 / 246 (16.26%)
    40 / 247 (16.19%)
    17 / 164 (10.37%)
    6 / 179 (3.35%)
         occurrences all number
    66
    76
    39
    9
    Leukopenia
         subjects affected / exposed
    40 / 246 (16.26%)
    40 / 247 (16.19%)
    4 / 164 (2.44%)
    2 / 179 (1.12%)
         occurrences all number
    57
    62
    5
    3
    Neutropenia
         subjects affected / exposed
    79 / 246 (32.11%)
    90 / 247 (36.44%)
    6 / 164 (3.66%)
    2 / 179 (1.12%)
         occurrences all number
    114
    133
    9
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    32 / 246 (13.01%)
    28 / 247 (11.34%)
    7 / 164 (4.27%)
    9 / 179 (5.03%)
         occurrences all number
    58
    61
    7
    11
    Oedema peripheral
         subjects affected / exposed
    28 / 246 (11.38%)
    35 / 247 (14.17%)
    4 / 164 (2.44%)
    2 / 179 (1.12%)
         occurrences all number
    38
    53
    4
    2
    Pyrexia
         subjects affected / exposed
    28 / 246 (11.38%)
    21 / 247 (8.50%)
    4 / 164 (2.44%)
    6 / 179 (3.35%)
         occurrences all number
    33
    27
    4
    6
    Asthenia
         subjects affected / exposed
    40 / 246 (16.26%)
    54 / 247 (21.86%)
    7 / 164 (4.27%)
    7 / 179 (3.91%)
         occurrences all number
    78
    123
    8
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    49 / 246 (19.92%)
    49 / 247 (19.84%)
    2 / 164 (1.22%)
    8 / 179 (4.47%)
         occurrences all number
    69
    80
    4
    13
    Nausea
         subjects affected / exposed
    34 / 246 (13.82%)
    48 / 247 (19.43%)
    6 / 164 (3.66%)
    8 / 179 (4.47%)
         occurrences all number
    60
    79
    6
    10
    Vomiting
         subjects affected / exposed
    17 / 246 (6.91%)
    25 / 247 (10.12%)
    6 / 164 (3.66%)
    10 / 179 (5.59%)
         occurrences all number
    22
    41
    6
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 246 (6.50%)
    14 / 247 (5.67%)
    3 / 164 (1.83%)
    9 / 179 (5.03%)
         occurrences all number
    17
    16
    5
    12
    Dyspnoea
         subjects affected / exposed
    17 / 246 (6.91%)
    13 / 247 (5.26%)
    2 / 164 (1.22%)
    6 / 179 (3.35%)
         occurrences all number
    22
    15
    2
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    135 / 246 (54.88%)
    142 / 247 (57.49%)
    5 / 164 (3.05%)
    7 / 179 (3.91%)
         occurrences all number
    162
    175
    5
    7
    Nail disorder
         subjects affected / exposed
    20 / 246 (8.13%)
    17 / 247 (6.88%)
    0 / 164 (0.00%)
    1 / 179 (0.56%)
         occurrences all number
    21
    18
    0
    1
    Rash
         subjects affected / exposed
    23 / 246 (9.35%)
    21 / 247 (8.50%)
    4 / 164 (2.44%)
    6 / 179 (3.35%)
         occurrences all number
    41
    26
    5
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 246 (4.47%)
    30 / 247 (12.15%)
    3 / 164 (1.83%)
    9 / 179 (5.03%)
         occurrences all number
    17
    46
    3
    12
    Bone pain
         subjects affected / exposed
    13 / 246 (5.28%)
    17 / 247 (6.88%)
    3 / 164 (1.83%)
    4 / 179 (2.23%)
         occurrences all number
    23
    21
    3
    4
    Myalgia
         subjects affected / exposed
    23 / 246 (9.35%)
    23 / 247 (9.31%)
    4 / 164 (2.44%)
    7 / 179 (3.91%)
         occurrences all number
    39
    45
    4
    10
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 246 (1.63%)
    14 / 247 (5.67%)
    4 / 164 (2.44%)
    10 / 179 (5.59%)
         occurrences all number
    6
    14
    4
    12
    Urinary tract infection
         subjects affected / exposed
    16 / 246 (6.50%)
    20 / 247 (8.10%)
    5 / 164 (3.05%)
    6 / 179 (3.35%)
         occurrences all number
    26
    30
    7
    14
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    19 / 246 (7.72%)
    13 / 247 (5.26%)
    7 / 164 (4.27%)
    5 / 179 (2.79%)
         occurrences all number
    29
    15
    39
    9
    Decreased appetite
         subjects affected / exposed
    24 / 246 (9.76%)
    21 / 247 (8.50%)
    5 / 164 (3.05%)
    4 / 179 (2.23%)
         occurrences all number
    44
    56
    7
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2013
    Amendment 2 addressed the following: - Incorporate the current standards of care practices for treatment of metastatic breast cancer (MBC); - Address delays related to the centrally performed IHC testing for patient randomization by switching the laboratory vendor to Phenopath Laboratories to avoid continued protocol violations; - Remove the requirement of the central safety laboratory and move solely to local laboratory testing for safety labs for treatment decisions; - Adjust and control for the global variances in MBC patients through appropriate stratification at randomization; - Provide an adaptable study design allowing an interim sample size estimation to ensure a sufficiently statistically powered clinical trial; and - Address the need for subject treatment until disease progression (i.e., Identified as a continuation study outlined in Amendment 1).
    10 Apr 2015
    Amendment 6: The goal of this protocol amendment was to 1) reflect updates in the current SmPC of Herceptin® 2) modify some operational procedures that allow appropriate management of the trial and 3) update the Data Analysis and Statistical Methods section to reflect updates made to the SAP. Additionally, content of the document “Errata” dated 21 November 2013, has been incorporated in this amended global protocol.
    03 Mar 2017
    Amendment 7: The goal of this protocol amendment was to 1) include the analysis for best ORR difference and to describe the associated statistical assumptions as indicated in the statistical analysis plan; and 2) modify select operational procedures that allow appropriate management of the trial. Additionally, content of the document “Errata,” dated 21 November 2013, has been incorporated in this amended global protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Jul 2013
    Following careful evaluation and review of the current study protocol and the need to address scientific advice from both, the U.S. Food & Drug Administration and the European Medicines Agency, Mylan has decided to put a temporary hold on site initiations and patient screening (patients currently in screening with a signed consent form will be allowed to proceed to randomization, if eligible) into the Her-3001 clinical trial effective immediately until the amendment to the protocol is approved and the study has been re-initiated.
    13 Sep 2013

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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