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    Clinical Trial Results:
    A Randomised, Multicentre, Open Label, Phase II study of Prophylactic Octreotide to Prevent or Reduce the Frequency and Severity of Diarrhoea in Subjects Receiving Lapatinib with Capecitabine for the Treatment of Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2014-000256-28
    Trial protocol
    		 CZ   GB   IT   GR   PL   FR  
    Global end of trial date
    19 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Nov 2018
    First version publication date
    04 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LAP117314
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02294786
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the efficacy of prophylactic octreotide in reducing the proportion of subjects experiencing diarrhea with a severity of National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) grade 2 and above.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 All subjects received treatment with lapatinib 1250 mg orally once daily and capecitabine 1000 mg/m2 orally twice daily until disease progression. Lapatinib was given every day; capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Dec 2014
    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
    Israel: 1
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    United Kingdom: 9
    Worldwide total number of subjects
    62
    EEA total number of subjects
    26
    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)
    48
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study enrolled 62 women in 17 centers; Czech Republic (1), Israel (1), Poland (3), the United Kingdom (4) Russian Federation (8)

    Pre-assignment
    Screening details
    		 The study was terminated early after 62 patients (out of 140 planned) were randomized as criteria for futility was met.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Octreotide treatment
    Arm description
    		 Subjects randomised to receive Octreotide were administered with Octreotide (Sandostatin LAR™) 40mg 7 days before the start of treatment with Lapatinib and Capecitabine and again 28 days later. All subjects received treatment with Lapatinib 1250milligram (mg) once daily and Capecitabine 1000 milligram/square meter (mg/m^2) twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment. SANDOSTATIN™ is a trademark of Novartis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Octreotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    two doses of octreotide: one each on 7 days before the start of treatment with lapatinib and capecitabine, and Day 28 of the study, in addition to the doses of lapatinib and capecitabine mentioned above. The first dose was administered as a 0.1 mg sc injection, the second dose of 40 mg was administered as an intramuscular injection.

    Arm title
    		 No Octreotide treatment
    Arm description
    		 Subjects randomised to receive no octreotide, treatment with Lapatinib and Capecitabine was initiated immediately following enrolment. All subjects received treatment with Lapatinib 1250mg once daily and Capecitabine 1000mg/m^2 twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Octreotide treatment No Octreotide treatment
    Started
    30
    32
    ITT Population
    30
    32
    Completed
    19
    18
    Not completed
    11
    14
         Adverse event, serious fatal
    2
    3
         Physician decision
    6
    7
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    1
    2
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Octreotide treatment
    Reporting group description
    		 Subjects randomised to receive Octreotide were administered with Octreotide (Sandostatin LAR™) 40mg 7 days before the start of treatment with Lapatinib and Capecitabine and again 28 days later. All subjects received treatment with Lapatinib 1250milligram (mg) once daily and Capecitabine 1000 milligram/square meter (mg/m^2) twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment. SANDOSTATIN™ is a trademark of Novartis.

    Reporting group title
    No Octreotide treatment
    Reporting group description
    		 Subjects randomised to receive no octreotide, treatment with Lapatinib and Capecitabine was initiated immediately following enrolment. All subjects received treatment with Lapatinib 1250mg once daily and Capecitabine 1000mg/m^2 twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment

    Reporting group values
    		 Octreotide treatment No Octreotide treatment Total
    Number of subjects
    		 30 32 62
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 23 25 48
        From 65-84 years
    		 7 7 14
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 57.4 ( 10.07 ) 55.9 ( 9.08 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 30 32 62
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 0 1 1
        Not Hispanic or Latino
    		 30 31 61

    End points

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    End points reporting groups
    Reporting group title
    Octreotide treatment
    Reporting group description
    		 Subjects randomised to receive Octreotide were administered with Octreotide (Sandostatin LAR™) 40mg 7 days before the start of treatment with Lapatinib and Capecitabine and again 28 days later. All subjects received treatment with Lapatinib 1250milligram (mg) once daily and Capecitabine 1000 milligram/square meter (mg/m^2) twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment. SANDOSTATIN™ is a trademark of Novartis.

    Reporting group title
    No Octreotide treatment
    Reporting group description
    		 Subjects randomised to receive no octreotide, treatment with Lapatinib and Capecitabine was initiated immediately following enrolment. All subjects received treatment with Lapatinib 1250mg once daily and Capecitabine 1000mg/m^2 twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment

    Primary: Proportion of Subjects experiencing diarrhoea of Grade 2 and above

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    End point title
    		 Proportion of Subjects experiencing diarrhoea of Grade 2 and above
    End point description
    Proportion of subjects experiencing at least one episode of diarrhoea with a severity of Grade 2 and above, as defined by the National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) version 4.03, recorded as AEs in the Electronic case report form (eCRF). Subjects that withdrew from the study on or prior to the Cycle 4 visit date were assumed to have experienced diarrhoea.
    End point type
    Primary
    End point timeframe
    9 weeks (first 3 cycles of treatment)
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    30
    32
    Units: Participants
    7
    9
    Statistical analysis title
    		 Diarrhoea of Grade 2 and above
    Comparison groups
    No Octreotide treatment v Octreotide treatment
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.775
    Method
    		 Chi-squared
    Parameter type
    		 Difference in Percentages
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.2
         upper limit
    		 20

    Secondary: Proportion of subjects experiencing diarrhoea of Grade 3 and above

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    End point title
    		 Proportion of subjects experiencing diarrhoea of Grade 3 and above
    End point description
    Proportion of subjects experiencing diarrhoea with a severity of Grade 3 and above, as defined by the NCI CTCAE, version 4.03 and recorded as AEs in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    30
    32
    Units: Participants
    2
    0
    No statistical analyses for this end point

    Secondary: Proportion of subjects experiencing diarrhoea of any grade of severity

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    End point title
    		 Proportion of subjects experiencing diarrhoea of any grade of severity
    End point description
    Proportion of subjects experiencing diarrhoea of any grade of severity as defined by the NCI CTCAE, version 4.03 and recorded as AEs in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    30
    32
    Units: Participants
    18
    14
    No statistical analyses for this end point

    Secondary: Duration of diarrhoea of any grade of severity

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    End point title
    		 Duration of diarrhoea of any grade of severity
    End point description
    Duration of diarrhoea of any grade of severity, recorded as AEs in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: days
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [1] - Not analyzed as study was terminated early
    [2] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Time to onset of the first episode of diarrhoea of any grade of severity

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    End point title
    		 Time to onset of the first episode of diarrhoea of any grade of severity
    End point description
    Time to onset of the first episode of diarrhoea of any grade of severity, recorded as an AE in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Days
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [3] - Not analyzed as study was terminated early
    [4] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects taking anti-diarrhoeal medication

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    End point title
    		 Proportion of subjects taking anti-diarrhoeal medication
    End point description
    Proportion of subjects taking anti-diarrhoeal medication as recorded in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Participants
    Notes
    [5] - Not analyzed as study was terminated early
    [6] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects who had unscheduled visits to healthcare professionals due to diarrhoea

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    End point title
    		 Proportion of subjects who had unscheduled visits to healthcare professionals due to diarrhoea
    End point description
    Proportion of subjects making diarrhoea related unscheduled visits to healthcare professionals as recorded in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Participants
    Notes
    [7] - Not analyzed as study was terminated early
    [8] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects requiring dose reduction in Lapatinib and Capecitabine

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    End point title
    		 Proportion of subjects requiring dose reduction in Lapatinib and Capecitabine
    End point description
    Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine dose reduction as recorded in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Participants
    Notes
    [9] - Not analyzed as study was terminated early
    [10] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects requiring dose delay in Lapatinib and Capecitabine

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    End point title
    		 Proportion of subjects requiring dose delay in Lapatinib and Capecitabine
    End point description
    Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine dose delay as recorded in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Participants
    Notes
    [11] - Not analyzed as study was terminated early
    [12] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects requiring treatment withdrawal in Lapatinib and Capecitabine

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    End point title
    		 Proportion of subjects requiring treatment withdrawal in Lapatinib and Capecitabine
    End point description
    Proportion of subjects requiring diarrhoea related Lapatinib and Capecitabine treatment withdrawal as recorded in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Participants
    Notes
    [13] - Not analyzed as study was terminated early
    [14] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects requiring use of diarrhoea-related intravenous fluids

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    End point title
    		 Proportion of subjects requiring use of diarrhoea-related intravenous fluids
    End point description
    Proportion of subjects requiring use of diarrhoea-related intravenous fluids for rehydration as recorded in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: Participants
    Notes
    [15] - Not analyzed as study was terminated early
    [16] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Number of Lapatinib and Capecitabine tablets dispensed and returned

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    End point title
    		 Number of Lapatinib and Capecitabine tablets dispensed and returned
    End point description
    Number of Lapatinib and Capecitabine tablets dispensed and returned as recorded in the eCRF
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: tablets
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [17] - Not analyzed as study was terminated early
    [18] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Overall response rate as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    30
    32
    Units: Participants
        complete response (CR)
    0
    2
        partial response (PR)
    6
    4
        stable disease (SD)
    4
    5
        Progressive Disease
    14
    17
        Not Evaluable
    6
    4
    No statistical analyses for this end point

    Secondary: Clinical Benefit Response

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    End point title
    		 Clinical Benefit Response
    End point description
    Clinical benefit response as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    30
    32
    Units: Participants
        complete response (CR)
    0
    2
        partial response (PR)
    6
    4
        stable disease (SD) >= 24 weeks
    1
    3
        stable disease (SD) < 24 weeks
    3
    2
        Progressive Disease
    14
    17
        Not Evaluable
    6
    4
    No statistical analyses for this end point

    Secondary: Proportion of subjects reporting changes in bowel movements from baseline (frequency and/or consistency) as recorded in the Diarrhoea Management Diary (DMD)

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    End point title
    		 Proportion of subjects reporting changes in bowel movements from baseline (frequency and/or consistency) as recorded in the Diarrhoea Management Diary (DMD)
    End point description
    All subjects will complete the baseline DMD during the 3 days prior to randomisation, before any study-related treatment is administered. Subjects randomised to receive Octreotide will complete a second baseline DMD before starting the first cycle of treatment with Lapatinib and Capecitabine. The baseline DMD will comprise of 3 questions to record stool form and consistency. The DMD to be completed throughout the rest of the study will comprise of 3 questions in the baseline DMD and a further 5 questions and 6 sub-questions to evaluate the consequences and management of diarrhoea
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: Participants
    Notes
    [19] - Not analyzed as study was terminated early
    [20] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Time to the first subject reported change in frequency and/or consistency of bowel movements from baseline as recorded in the DMD

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    End point title
    		 Time to the first subject reported change in frequency and/or consistency of bowel movements from baseline as recorded in the DMD
    End point description
    The time to onset of the first subject-reported increase in frequency and/or worsening of consistency of bowel movements will be summarised by treatment arm
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [21]
    0 [22]
    Units: Days
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [21] - Not analyzed as study was terminated early
    [22] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects taking anti-diarrhoeal medication as recorded in the DMD

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    End point title
    		 Proportion of subjects taking anti-diarrhoeal medication as recorded in the DMD
    End point description
    The proportion of subjects taking medication at least once as a result of diarrhoea will be summarised and analysed
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [23]
    0 [24]
    Units: Participants
    Notes
    [23] - Not analyzed as study was terminated early
    [24] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects making dietary changes due to diarrhoea as recorded in the DMD

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    End point title
    		 Proportion of subjects making dietary changes due to diarrhoea as recorded in the DMD
    End point description
    The proportion of subjects making dietary changes to help with the diarrhoea will be summarised and analysed using the Generalised Estimating Equations (GEE) analysis and plots
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [25]
    0 [26]
    Units: Participants
    Notes
    [25] - Not analyzed as study was terminated early
    [26] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects contacting other non-hospital healthcare professionals to discuss diarrhoea as recorded in the DMD

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    End point title
    		 Proportion of subjects contacting other non-hospital healthcare professionals to discuss diarrhoea as recorded in the DMD
    End point description
    The proportion of subjects contacting a health care professional other than the hospital doctors/nurses to discuss diarrhoea will be summarised and analysed using the GEE analysis and plots
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [27]
    0 [28]
    Units: Participants
    Notes
    [27] - Not analyzed as study was terminated early
    [28] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of subjects reporting stopping completely or missing doses of anti-cancer tablets due to diarrhoea as recorded in the DMD

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    End point title
    		 Proportion of subjects reporting stopping completely or missing doses of anti-cancer tablets due to diarrhoea as recorded in the DMD
    End point description
    The proportion of subjects reducing or completely stopping the number of anti-cancer tablets to help with diarrhoea will be summarised and analysed using the GEE analysis and plots. Summaries will be performed separately for each type of change in anti-cancer tablets (i.e. reducing tablets and stopping completely) as well as overall
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    0 [29]
    0 [30]
    Units: Participants
    Notes
    [29] - Not analyzed as study was terminated early
    [30] - Not analyzed as study was terminated early
    No statistical analyses for this end point

    Secondary: Proportion of Subjects experiencing diarrhoea of Grade 2 and above

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    End point title
    		 Proportion of Subjects experiencing diarrhoea of Grade 2 and above
    End point description
    Proportion of subjects experiencing at least one episode of diarrhoea with a severity of Grade 2 and above, as defined by the National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) version 4.03, recorded as AEs in the Electronic case report form (eCRF). Subjects who did not have diarrhea event prior to the End of Study/Withdrawal visit date were not assumed to have experienced diarrhoea.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Octreotide treatment No Octreotide treatment
    Number of subjects analysed
    30
    32
    Units: Participants
    6
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the SAE field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator. One patient randomized to Oct analyzed in non-Oct group (got only 0.1 mg dose).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    No Octreotide treatment
    Reporting group description
    		 Lap+Cap

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Reporting group title
    Octreotide treatment
    Reporting group description
    		 Octreotide+Lap+Cap

    Serious adverse events
    		 No Octreotide treatment All Patients Octreotide treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 33 (9.09%)
    8 / 62 (12.90%)
    5 / 29 (17.24%)
         number of deaths (all causes)
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 62 (1.61%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 62 (1.61%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Paraparesis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 62 (1.61%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 62 (1.61%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 62 (1.61%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 62 (1.61%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 62 (1.61%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 62 (1.61%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 No Octreotide treatment All Patients Octreotide treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 33 (81.82%)
    53 / 62 (85.48%)
    26 / 29 (89.66%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 33 (6.06%)
    6 / 62 (9.68%)
    4 / 29 (13.79%)
         occurrences all number
    2
    7
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 33 (3.03%)
    5 / 62 (8.06%)
    4 / 29 (13.79%)
         occurrences all number
    1
    5
    4
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 62 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    0
    3
    3
    Blood bilirubin increased
         subjects affected / exposed
    3 / 33 (9.09%)
    7 / 62 (11.29%)
    4 / 29 (13.79%)
         occurrences all number
    3
    10
    7
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 62 (4.84%)
    1 / 29 (3.45%)
         occurrences all number
    2
    3
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 33 (18.18%)
    7 / 62 (11.29%)
    1 / 29 (3.45%)
         occurrences all number
    10
    11
    1
    Neutropenia
         subjects affected / exposed
    4 / 33 (12.12%)
    5 / 62 (8.06%)
    1 / 29 (3.45%)
         occurrences all number
    7
    8
    1
    Thrombocytopenia
         subjects affected / exposed
    3 / 33 (9.09%)
    6 / 62 (9.68%)
    3 / 29 (10.34%)
         occurrences all number
    3
    6
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 33 (21.21%)
    9 / 62 (14.52%)
    2 / 29 (6.90%)
         occurrences all number
    7
    10
    3
    Fatigue
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 62 (6.45%)
    3 / 29 (10.34%)
         occurrences all number
    1
    4
    3
    Oedema peripheral
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 62 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 62 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    0
    3
    3
    Diarrhoea
         subjects affected / exposed
    15 / 33 (45.45%)
    32 / 62 (51.61%)
    17 / 29 (58.62%)
         occurrences all number
    38
    64
    26
    Dry mouth
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 62 (4.84%)
    2 / 29 (6.90%)
         occurrences all number
    1
    3
    2
    Mouth ulceration
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 62 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    2
    2
    0
    Nausea
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 62 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    3
    5
    2
    Oral pain
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 62 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    2
    2
    0
    Stomatitis
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 62 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    2
    4
    2
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 62 (4.84%)
    2 / 29 (6.90%)
         occurrences all number
    1
    4
    3
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 62 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    4
    6
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 62 (8.06%)
    2 / 29 (6.90%)
         occurrences all number
    3
    6
    3
    Epistaxis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 62 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    2
    2
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 62 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    11 / 33 (33.33%)
    24 / 62 (38.71%)
    13 / 29 (44.83%)
         occurrences all number
    11
    24
    13
    Rash
         subjects affected / exposed
    7 / 33 (21.21%)
    11 / 62 (17.74%)
    4 / 29 (13.79%)
         occurrences all number
    11
    16
    5
    Skin fissures
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 62 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    3
    5
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 62 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    2
    2
    0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 62 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    2
    2
    0
    Pain in extremity
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 62 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    2
    4
    2
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 62 (6.45%)
    3 / 29 (10.34%)
         occurrences all number
    1
    4
    3
    Oral candidiasis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 62 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    2
    Paronychia
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 62 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    2
    4
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 62 (4.84%)
    1 / 29 (3.45%)
         occurrences all number
    2
    3
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2014
    - Prior treatment with lapatinib was added as an exclusion criterion - Additional detail was provided for dermatological monitoring - Secondary endpoints related to patient reported outcomes were updated - The schedule for completion of the DMD and FACIT-D was clarified - The schedule of study visits relative to the week numbers and cycles of treatment with lapatinib and capecitabine was clarified - The use of octreotide sc within the diarrhea management guidelines was clarified
    11 Sep 2015
    - Details of planned interim analysis included in Protocol Summary, Study Assessments, for early assessment of the primary endpoint - Recruitment Plan Section was included as an interim analysis was being incorporated - Blinding Section was updated with further clarification to support addition of an interim analysis - Number of subjects undergoing formal review of safety data was updated to reflect consistency with planned interim analysis - Details of tertiary Sponsor Medical Monitor Contact Information added. Author list, Sponsor Signatory, address and telephone numbers of medical monitors updated - Instructive text presented in Appendix for Country Specific Requirements deleted - Statement regarding application of amendment 01 to all participating sites added to improve the quality of the protocol

    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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