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    Clinical Trial Results:
    Prospective, Multicenter, Open-label Phase IV trial of Trifluridine/Tipiracil to Evaluate the Health-related Quality of Life in Patients with Metastatic Colorectal Cancer

    Summary
    EudraCT number
    		 2017-000292-83
    Trial protocol
    		 DE  
    Global end of trial date
    24 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Tallisur
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Servier Deutschland GmbH
    Sponsor organisation address
    Elsenheimerstraße 53, München, Germany, 80687
    Public contact
    Dr. Timo Reisländer, Servier Deutschland GmbH, +49 (0)89 570 95 167, Timo.Reislaender@servier.com
    Scientific contact
    Dr. Timo Reisländer, Servier Deutschland GmbH, +49 (0)89 570 95 167, Timo.Reislaender@servier.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
    12 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of treatment with FTD/TPI on HRQoL as measured by EORTC QLQ-C30 (global health status/quality of life scale)
    Protection of trial subjects
    The clinical study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and in accordance with the International Council on Harmonisation (ICH) guideline for good clinical practice (GCP). The investigator obtained written informed consent of a patient prior to any study-related procedures including the documentation of results of clinical routine procedures for study purposes as set forth in the ICH-GCP guidelines and the respective European Union’s and national legislation. Subjects had the right to withdraw consent at any time and without giving any reasons without prejudice to his or her future medical care by the investigator or other medical health care personnel at the institution. The investigator discussed with the subject the most appropriate way to withdraw to ensure the subject’s health.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 Not applicable. To evaluate the effect of treatment with trifluridine/tipiracil on quality of life, a controlled study with best supportive care (BSC) was chosen and considered appropriate comparative treatment according to the advice from the German Federal Joint Committee (G-BA) on 29 September 2016.
    Actual start date of recruitment
    22 Sep 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 195
    Worldwide total number of subjects
    195
    EEA total number of subjects
    195
    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)
    76
    From 65 to 84 years
    116
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment period of this clinical study lasted from 22 September 2017 (first patient registered) to 08 January 2019 (last patient registered). 202 patients were recruited to 44 study centres in Germany, 7 of which did not enter the treatment / close observation phase (2 deaths, 3 patient`s wish, 1 AE, 1 violation of selection criteria).

    Pre-assignment
    Screening details
    		 Adult patients with histologically or cytologically confirmed UICC stage IV carcinoma of the colon or rectum with metastatic colorectal cancer, at least one measurable or non-measurable lesion as defined by RECIST version 1.1, any ECOG performance status, previously treated with or not considered candidates for available therapies.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FTD/TPI (trifluridine/tipiracil)
    Arm description
    		 FTD/TPI (starting dose 35 mg/m2 BSA/dose) was taken orally twice daily (BID) on Days 1 to 5 and Days 8 to 12 of each 28-day cycle as long as a benefit was observed or until unacceptable toxicity occurred.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trifluridine/tipiracil
    Investigational medicinal product code
    Other name
    Lonsurf (R)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The daily FTD/TPI dosage was calculated according to the body surface area (BSA). FTD/TPI (starting dose 35 mg/m2 BSA/dose) was taken orally twice daily (BID) on Days 1 to 5 and Days 8 to 12 of each 28-day cycle as long as a benefit was observed or until unacceptable toxicity occurred. The dosage was not allowed to exceed 80 mg per dose. In case of haematological or non-haematological toxicities, criteria for dose interruption and dose modification applied. A maximum of 3 dose reduction levels (30 mg/m2 BSA BID, 25 mg/m2 BSA BID, and 20 mg/m2 BSA BID) was permitted to a minimum dose of 20 mg/m2 BID.

    Arm title
    		 BSC (Best Supportive Care)
    Arm description
    		 Best supportive care, tailored to the patient`s individual needs.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care)
    Started
    186
    9
    Completed
    0
    0
    Not completed
    186
    9
         Disease progression (clinical)
    23
    -
         Consent withdrawn by subject
    12
    1
         Physician decision
    6
    -
         Adverse event, non-fatal
    25
    1
         Death
    10
    3
         Patient non-compliance
    1
    -
         Other / unknown
    10
    -
         Lost to follow-up
    2
    1
         Start of further anti-tumour therapy
    -
    2
         Disease progression (RECIST 1.1)
    95
    1
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FTD/TPI (trifluridine/tipiracil)
    Reporting group description
    		 FTD/TPI (starting dose 35 mg/m2 BSA/dose) was taken orally twice daily (BID) on Days 1 to 5 and Days 8 to 12 of each 28-day cycle as long as a benefit was observed or until unacceptable toxicity occurred.

    Reporting group title
    BSC (Best Supportive Care)
    Reporting group description
    		 Best supportive care, tailored to the patient`s individual needs.

    Reporting group values
    		 FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care) Total
    Number of subjects
    		 186 9 195
    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)
    		 74 2 76
        From 65-84 years
    		 109 7 116
        85 years and over
    		 3 0 3
    Age continuous
    Units: years
        median (full range (min-max))
    		 67.0 (40 to 88) 78.0 (54 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 69 4 73
        Male
    		 117 5 122
    ECOG Performance Status
    Units: Subjects
        ECOG PS 0
    		 72 0 72
        ECOG PS 1
    		 94 4 98
        ECOG PS 2
    		 18 3 21
        ECOG PS 3
    		 0 1 1
        Unknown
    		 2 1 3
    Number of previouis therapy lines of mCRC
    Only systemic anticancer therapies; a new therapy was defined as administration of a substance that was not part of the preceding therapy line.
    Units: Subjects
        0 previous therapy lines
    		 8 2 10
        1 previous therapy line
    		 23 1 24
        2 previous therapy lines
    		 71 3 74
        3 previous therapy lines
    		 49 0 49
        ≥ 4 previous therapy lines
    		 35 3 38
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All enrolled patients who received at least one dose of FTD/TPI (Group A) or started the close observation period (Group B).

    Subject analysis set title
    FAS-C30
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS HR QoL subset 1: Patients of the FAS who answered the baseline and at least one additional EORTC QLQ-C30 questionnaire between start of FTD/TPI treatment (Group A) or the start of the close observation period (Group B) and the end of treatment/close observation.

    Subject analysis set title
    FAS-EQ
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS HR QoL subset 2: Patients of the FAS who answered the baseline and at least one additional EQ-5D-5L questionnaire between start of FTD/TPI treatment (Group A) or the start of the close observation period (Group B) and the end of treatment/close observation.

    Subject analysis set title
    FAS-C30 (pe)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS-C30 evaluable for the primary endpoint (pe): a subset of the FAS-C30 comprising all patients who received at least two cycles of FTD/TPI and who completed the baseline EORTC-QLQ-C30 questionnaire and at least one more questionnaire AFTER Cycle 1 (i.e., the earliest within two days before Day 1 of Cycle 2).

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of the FAS/SAF without any relevant violation of selection criteria; moreover, patients from two centres were excluded from the PP due to inspection findings.

    Subject analysis sets values
    		 Full Analysis Set (FAS) FAS-C30 FAS-EQ FAS-C30 (pe) Per protocol
    Number of subjects
    195
    129
    128
    112
    171
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    76
        From 65-84 years
    116
        85 years and over
    3
    Age continuous
    Units: years
        median (full range (min-max))
    67.0 (40 to 88)
    Gender categorical
    Units: Subjects
        Female
    73
        Male
    122
    ECOG Performance Status
    Units: Subjects
        ECOG PS 0
    72
        ECOG PS 1
    98
        ECOG PS 2
    21
        ECOG PS 3
    1
        Unknown
    3
    Number of previouis therapy lines of mCRC
    Only systemic anticancer therapies; a new therapy was defined as administration of a substance that was not part of the preceding therapy line.
    Units: Subjects
        0 previous therapy lines
    10
        1 previous therapy line
    24
        2 previous therapy lines
    74
        3 previous therapy lines
    49
        ≥ 4 previous therapy lines
    38

    End points

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    End points reporting groups
    Reporting group title
    FTD/TPI (trifluridine/tipiracil)
    Reporting group description
    		 FTD/TPI (starting dose 35 mg/m2 BSA/dose) was taken orally twice daily (BID) on Days 1 to 5 and Days 8 to 12 of each 28-day cycle as long as a benefit was observed or until unacceptable toxicity occurred.

    Reporting group title
    BSC (Best Supportive Care)
    Reporting group description
    		 Best supportive care, tailored to the patient`s individual needs.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All enrolled patients who received at least one dose of FTD/TPI (Group A) or started the close observation period (Group B).

    Subject analysis set title
    FAS-C30
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS HR QoL subset 1: Patients of the FAS who answered the baseline and at least one additional EORTC QLQ-C30 questionnaire between start of FTD/TPI treatment (Group A) or the start of the close observation period (Group B) and the end of treatment/close observation.

    Subject analysis set title
    FAS-EQ
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS HR QoL subset 2: Patients of the FAS who answered the baseline and at least one additional EQ-5D-5L questionnaire between start of FTD/TPI treatment (Group A) or the start of the close observation period (Group B) and the end of treatment/close observation.

    Subject analysis set title
    FAS-C30 (pe)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS-C30 evaluable for the primary endpoint (pe): a subset of the FAS-C30 comprising all patients who received at least two cycles of FTD/TPI and who completed the baseline EORTC-QLQ-C30 questionnaire and at least one more questionnaire AFTER Cycle 1 (i.e., the earliest within two days before Day 1 of Cycle 2).

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of the FAS/SAF without any relevant violation of selection criteria; moreover, patients from two centres were excluded from the PP due to inspection findings.

    Primary: Rate of responders with unchanged or improved HRQoL

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    End point title
    		 Rate of responders with unchanged or improved HRQoL
    End point description
    Response was calculated as the mean of the score of the EORTC QLQ C30 global health status/quality of life scale (QL2) at all scheduled time points of HR-QoL analysis in the time interval from two days before start of Cycle 2 until the end of treatment/end of close observation compared to the baseline score of the global health status/quality of life (QL2) scale. The rate of responders was defined as the proportion of patients with response, i.e. improvement (≥10 scores) or stabilization (>-10 and <10 scores) of the EORTC QLQ C30 global health status/ quality of life (QL2) score compared to the baseline score. CAVE: Only the analyses in FAS-C30 (pe) are the primary endpoint of the study.
    End point type
    Primary
    End point timeframe
    From two days before start of Cycle 2 until the end of treatment/end of close observation.
    End point values
    		 FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care)
    Number of subjects analysed
    106 [1]
    6 [2]
    Units: Response rate, %
    number (confidence interval 95%)
        FAS-C30 pe, Group A: 62/106
    58.5 (48.5 to 68.0)
    0 (0 to 0)
        FAS-C30 pe, Group B: 3/6
    0 (0 to 0)
    50.0 (11.8 to 88.2)
        FAS-C30 pe, Group A, ECOG 0: 24/43
    55.8 (39.9 to 70.9)
    0 (0 to 0)
        FAS-C30 pe, Group A, ECOG 1: 33/54
    61.1 (46.9 to 74.1)
    0 (0 to 0)
        FAS-C30 pe, Group B, ECOG 1: 1/3
    0 (0 to 0)
    33.3 (0.8 to 90.6)
        FAS-C30 pe, Group A, ECOG 2-3: 4/8
    50.0 (15.7 to 84.3)
    0 (0 to 0)
        FAS-C30 pe, Group B, ECOG 2-3: 1/2
    0 (0 to 0)
    50.0 (1.3 to 98.7)
        FAS-C30 pe, Grp. A, 0 prev. therapy lines: 4/6
    66.7 (22.3 to 95.7)
    0 (0 to 0)
        FAS-C30 pe, Grp. B, 0 prev. therapy lines: 1/1
    0 (0 to 0)
    100.0 (2.5 to 100.0)
        FAS-C30 pe, Grp. A, 1-2 prev. therapy lines: 29/54
    53.7 (39.6 to 67.4)
    0 (0 to 0)
        FAS-C30 pe, Grp. B, 1-2 prev. therapy lines: 2/4
    0 (0 to 0)
    50.0 (6.8 to 93.2)
        FAS-C30 pe, Grp. A, 2 prev. therapy lines: 23/42
    54.8 (38.7 to 70.2)
    0 (0 to 0)
        FAS-C30 pe, Grp. B, 2 prev. therapy lines: 1/3
    0 (0 to 0)
    33.3 (0.8 to 90.6)
        FAS-C30 pe, Grp. A, > 2 prev. therapy lines: 29/46
    63.0 (47.5 to 76.8)
    0 (0 to 0)
        FAS-C30 pe, Grp. B, > 2 prev. therapy lines: 0/1
    0 (0 to 0)
    0.0 (0 to 0)
        PP pe, Group A: 56/96
    58.3 (47.8 to 68.3)
    0 (0 to 0)
        PP pe, Group B: 3/6
    0 (0 to 0)
    50.0 (11.8 to 88.2)
    Notes
    [1] - 106 in FAS-C30 pe; subgroup numbers identified in category headers.
    [2] - 6 in FAS-C30 pe; subgroup numbers identified in category headers.
    Statistical analysis title
    		 Primary endpoint analysis
    Statistical analysis description
    Calculation of the 2-sided 95% confidence interval for the response rate separately for both groups.
    Comparison groups
    FTD/TPI (trifluridine/tipiracil) v BSC (Best Supportive Care)
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 Confidence interval
    Point estimate
    58.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 48.5
         upper limit
    		 68
    Notes
    [3] - A response rate of 45% ± 10% was assessed as appropriate in Group A (patients with ≥ 2 cycles FTD/TPI). A response rate of 45% ± 20% was assessed as appropriate in Group B (patients with ≥ 2 cycles BSC). Note: Number of patients needed was not achieved in Group B. Parameter estimate presented is estimate for Group A.

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    PFS (based on RECIST version 1.1) was defined as the duration from the first administration of FTD/TPI (Group A) or Day 1 of observation Cycle 1 (Group B) to the day of radiological or clinical tumour progression or death of any cause, whichever came first. Patients who were not known to have had a radiological or clinical progression were censored for PFS analysis at the last date they were known not to have experienced progression.
    End point type
    Secondary
    End point timeframe
    Patients were followed until the end of study, at least one year after start of FTD/TPI / close observation.
    End point values
    		 FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care) Full Analysis Set (FAS) Per protocol
    Number of subjects analysed
    186
    9
    195
    171
    Units: months
        median (confidence interval 95%)
    2.5 (2.1 to 2.9)
    3.7 (2.2 to 4.7)
    2.5 (2.2 to 3.1)
    2.5 (2.1 to 3.2)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Duration from first administration of FTD/TPI (Group A) or Day 1 of observation Cycle 1 (Group B) to the day of death from any cause. Patients who were not known to have died were censored for OS analysis on the last day they were known to have been alive.
    End point type
    Secondary
    End point timeframe
    Patients were followed until the end of study, at least one year after start of FTD/TPI / close observation.
    End point values
    		 FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care) Full Analysis Set (FAS) Per protocol
    Number of subjects analysed
    186
    9
    195
    171
    Units: months
        median (confidence interval 95%)
    6.9 (6.1 to 8.3)
    4.7 (3.6 to 11.6)
    6.8 (6.0 to 8.2)
    6.8 (5.9 to 8.6)
    No statistical analyses for this end point

    Secondary: Average EORTC QLQ-C30 scores

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    End point title
    		 Average EORTC QLQ-C30 scores
    End point description
    EORTC QLQ-C30 consists of the global health status (QL2) scale, the functional scales physical functioning (PF2), role functioning (RF2), emotional functioning (EF), cognitive functioning (CF), and social functioning (SF), and the symptom scales / items fatigue (FA), nausea and vomiting (NV), pain (PA), dyspnoea (DY), insomnia (SL), appetite loss (AP), constipation (CO), diarrhoea (DI), and financial difficulties (FI). For the global health status and functional scales higher scores (on a scale of 0 - 100) represent a higher QoL / higher/healthier level of functioning. For a symptom scale/item, higher scores represent a higher level of symptomatology/problems.
    End point type
    Secondary
    End point timeframe
    At baseline, during and after treatment/close observation. After treatment includes all questionnaires completed at the end of treatment visit and during follow-up. Only questionnaires completed within prespecified time windows were considered.
    End point values
    		 FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care)
    Number of subjects analysed
    123 [4]
    6 [5]
    Units: Score points
    arithmetic mean (standard deviation)
        QL2 at baseline
    59.4 ( 20.5 )
    50.0 ( 14.9 )
        QL2 during treatment
    54.2 ( 22.3 )
    61.8 ( 31.0 )
        QL2 after treatment
    45.0 ( 25.1 )
    52.8 ( 21.0 )
        PF2 at baseline
    65.1 ( 24.5 )
    33.3 ( 34.8 )
        PF2 during treatment
    60.1 ( 25.2 )
    43.3 ( 47.0 )
        PF2 after treatment
    52.8 ( 28.5 )
    39.7 ( 44.8 )
        RF2 at baseline
    57.9 ( 31.6 )
    25.0 ( 39.1 )
        RF2 during treatment
    51.8 ( 31.1 )
    43.1 ( 51.0 )
        RF2 after treatment
    39.5 ( 34.0 )
    42.2 ( 51.8 )
        EF at baseline
    67.7 ( 23.9 )
    62.5 ( 35.3 )
        EF during treatment
    66.8 ( 26.4 )
    80.6 ( 21.2 )
        EF after treatment
    63.5 ( 26.5 )
    75.8 ( 29.7 )
        CF at baseline
    79.2 ( 23.2 )
    75.0 ( 23.0 )
        CF during treatment
    76.2 ( 22.7 )
    59.7 ( 37.8 )
        CF after treatment
    74.6 ( 23.3 )
    82.8 ( 9.2 )
        SF at baseline
    63.1 ( 30.7 )
    61.1 ( 44.3 )
        SF during treatment
    60.0 ( 31.5 )
    68.1 ( 31.5 )
        SF after treatment
    56.0 ( 33.7 )
    76.7 ( 20.3 )
        FA at baseline
    46.0 ( 27.0 )
    72.2 ( 23.0 )
        FA during treatment
    52.3 ( 26.9 )
    56.5 ( 34.4 )
        FA after treatment
    57.8 ( 30.6 )
    61.7 ( 33.0 )
        NV at baseline
    9.6 ( 19.1 )
    19.4 ( 19.5 )
        NV during treatment
    14.1 ( 16.5 )
    8.3 ( 16.7 )
        NV after treatment
    16.3 ( 20.5 )
    8.6 ( 7.5 )
        PA at baseline
    34.3 ( 32.7 )
    41.7 ( 27.4 )
        PA during treatment
    43.7 ( 34.0 )
    31.9 ( 25.0 )
        PA after treatment
    47.2 ( 34.9 )
    48.6 ( 35.4 )
        DY at baseline
    29.8 ( 30.7 )
    55.6 ( 34.4 )
        DY during treatment
    38.3 ( 30.1 )
    38.9 ( 43.0 )
        DY after treatment
    43.7 ( 34.3 )
    40.0 ( 43.7 )
        SL at baseline
    30.1 ( 31.2 )
    38.9 ( 25.1 )
        SL during treatment
    36.8 ( 31.5 )
    25.0 ( 31.9 )
        SL after treatment
    40.9 ( 35.0 )
    60.6 ( 47.2 )
        AP at baseline
    29.8 ( 33.3 )
    38.9 ( 49.1 )
        AP during treatment
    39.2 ( 31.9 )
    25.0 ( 50.0 )
        AP after treatment
    42.0 ( 30.9 )
    47.2 ( 33.7 )
        CO at baseline
    18.9 ( 28.7 )
    11.1 ( 17.2 )
        CO during treatment
    19.5 ( 26.3 )
    8.3 ( 16.7 )
        CO after treatment
    16.4 ( 23.6 )
    8.9 ( 15.4 )
        DI at baseline
    19.4 ( 27.0 )
    16.7 ( 27.9 )
        DI during treatment
    19.5 ( 27.2 )
    0.0 ( 0.0 )
        DI after treatment
    24.2 ( 27.6 )
    10.6 ( 12.9 )
        FI at baseline
    17.8 ( 27.2 )
    5.6 ( 13.6 )
        FI during treatment
    19.9 ( 26.9 )
    0.0 ( 0.0 )
        FI after treatment
    20.2 ( 26.5 )
    0.0 ( 0.0 )
    Notes
    [4] - 123 in FAS-C30; 123 (121-123 per item) at BL, 92 (91-92) during, 55 (54-55) after treatment.
    [5] - 6in FAS-C30; 6 at baseline, 4 during treatment, 3 after treatment.
    No statistical analyses for this end point

    Secondary: Average EQ-5D-5L index and EQ VAS scores

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    End point title
    		 Average EQ-5D-5L index and EQ VAS scores
    End point description
    EQ-5D-5L consists of the EQ-5D descriptive system comprising 5 dimensions mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and the EQ 20 cm vertical visual anlogue scale (VAS). EQ-5D-5L results are represented by an index value between 0 and 1 computed by the Crosswalk Index Value Calculator, where a higher value represents a higher level of problems; EQ VAS scores are presented as continuous parameter (0-100) where a high value represents a high health profile.
    End point type
    Secondary
    End point timeframe
    At baseline, during and after treatment/close observation. After treatment includes all questionnaires completed at the end of treatment visit and during follow-up. Only questionnaires completed within prespecified time windows were considered.
    End point values
    		 FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care)
    Number of subjects analysed
    122 [6]
    6 [7]
    Units: score points
    arithmetic mean (standard deviation)
        EQ-5D-5L index at baseline
    0.8 ( 0.2 )
    0.7 ( 0.4 )
        EQ-5D-5L index during treatment
    0.7 ( 0.2 )
    0.6 ( 0.4 )
        EQ-5D-5L index after treatment
    0.6 ( 0.3 )
    0.5 ( 0.5 )
        EQ VAS at baseline
    62.7 ( 20.0 )
    65.0 ( 15.8 )
        EQ VAS during treatment
    58.1 ( 23.1 )
    68.5 ( 26.1 )
        EQ VAS after treatment
    49.5 ( 27.1 )
    61.9 ( 18.9 )
    Notes
    [6] - 122 in FAS-EQ; EQ-5D-5L index n=120 at BL, 86 during, 57 after treatment; VAS n=120, 90, and 57.
    [7] - 6 in FAS-EQ; EQ-5D-5L index n=5 and VAS n=6 at BL; both n=4 during and n=3 after treatment.
    No statistical analyses for this end point

    Secondary: Time to deterioration of HR-QoL according to EORTC QLQ-C30 global health status QL2

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    End point title
    		 Time to deterioration of HR-QoL according to EORTC QLQ-C30 global health status QL2
    End point description
    From day 1 of cycle 1 of treatment with FTD/TPI / close observation to first change of global health/quality of life scale of ≤-10 scores compared to the baseline score.
    End point type
    Secondary
    End point timeframe
    From day 1 of cycle 1 of treatment with FTD/TPI / close observation to end of treatment / close observation (EoT) and end of follow-up (EoF), respectively.
    End point values
    		 FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care) FAS-C30
    Number of subjects analysed
    123 [8]
    6 [9]
    129 [10]
    Units: months
    median (confidence interval 95%)
        until end of treatment/close observation
    84.0 (64.0 to 391.0)
    9999 (60.0 to 9999)
    84.0 (64.0 to 391.0)
        until end of follow-up
    121.0 (84.0 to 172.0)
    104.0 (60.0 to 9999)
    121.0 (87.0 to 172.0)
    Notes
    [8] - 123 in FAS-C30. Deteriorations n=39 (31.7%) until EoT, n=63 (51.2%) until EoF.
    [9] - 6 in FAS-C30. Deteriorations n=1 (16.7%) until EoT, n=2 (33.3%) until EoF.
    [10] - N=40 deteriorations until EoT, n=65 (50.4%) deteriorations until EoF.
    No statistical analyses for this end point

    Other pre-specified: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Proportion of patients experiencing a response (complete [CR] or partial response [PR] based on RECIST version 1.1) in the period from start of Cycle 1 until the last administration of FTD/TPI (Group A) or close observation (Group B) plus 28 days.
    End point values
    		 FTD/TPI (trifluridine/tipiracil) BSC (Best Supportive Care) Full Analysis Set (FAS)
    Number of subjects analysed
    186
    9
    195
    Units: Responders
    4
    0
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first administration of FTD/TPI (Group A) or Day 1 of the close observation Cycle 1 (Group B) to 28 days after the last administration of FTD/TPI (Group A) or until the end of close observation (Group B)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    A: FTD/TPI (trifluridine/tipiracil) (SAF)
    Reporting group description
    		 FTD/TPI (starting dose 35 mg/m2 BSA/dose) was taken orally twice daily (BID) on Days 1 to 5 and Days 8 to 12 of each 28-day cycle as long as a benefit was observed or until unacceptable toxicity occurred.

    Reporting group title
    B: BSC (Best Supportive Care) (SAF)
    Reporting group description
    		 Best supportive care, tailored to the patient`s individual needs.

    Serious adverse events
    		 A: FTD/TPI (trifluridine/tipiracil) (SAF) B: BSC (Best Supportive Care) (SAF)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    83 / 186 (44.62%)
    5 / 9 (55.56%)
         number of deaths (all causes)
    147
    7
         number of deaths resulting from adverse events
    25
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant ascites
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    23 / 186 (12.37%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 1
         deaths causally related to treatment / all
    0 / 13
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    3 / 186 (1.61%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    3 / 186 (1.61%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 186 (2.15%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis radiation
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract stoma complication
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Coma hepatic
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 186 (2.15%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 186 (1.61%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 186 (2.15%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    4 / 186 (2.15%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    5 / 186 (2.69%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 186 (2.15%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bladder perforation
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 186 (1.61%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 186 (1.61%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Superinfection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound abscess
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 A: FTD/TPI (trifluridine/tipiracil) (SAF) B: BSC (Best Supportive Care) (SAF)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    170 / 186 (91.40%)
    6 / 9 (66.67%)
    Nervous system disorders
    Polyneuropathy
    Additional description: Includes PTs polyneuropathy (n=8, FTD/TPI), neuropathy peripheral (n=1, FTD/TPI) and peripheral motor neuropathy (n=1, FTD/TPI).
         subjects affected / exposed
    10 / 186 (5.38%)
    0 / 9 (0.00%)
         occurrences all number
    10
    0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Includes PTs anaemia (n=39, FTD/TPI; n=1, BSC) and haemoglobin decreased (n=4, FTD/TPI).
         subjects affected / exposed
    43 / 186 (23.12%)
    1 / 9 (11.11%)
         occurrences all number
    56
    1
    Leukopenia
    Additional description: Includes PTs leukopenia (n=29, FTD/TPI) and white blood cell count decreased (n=8, FTD/TPI).
         subjects affected / exposed
    37 / 186 (19.89%)
    0 / 9 (0.00%)
         occurrences all number
    79
    0
    Neutropenia
    Additional description: Includes PTs neutropenia (n=48, FTD/TPI) and neutrophil count decreased (n=8, FTD/TPI).
         subjects affected / exposed
    55 / 186 (29.57%)
    0 / 9 (0.00%)
         occurrences all number
    117
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    42 / 186 (22.58%)
    2 / 9 (22.22%)
         occurrences all number
    53
    3
    Oedema
    Additional description: Includes PTs oedema (n=3, FTD/TPI) and oedema peripheral (n=17, FTD/TPI).
         subjects affected / exposed
    19 / 186 (10.22%)
    0 / 9 (0.00%)
         occurrences all number
    22
    0
    Pain
         subjects affected / exposed
    8 / 186 (4.30%)
    2 / 9 (22.22%)
         occurrences all number
    9
    2
    Pyrexia
         subjects affected / exposed
    16 / 186 (8.60%)
    0 / 9 (0.00%)
         occurrences all number
    24
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 186 (6.99%)
    1 / 9 (11.11%)
         occurrences all number
    14
    1
    Ascites
         subjects affected / exposed
    9 / 186 (4.84%)
    1 / 9 (11.11%)
         occurrences all number
    13
    1
    Constipation
         subjects affected / exposed
    22 / 186 (11.83%)
    0 / 9 (0.00%)
         occurrences all number
    25
    0
    Diarrhoea
         subjects affected / exposed
    38 / 186 (20.43%)
    0 / 9 (0.00%)
         occurrences all number
    45
    0
    Nausea
         subjects affected / exposed
    42 / 186 (22.58%)
    1 / 9 (11.11%)
         occurrences all number
    49
    1
    Vomiting
         subjects affected / exposed
    24 / 186 (12.90%)
    1 / 9 (11.11%)
         occurrences all number
    32
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    Additional description: Includes PTs dyspnoea (n=16, FTD/TPI) and dyspnoea exertional (n=2, FTD/TPI).
         subjects affected / exposed
    18 / 186 (9.68%)
    0 / 9 (0.00%)
         occurrences all number
    21
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    13 / 186 (6.99%)
    0 / 9 (0.00%)
         occurrences all number
    13
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    7 / 186 (3.76%)
    0 / 9 (0.00%)
         occurrences all number
    8
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    28 / 186 (15.05%)
    0 / 9 (0.00%)
         occurrences all number
    31
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2018
    Amendment 1, Protocol version 3.0: Change of allowed periods and time points for study procedures during treatment phase: Study procedures on ‘Day 1 of each treatment cycle before administration of FTD/TPI in the respective cycle/start of the observation cycle or within previous 3 days (maximum 72 hours) unless otherwise indicated below’ (previously 2 days). Addition of a note: In case of any delay of the treatment start in the following treatment cycle, restaging has to be performed after 8 weeks or within previous 7 days (equivalent to duration of two treatment cycles with FTD/TPI without any treatment delay). Adjustment of text according to schedule of assessments (Section 2): Questionnaires EORTC-QLQ C30 and EQ-5D-5L including EQ VAS as paper version on Day 1 of the respective cycle or within previous 2 days. Update of information according to new SmPC for Lonsurf®: Update of one sentence on hepatic impairment: FTD/TPI is not recommended for use in patients with baseline moderate or severe hepatic impairment (National Cancer Institute [NCI] Criteria Group C and D defined by total bilirubin > 1.5 x ULN), as a higher incidence of Grade 3 or 4 hyperbilirubinaemia is observed in patients with baseline moderate hepatic impairment, although this is based on very limited data. Update of information on interactions: Deletion of one sentence: Inductive effect of tipiracil on human CYP isoforms cannot be excluded.
    30 Jul 2018
    Amendment 2, Protocol version 4.0: Updated information: Extension of the limitation of the early benefit assessment for Lonsurf® to 1 April 2020 (previously two years from 02 Feb 2017). The 1st of October 2018 as an optional data extract date for interim analysis – depending on whether this date or the time point of 50 evaluable patients permanently termination study treatment is earlier – was deleted. The following sentence was deleted: An interim report in the format of an integrated clinical study report will be prepared within three months after data extract date of the interim statistical analysis.
    07 Dec 2018
    Amendment 3, Protocol version 5.0: Change of study duration: Extension of the estimated accrual period from 1 year to 15 months. Extension of estimated study duration from 24 to 27 months. Change of Planned end of study from QII 2019 to QIV 2019. Change of sample size calculation: Addition of a table for sample sizes for alternative values of type I error if recruitment of 24 patients in Group B could not be achieved.
    29 Apr 2019
    Amendment 4, Protocol version 6.0: Change of duration of questioning quality of life: Extension of the time period for questioning of quality of life for patients treated with FTD/TPI for more than one year: questioning for the duration of treatment, at the end-of-treatment visit and at Month 1 of follow up.
    31 Jan 2020
    Amendment 5, Protocol version 7.0: Extension of the study duration until the end of 2020. Additional analysis, study report and annual safety report (required because of extension of study duration).

    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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