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    Clinical Trial Results:
    Multicentre randomized phase II study of neoadjuvant trastuzumab plus docetaxel with and without bevacizumab and trastuzumab plus docetaxel plus non-pegylated liposome-encapsulated doxorubicin (NPLD) with and without bevacizumab in HER2-positive early breast cancer

    Summary
    EudraCT number
    		 2010-023324-25
    Trial protocol
    		 AT  
    Global end of trial date
    16 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Sep 2021
    First version publication date
    11 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ABCSG32
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01367028
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ABCSG (Austrian Breast & Colorectal Cancer Study Group)
    Sponsor organisation address
    Nußdorfer Platz 8/12, Vienna, Austria, 1190
    Public contact
    Hannes Fohler (Trial Office Director), ABCSG (Austrian Breast & Colorectal Cancer Study Group), +43 1408 92 30, info@abcsg.at
    Scientific contact
    Prof. Guenther Steger, ABCSG (Austrian Breast & Colorectal Cancer Study Group), +43 1408 92 30, info@abcsg.at
    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
    16 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the cardiac toxicity of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD plus/minus bevacizumab in comparison to the standard therapy, i.e. trastuzumab and docetaxel.
    Protection of trial subjects
    An independent Data Monitoring Committee (IDMC) was established to assess Patient Safety. The responsibility of the IDMC was to evaluate deviations of medical relevance and safety issues. The DMC decided whether or not the patient should continue the study treatment due to safety issues. Furthermore, a dedicated meeting took place after 25 patients have finished therapy. In addition, the study specific ICF included guidance for patients where to reach the study doctor as well as patient advocacy in case of any questions and patients were encouraged to consult the study doctor in case of any questions (e.g. concerning cardiac insufficiency).
    Background therapy
    		 Docetaxel + Trastuzumab were considered as standard therapy (Trastuzumab was provided for this study whereas Docetaxel was considered SoC and used as per local standard).
    Evidence for comparator
    		 In most of Europe, trastuzumab is licensed in combination with docetaxel as first-line therapy of HER2 positive metastatic breast cancer, where a significant survival benefit has been demonstrated for the combination compared with chemotherapy.
    Actual start date of recruitment
    07 Jun 2011
    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
    Austria: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    78
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 100 patients was recruited (devided into the 4 arms). Recruitment was completed within 27 months.

    Pre-assignment
    Screening details
    		 Once a potential patient signed the ICF, their screening period started and screening assessments were performed within 28 days prior to randomization. Among other criteria, patients were required to have an LVEF ≥ 55% at screening.

    Pre-assignment period milestones
    Number of subjects started
    		 100
    Number of subjects completed
    		 100

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doc+Trast
    Arm description
    		 Docetaxel + Trastuzumab
    Arm type
    		 Active comparator

    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 is an approved treatment and therefore was no study treatment (NIMP). 100mg/m2 (in arms A and B) or 75mg/m2 (in arms C and D); 6 cycles in 3-weekly treatment cycles.

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8mg/kg loading dose on Day 1 of the first study treatment cycle; followed by 6mg/kg maintenance dose on Day 1 of subsequent cycles.

    Arm title
    		 Doc+Trast+Bev
    Arm description
    		 Docetaxel + Trastuzumab + Bevacizumab
    Arm type
    		 Experimental

    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 is an approved treatment and therefore was no study treatment (NIMP). 100mg/m2 (in arms A and B) or 75mg/m2 (in arms C and D); 6 cycles in 3-weekly treatment cycles.

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8mg/kg loading dose on Day 1 of the first study treatment cycle; followed by 6mg/kg maintenance dose on Day 1 of subsequent cycles.

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg on Day 1 of each treatment cycle; 6 cycles in 3-weekly treatment cycles.

    Arm title
    		 Doc+Trast+NPLD
    Arm description
    		 Docetaxel + Trastuzumab + NPLD
    Arm type
    		 Experimental

    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 is an approved treatment and therefore was no study treatment (NIMP). 100mg/m2 (in arms A and B) or 75mg/m2 (in arms C and D); 6 cycles in 3-weekly treatment cycles.

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8mg/kg loading dose on Day 1 of the first study treatment cycle; followed by 6mg/kg maintenance dose on Day 1 of subsequent cycles.

    Investigational medicinal product name
    Myocet
    Investigational medicinal product code
    Other name
    NLPD (non-pegylated liposomal doxorubiscin)
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50mg/m2 by 60 min IV infusion on Day 1 of each treatment cycle; 6 cycles in 3-weekly treatment cycles.

    Arm title
    		 Doc+Trast+Bev+NPLD
    Arm description
    		 Docetaxel +Trastuzumab + Bevacizumab + NPLD
    Arm type
    		 Experimental

    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 is an approved treatment and therefore was no study treatment (NIMP). 100mg/m2 (in arms A and B) or 75mg/m2 (in arms C and D); 6 cycles in 3-weekly treatment cycles.

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8mg/kg loading dose on Day 1 of the first study treatment cycle; followed by 6mg/kg maintenance dose on Day 1 of subsequent cycles.

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg on Day 1 of each treatment cycle; 6 cycles in 3-weekly treatment cycles.

    Investigational medicinal product name
    Myocet
    Investigational medicinal product code
    Other name
    NLPD (non-pegylated liposomal doxorubiscin)
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50mg/m2 by 60 min IV infusion on Day 1 of each treatment cycle; 6 cycles in 3-weekly treatment cycles.

    Number of subjects in period 1
    		Doc+Trast Doc+Trast+Bev Doc+Trast+NPLD Doc+Trast+Bev+NPLD
    Started
    25
    25
    26
    24
    Completed
    24
    20
    24
    21
    Not completed
    1
    5
    2
    3
         Consent withdrawn by subject
    -
    3
    2
    3
         wrong regime
    -
    1
    -
    -
         Adverse event, non-fatal
    1
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Doc+Trast
    Reporting group description
    		 Docetaxel + Trastuzumab

    Reporting group title
    Doc+Trast+Bev
    Reporting group description
    		 Docetaxel + Trastuzumab + Bevacizumab

    Reporting group title
    Doc+Trast+NPLD
    Reporting group description
    		 Docetaxel + Trastuzumab + NPLD

    Reporting group title
    Doc+Trast+Bev+NPLD
    Reporting group description
    		 Docetaxel +Trastuzumab + Bevacizumab + NPLD

    Reporting group values
    		 Doc+Trast Doc+Trast+Bev Doc+Trast+NPLD Doc+Trast+Bev+NPLD Total
    Number of subjects
    		 25 25 26 24 100
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 20 20 21 17 78
        From 65-84 years
    		 5 5 5 7 22
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 49 (23 to 75) 51 (28 to 79) 51.5 (30 to 75) 52 (29 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 25 25 26 24 100
        Male
    		 0 0 0 0 0
    Menopausal status
    Units: Subjects
        perimenopausal
    		 0 2 0 0 2
        postmenopausal
    		 12 12 13 14 51
        premenopausal
    		 13 11 13 10 47
    ECOG
    Units: Subjects
        0 (zero)
    		 25 25 26 23 99
        1 (one)
    		 0 0 0 1 1
    T-stage
    Units: Subjects
        T1
    		 7 5 10 7 29
        T2
    		 15 18 12 14 59
        T3
    		 1 1 3 3 8
        T4
    		 1 1 1 0 3
        Missing
    		 1 0 0 0 1
    N-stage
    Units: Subjects
        N0
    		 15 15 19 14 63
        N1
    		 9 8 7 10 34
        N2
    		 1 1 0 0 2
        N3
    		 0 1 0 0 1
    Grading
    Units: Subjects
        G1
    		 0 0 1 1 2
        G2
    		 8 9 7 6 30
        G3
    		 16 15 16 16 63
        GX
    		 1 1 1 1 4
        Missing
    		 0 0 1 0 1
    Hormone receptor status
    Units: Subjects
        negative
    		 13 12 12 10 47
        positive
    		 12 13 14 14 53
    Height
    Units: cm
        median (full range (min-max))
    		 166 (150 to 176) 166 (151 to 176) 164.5 (155 to 179) 163.75 (155 to 173) -
    Weight
    Units: kg
        median (full range (min-max))
    		 64 (51.6 to 92) 67.9 (46 to 113) 68.8 (47 to 94) 66 (51 to 110) -

    End points

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    End points reporting groups
    Reporting group title
    Doc+Trast
    Reporting group description
    		 Docetaxel + Trastuzumab

    Reporting group title
    Doc+Trast+Bev
    Reporting group description
    		 Docetaxel + Trastuzumab + Bevacizumab

    Reporting group title
    Doc+Trast+NPLD
    Reporting group description
    		 Docetaxel + Trastuzumab + NPLD

    Reporting group title
    Doc+Trast+Bev+NPLD
    Reporting group description
    		 Docetaxel +Trastuzumab + Bevacizumab + NPLD

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consists of all randomized patients with signed informed consent. Every subject is analysed according to the randomized treatment independent of the treatment administered. Efficacy endpoints as well as demographic and baseline characteristics are based on the ITT population.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population comprises all randomized patients with informed consent who received at least one dose of any study medication. Every patient is analysed according to the actual treatment received. Safety endpoints (including all adverse events) are based on the safety population. Since the primary endpoint represents a safety issue, it is analysed based on the SAF population as well.

    Primary: Cardiac toxicity

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    End point title
    		 Cardiac toxicity [1]
    End point description
    The primary study endpoint is cardiac toxicity of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD plus/minus bevacizumab using a composite endpoint. The composite endpoint of cardiac toxicity is defined by the appearance of either of the following variables: • symptomatic left ventricular dysfunction NYHA grade II, III, or IV or • asymptomatic left ventricular dysfunction defined as a decrease of the left ventricular ejection fraction of ≥ 15%-points as compared to base-line with a measured value still above the lower limit of normal (55%) or • asymptomatic left ventricular dysfunction defined as a decrease of the left ventricular ejection fraction (as measured by echocardiography of ≥ 10%-points as compared to baseline with a measured value below the lower limit of normal (55%) or • significant arrhythmias requiring medical treatment or invasive diagnostic measures
    End point type
    Primary
    End point timeframe
    Between day 1 of cycle 1 and day 28 ± 3 days after the day of final surgery
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Analysis is descriptive only.
    End point values
    		 Doc+Trast Doc+Trast+Bev Doc+Trast+NPLD Doc+Trast+Bev+NPLD Safety
    Number of subjects analysed
    25 [2]
    25 [3]
    26 [4]
    24 [5]
    100 [6]
    Units: Subjects
    0
    0
    2
    1
    3
    Notes
    [2] - Number in safety analysis set:25
    [3] - Number in safety analysis set:21
    [4] - Number in safety analysis set:27
    [5] - Number in safety analysis set:24
    [6] - Number in safety analysis set:97
    No statistical analyses for this end point

    Secondary: Pathological Complete Response (ypCR)

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    End point title
    		 Pathological Complete Response (ypCR)
    End point description
    Pathological complete response (ypCR), defined as absence of invasive tumor (ypT0 or ypTis). Secondary efficacy endpoints are described using frequency tables and associated 95% confidence intervals.
    End point type
    Secondary
    End point timeframe
    At final surgery
    End point values
    		 Doc+Trast Doc+Trast+Bev Doc+Trast+NPLD Doc+Trast+Bev+NPLD
    Number of subjects analysed
    25
    22
    24
    21
    Units: percent
        number (confidence interval 95%)
    0.36 (0.17 to 0.55)
    0.5 (0.29 to 0.71)
    0.63 (0.43 to 0.82)
    0.62 (0.41 to 0.83)
    Statistical analysis title
    		 D+T+B vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + bevacizumab is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast v Doc+Trast+Bev
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.386
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 D+T+N vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + NPLD is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast v Doc+Trast+NPLD
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0887
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 D+T+B+N vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + bevacizumab + NPLD is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast+Bev+NPLD v Doc+Trast
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1378
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Total pathological complete response (ytpCR)

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    End point title
    		 Total pathological complete response (ytpCR)
    End point description
    Total pathological complete response (ytpCR), defined as absence of invasive tumor and tumor cells in the breast (ypT0 or ypTis) and the axillar lymphnodes (ypN=0). Secondary efficacy endpoints are described using frequency tables and associated 95% confidence intervals.
    End point type
    Secondary
    End point timeframe
    At final surgery
    End point values
    		 Doc+Trast Doc+Trast+Bev Doc+Trast+NPLD Doc+Trast+Bev+NPLD
    Number of subjects analysed
    25
    22
    24
    21
    Units: percent
        number (confidence interval 95%)
    0.36 (0.17 to 0.55)
    0.41 (0.2 to 0.61)
    0.58 (0.39 to 0.78)
    0.57 (0.36 to 0.78)
    Statistical analysis title
    		 D+T+B vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + bevacizumab is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast v Doc+Trast+Bev
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7712
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 D+T+N vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + NPLD is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast v Doc+Trast+NPLD
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1564
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 D+T+B+N vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + bevacizumab + NPLD is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast v Doc+Trast+Bev+NPLD
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.235
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Overall clinical response rate (cORR)

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    End point title
    		 Overall clinical response rate (cORR)
    End point description
    Overall clinical response rate (cORR) defined as the percentage of patients with either a complete clinical response (cCR) or a partial clinical response (cPR). Secondary efficacy endpoints are described using frequency tables and associated 95% confidence intervals.
    End point type
    Secondary
    End point timeframe
    At final surgery
    End point values
    		 Doc+Trast Doc+Trast+Bev Doc+Trast+NPLD Doc+Trast+Bev+NPLD
    Number of subjects analysed
    25
    22
    24
    21
    Units: percent
        number (confidence interval 95%)
    0.56 (0.37 to 0.75)
    0.36 (0.16 to 0.56)
    0.25 (0.08 to 0.42)
    0.24 (0.06 to 0.42)
    Statistical analysis title
    		 D+T+B vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + bevacizumab is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast v Doc+Trast+Bev
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2445
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 D+T+N vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + NPLD is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast v Doc+Trast+NPLD
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0421
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 D+T+B+N vs. D+T
    Statistical analysis description
    The group receiving treatment combination docetaxel + trastuzumab + bevacizumab + NPLD is compared to the control group receiving standard therapy (docetaxel + trastuzumab) using Fisher’s Exact test.
    Comparison groups
    Doc+Trast v Doc+Trast+Bev+NPLD
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0376
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from Informed Consent Form signature until the Follow up visit (scheduled 28 days +- 3days after surgery)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Doc+Trast
    Reporting group description
    		 -

    Reporting group title
    Doc+Trast+Bev
    Reporting group description
    		 -

    Reporting group title
    Doc+Trast+NPLD
    Reporting group description
    		 -

    Reporting group title
    Doc+Trast+Bev+NPLD
    Reporting group description
    		 -

    Serious adverse events
    		 Doc+Trast Doc+Trast+Bev Doc+Trast+NPLD Doc+Trast+Bev+NPLD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 25 (16.00%)
    6 / 21 (28.57%)
    9 / 27 (33.33%)
    9 / 24 (37.50%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Hypertensive crisis
    Additional description: Hypertensive crisis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
    Additional description: Febrile neutropenia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    4 / 24 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
    Additional description: Leukopenia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
    Additional description: Asthenia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
    Additional description: General physical health deterioration
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Pain
    Additional description: Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Gastrointestinal disorders
    Abdominal rigidity
    Additional description: Abdominal rigidity
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
    Additional description: Colitis ulcerative
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
    Additional description: Large intestine perforation
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
    Additional description: Hyperventilation
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
    Additional description: Pneumothorax
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         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
    Skin and subcutaneous tissue disorders
    Acne
    Additional description: Acne
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (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
    Night sweats
    Additional description: Night sweats
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
    Additional description: Depression
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal pain
    Additional description: Renal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Infections and infestations
    Abdominal abscess
    Additional description: Abdominal abscess
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
    Additional description: Device related infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
    Additional description: Febrile infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (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
    Infected epidermal cyst
    Additional description: Infected epidermal cyst
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
    Additional description: Infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (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
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
    Additional description: Postoperative wound infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Additional description: Sepsis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superinfection
    Additional description: Superinfection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (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
    Wound infection
    Additional description: Wound infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Metabolism and nutrition disorders
    Hypercalcaemia
    Additional description: Hypercalcaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Doc+Trast Doc+Trast+Bev Doc+Trast+NPLD Doc+Trast+Bev+NPLD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 25 (100.00%)
    21 / 21 (100.00%)
    26 / 27 (96.30%)
    23 / 24 (95.83%)
    Vascular disorders
    Flushing
    Additional description: Flushing
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    0
    3
    Hot flush
    Additional description: Hot flush
         subjects affected / exposed
    4 / 25 (16.00%)
    2 / 21 (9.52%)
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    5
    2
    3
    0
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
    4 / 24 (16.67%)
         occurrences all number
    0
    2
    3
    11
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    2
    2
    General disorders and administration site conditions
    Asthenia
    Additional description: Asthenia
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    2
    1
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Chills
    Additional description: Chills
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    4 / 27 (14.81%)
    3 / 24 (12.50%)
         occurrences all number
    0
    0
    4
    3
    Impaired healing
    Additional description: Impaired healing
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    0
    1
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    17 / 25 (68.00%)
    15 / 21 (71.43%)
    18 / 27 (66.67%)
    18 / 24 (75.00%)
         occurrences all number
    32
    29
    30
    54
    Influenza like illness
    Additional description: Influenza like illness
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    1
    1
    2
    4
    Mucosal dryness
    Additional description: Mucosal dryness
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    5
    2
    4
    2
    Mucosal inflammation
    Additional description: Mucosal inflammation
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
    3 / 24 (12.50%)
         occurrences all number
    2
    4
    3
    4
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    8 / 25 (32.00%)
    1 / 21 (4.76%)
    7 / 27 (25.93%)
    1 / 24 (4.17%)
         occurrences all number
    14
    1
    8
    2
    Pain
    Additional description: Pain
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 21 (9.52%)
    4 / 27 (14.81%)
    1 / 24 (4.17%)
         occurrences all number
    7
    2
    4
    1
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 21 (14.29%)
    8 / 27 (29.63%)
    1 / 24 (4.17%)
         occurrences all number
    3
    3
    8
    1
    Immune system disorders
    Hypersensitivity
    Additional description: Hypersensitivity
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 21 (4.76%)
    1 / 27 (3.70%)
    3 / 24 (12.50%)
         occurrences all number
    6
    1
    1
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Cough
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    4
    1
    2
    3
    Dysphonia
    Additional description: Dysphonia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    0
    3
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    5 / 25 (20.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    8
    0
    1
    0
    Dyspnoea exertional
    Additional description: Dyspnoea exertional
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    5 / 25 (20.00%)
    10 / 21 (47.62%)
    8 / 27 (29.63%)
    10 / 24 (41.67%)
         occurrences all number
    7
    13
    11
    20
    Nasal dryness
    Additional description: Nasal dryness
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
         subjects affected / exposed
    1 / 25 (4.00%)
    5 / 21 (23.81%)
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    2
    7
    0
    4
    Rhinorrhoea
    Additional description: Rhinorrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    2
    0
    0
    3
    Psychiatric disorders
    Anxiety
    Additional description: Anxiety
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 21 (4.76%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    7
    1
    1
    0
    Sleep disorder
    Additional description: Sleep disorder
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 21 (14.29%)
    4 / 27 (14.81%)
    2 / 24 (8.33%)
         occurrences all number
    4
    3
    5
    2
    Investigations
    Body temperature increased
    Additional description: Body temperature increased
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 21 (9.52%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Injury, poisoning and procedural complications
    Seroma
    Additional description: Seroma
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    0
    1
    Cardiac disorders
    Pericardial effusion
    Additional description: Pericardial effusion
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Cardiovascular disorder
    Additional description: Cardiovascular disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sinus bradycardia
    Additional description: Sinus bradycardia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sinus tachycardia
    Additional description: Sinus tachycardia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Tachycardia
    Additional description: Tachycardia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    2
    1
    Nervous system disorders
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    8 / 25 (32.00%)
    6 / 21 (28.57%)
    9 / 27 (33.33%)
    5 / 24 (20.83%)
         occurrences all number
    9
    8
    12
    6
    Headache
    Additional description: Headache
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
    4 / 24 (16.67%)
         occurrences all number
    3
    3
    2
    7
    Neuropathy peripheral
    Additional description: Neuropathy peripheral
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 21 (14.29%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    5
    6
    0
    1
    Paraesthesia
    Additional description: Paraesthesia
         subjects affected / exposed
    5 / 25 (20.00%)
    1 / 21 (4.76%)
    7 / 27 (25.93%)
    2 / 24 (8.33%)
         occurrences all number
    8
    1
    7
    2
    Parosmia
    Additional description: Parosmia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Peripheral sensory neuropathy
    Additional description: Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    3
    1
    2
    1
    Polyneuropathy
    Additional description: Polyneuropathy
         subjects affected / exposed
    8 / 25 (32.00%)
    7 / 21 (33.33%)
    6 / 27 (22.22%)
    4 / 24 (16.67%)
         occurrences all number
    14
    11
    7
    4
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    2
    1
    3
    2
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 21 (14.29%)
    0 / 27 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    0
    3
    0
    4
    Ear and labyrinth disorders
    Ototoxicity
    Additional description: Ototoxicity
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Vertigo
    Additional description: Vertigo
         subjects affected / exposed
    4 / 25 (16.00%)
    2 / 21 (9.52%)
    3 / 27 (11.11%)
    4 / 24 (16.67%)
         occurrences all number
    4
    2
    5
    5
    Eye disorders
    Conjunctivitis
    Additional description: Conjunctivitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Dry eye
    Additional description: Dry eye
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Eye pruritus
    Additional description: Eye pruritus
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Lacrimation increased
    Additional description: Lacrimation increased
         subjects affected / exposed
    6 / 25 (24.00%)
    7 / 21 (33.33%)
    3 / 27 (11.11%)
    6 / 24 (25.00%)
         occurrences all number
    6
    10
    3
    6
    Gastrointestinal disorders
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 21 (9.52%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
         occurrences all number
    2
    3
    1
    2
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 21 (4.76%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
         occurrences all number
    2
    1
    1
    2
    Anal haemorrhage
    Additional description: Anal haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    10 / 25 (40.00%)
    4 / 21 (19.05%)
    10 / 27 (37.04%)
    7 / 24 (29.17%)
         occurrences all number
    17
    9
    17
    10
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    13 / 25 (52.00%)
    10 / 21 (47.62%)
    8 / 27 (29.63%)
    9 / 24 (37.50%)
         occurrences all number
    30
    20
    10
    17
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 21 (4.76%)
    3 / 27 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    5
    1
    3
    2
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    1
    1
    0
    2
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    0
    1
    Gingivitis
    Additional description: Gingivitis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    0
    2
    Haemorrhoids
    Additional description: Haemorrhoids
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    0
    1
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    7 / 25 (28.00%)
    9 / 21 (42.86%)
    14 / 27 (51.85%)
    5 / 24 (20.83%)
         occurrences all number
    15
    11
    26
    7
    Toothache
    Additional description: Toothache
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Stomatitis
    Additional description: Stomatitis
         subjects affected / exposed
    5 / 25 (20.00%)
    9 / 21 (42.86%)
    6 / 27 (22.22%)
    5 / 24 (20.83%)
         occurrences all number
    11
    16
    7
    12
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    2 / 25 (8.00%)
    5 / 21 (23.81%)
    3 / 27 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    2
    5
    6
    2
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    8 / 25 (32.00%)
    10 / 21 (47.62%)
    12 / 27 (44.44%)
    13 / 24 (54.17%)
         occurrences all number
    8
    11
    12
    15
    Dermatitis
    Additional description: Dermatitis
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Dry skin
    Additional description: Dry skin
         subjects affected / exposed
    2 / 25 (8.00%)
    5 / 21 (23.81%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    2
    5
    3
    1
    Erythema
    Additional description: Erythema
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 21 (9.52%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    3
    2
    1
    1
    Nail discolouration
    Additional description: Nail discolouration
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Nail disorder
    Additional description: Nail disorder
         subjects affected / exposed
    7 / 25 (28.00%)
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    10
    1
    2
    0
    Nail dystrophy
    Additional description: Nail dystrophy
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 21 (4.76%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
         occurrences all number
    4
    1
    1
    2
    Nail toxicity
    Additional description: Nail toxicity
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 21 (19.05%)
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    3
    8
    0
    4
    Onychalgia
    Additional description: Onychalgia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
    Additional description: Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 25 (8.00%)
    6 / 21 (28.57%)
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    2
    8
    3
    0
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Rash
    Additional description: Rash
         subjects affected / exposed
    9 / 25 (36.00%)
    7 / 21 (33.33%)
    2 / 27 (7.41%)
    4 / 24 (16.67%)
         occurrences all number
    11
    10
    3
    5
    Skin disorder
    Additional description: Skin disorder
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    2
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    11 / 25 (44.00%)
    6 / 21 (28.57%)
    4 / 27 (14.81%)
    4 / 24 (16.67%)
         occurrences all number
    12
    11
    5
    4
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 21 (4.76%)
    6 / 27 (22.22%)
    3 / 24 (12.50%)
         occurrences all number
    0
    1
    10
    6
    Bone pain
    Additional description: Bone pain
         subjects affected / exposed
    5 / 25 (20.00%)
    6 / 21 (28.57%)
    8 / 27 (29.63%)
    3 / 24 (12.50%)
         occurrences all number
    6
    8
    14
    3
    Muscular weakness
    Additional description: Muscular weakness
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    3
    4
    0
    3
    Musculoskeletal pain
    Additional description: Musculoskeletal pain
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    2
    1
    0
    3
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    7 / 25 (28.00%)
    5 / 21 (23.81%)
    4 / 27 (14.81%)
    1 / 24 (4.17%)
         occurrences all number
    12
    5
    9
    1
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 21 (9.52%)
    4 / 27 (14.81%)
    3 / 24 (12.50%)
         occurrences all number
    6
    2
    5
    3
    Infections and infestations
    Device related infection
    Additional description: Device related infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Folliculitis
    Additional description: Folliculitis
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    3 / 25 (12.00%)
    5 / 21 (23.81%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    6
    6
    2
    2
    Oral candidiasis
    Additional description: Oral candidiasis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    2 / 27 (7.41%)
    3 / 24 (12.50%)
         occurrences all number
    0
    5
    2
    7
    Paronychia
    Additional description: Paronychia
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Rhinitis
    Additional description: Rhinitis
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 21 (19.05%)
    5 / 27 (18.52%)
    5 / 24 (20.83%)
         occurrences all number
    2
    4
    6
    6
    Rash pustular
    Additional description: Rash pustular
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    5 / 25 (20.00%)
    3 / 21 (14.29%)
    2 / 27 (7.41%)
    5 / 24 (20.83%)
         occurrences all number
    7
    4
    2
    5
    Metabolism and nutrition disorders
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 21 (0.00%)
    6 / 27 (22.22%)
    3 / 24 (12.50%)
         occurrences all number
    3
    0
    6
    6
    Hyperglycaemia
    Additional description: Hyperglycaemia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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