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    Clinical Trial Results:
    A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of INCB054828 in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Including FGFR2 Translocations Who Failed Previous Therapy

    Summary
    EudraCT number
    2016-002422-36
    Trial protocol
    DE   BE   FR   GB   IT  
    Global end of trial date
    01 Feb 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Feb 2023
    First version publication date
    11 Feb 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INCB 54828-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Incyte Corporation
    Sponsor organisation address
    1801 Augustine Cutoff Drive, Wilmington, United States, 19803
    Public contact
    Study Director, Incyte Corporation, 1 18554633463, medinfo@incyte.com
    Scientific contact
    Study Director, Incyte Corporation, 1 18554633463, medinfo@incyte.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
    01 Feb 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was evaluate the efficacy of pemigatinib in participants with advanced/metastatic or surgically unresectable cholangiocarcinoma with fibroblast growth factor (FGF) receptor 2 (FGFR2) translocation who have failed at least 1 previous treatment.
    Protection of trial subjects
    This study was to be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the United States Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as International Conference on Harmonisation Good Clinical Practice (ICH GCP) consolidated guidelines (E6) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 89
    Worldwide total number of subjects
    147
    EEA total number of subjects
    29
    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)
    101
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study enrolled participants at 68 study sites in the United States, South Korea, United Kingdom, France, Italy, Thailand, Germany, Belgium, Israel, Spain, Japan, and Taiwan.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort A: FGFR2 rearrangements or fusions
    Arm description
    Participants with fibroblast growth factor (FGF) receptor 2 (FGFR2) rearrangements or fusions self-administered oral pemigatinib at a starting dose of 13.5 milligrams (mg) once daily (QD) on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    pemigatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.0- and 4.5-mg tablets; starting dose of 13.5 mg

    Arm title
    Cohort B: Other FGF/FGFR alterations
    Arm description
    Participants with all other FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    pemigatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.0- and 4.5-mg tablets; starting dose of 13.5 mg

    Arm title
    Cohort C: negative for FGF/FGFR alterations
    Arm description
    Participants with no FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles (United States only). Pemigatinib was administered until documented disease progression or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    pemigatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.0- and 4.5-mg tablets; starting dose of 13.5 mg

    Arm title
    Other
    Arm description
    Participants with an FGF/FGFR status for whom the local laboratory FGF/FGFR results could not be confirmed centrally self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    pemigatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.0- and 4.5-mg tablets; starting dose of 13.5 mg

    Number of subjects in period 1
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Started
    108
    20
    17
    2
    Completed
    0
    0
    0
    0
    Not completed
    108
    20
    17
    2
         Adverse event, serious fatal
    73
    18
    15
    2
         Physician decision
    1
    -
    -
    -
         Consent withdrawn by subject
    7
    2
    1
    -
         Rolled Over to Another Study
    1
    -
    -
    -
         Progressive Disease
    4
    -
    1
    -
         Study Terminated by Sponsor
    19
    -
    -
    -
         Lost to follow-up
    3
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: FGFR2 rearrangements or fusions
    Reporting group description
    Participants with fibroblast growth factor (FGF) receptor 2 (FGFR2) rearrangements or fusions self-administered oral pemigatinib at a starting dose of 13.5 milligrams (mg) once daily (QD) on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Cohort B: Other FGF/FGFR alterations
    Reporting group description
    Participants with all other FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Cohort C: negative for FGF/FGFR alterations
    Reporting group description
    Participants with no FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles (United States only). Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Other
    Reporting group description
    Participants with an FGF/FGFR status for whom the local laboratory FGF/FGFR results could not be confirmed centrally self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other Total
    Number of subjects
    108 20 17 2 147
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    83 10 6 2 101
        From 65-84 years
    25 10 11 0 46
        85 years and over
    0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    55.2 ± 12.00 61.9 ± 10.99 65.6 ± 7.12 41.0 ± 14.14 -
    Sex: Female, Male
    Units: participants
        Female
    66 11 7 1 85
        Male
    42 9 10 1 62
    Race, Customized
    Units: Subjects
        White
    79 9 14 2 104
        Black or African American
    7 0 1 0 8
        Asian
    12 11 0 0 23
        American-Indian/Alaska Native
    0 0 1 0 1
        Captured as "Other"
    4 0 1 0 5
        Missing
    6 0 0 0 6
    Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    2 0 4 0 6
        Not Hispanic or Latino
    88 18 13 2 121
        Not Reported
    15 0 0 0 15
        Unknown
    1 0 0 0 1
        Captured as "Other"
    2 2 0 0 4

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: FGFR2 rearrangements or fusions
    Reporting group description
    Participants with fibroblast growth factor (FGF) receptor 2 (FGFR2) rearrangements or fusions self-administered oral pemigatinib at a starting dose of 13.5 milligrams (mg) once daily (QD) on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Cohort B: Other FGF/FGFR alterations
    Reporting group description
    Participants with all other FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Cohort C: negative for FGF/FGFR alterations
    Reporting group description
    Participants with no FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles (United States only). Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Other
    Reporting group description
    Participants with an FGF/FGFR status for whom the local laboratory FGF/FGFR results could not be confirmed centrally self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Subject analysis set title
    Cohort A + Cohort B
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants with FGFR2 rearrangements or fusions (Cohort A) or with all other FGF/FGFR alterations (Cohort B) self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Subject analysis set title
    All cohorts
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants in the Pharmacokinetic Population with FGFR2 rearrangements or fusions (Cohort A), participants with all other FGF/FGFR alterations (Cohort B), participants with no FGF/FGFR alterations (Cohort C; United States only), and participants with an FGF/FGFR status for whom the local laboratory FGF/FGFR results could not be confirmed centrally (Other) self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Primary: Objective response rate (ORR) in participants with FGFR2 rearrangements or fusions

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    End point title
    Objective response rate (ORR) in participants with FGFR2 rearrangements or fusions [1]
    End point description
    ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) at any post-Baseline visit prior to first progressive disease (PD), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. ORR was based on central genomics laboratory results. Response was based on review of scans by an independent centralized radiological review committee.
    End point type
    Primary
    End point timeframe
    up to 1527 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not conducted for this endpoint.
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Number of subjects analysed
    108
    0 [2]
    0 [3]
    0 [4]
    Units: percentage of participants
        number (confidence interval 95%)
    37.0 (27.94 to 46.86)
    ( to )
    ( to )
    ( to )
    Notes
    [2] - Analysis was conducted in participants with FGFR2 rearrangements or fusions.
    [3] - Analysis was conducted in participants with FGFR2 rearrangements or fusions.
    [4] - Analysis was conducted in participants with FGFR2 rearrangements or fusions.
    No statistical analyses for this end point

    Secondary: ORR in participants FGF/FGFR alterations other than FGFR2 rearrangements or fusions

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    End point title
    ORR in participants FGF/FGFR alterations other than FGFR2 rearrangements or fusions
    End point description
    ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. ORR was based on central genomics laboratory results. Response was based on review of scans by an independent centralized radiological review committee.
    End point type
    Secondary
    End point timeframe
    up to 424 days
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Number of subjects analysed
    0 [5]
    20
    0 [6]
    0 [7]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    0.0 (0.0 to 16.84)
    ( to )
    ( to )
    Notes
    [5] - Analysis was conducted in participants with other FGF/FGFR alterations.
    [6] - Analysis was conducted in participants with other FGF/FGFR alterations.
    [7] - Analysis was conducted in participants with other FGF/FGFR alterations.
    No statistical analyses for this end point

    Secondary: ORR in all participants with FGF/FGFR alterations

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    End point title
    ORR in all participants with FGF/FGFR alterations
    End point description
    ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. ORR was based on central genomics laboratory results. Response was based on review of scans by an independent centralized radiological review committee.
    End point type
    Secondary
    End point timeframe
    up to 1527 days
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other Cohort A + Cohort B
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    0 [11]
    128
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    31.3 (23.35 to 40.04)
    Notes
    [8] - Analysis was conducted in all participants with FGF/FGFR alterations.
    [9] - Analysis was conducted in all participants with FGF/FGFR alterations.
    [10] - Analysis was conducted in all participants with FGF/FGFR alterations.
    [11] - Analysis was conducted in all participants with FGF/FGFR alterations.
    No statistical analyses for this end point

    Secondary: ORR in participants negative for FGF/FGFR alterations

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    End point title
    ORR in participants negative for FGF/FGFR alterations
    End point description
    ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. ORR was based on central genomics laboratory results. Response was based on review of scans by an independent centralized radiological review committee.
    End point type
    Secondary
    End point timeframe
    up to 143 days
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Number of subjects analysed
    0 [12]
    0 [13]
    17
    0 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    0.0 (0.0 to 19.51)
    ( to )
    Notes
    [12] - Analysis was conducted in participants negative for FGF/FGFR alterations.
    [13] - Analysis was conducted in participants negative for FGF/FGFR alterations.
    [14] - Analysis was conducted in participants negative for FGF/FGFR alterations.
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    Progression-free survival (PFS)
    End point description
    PFS was defined as the length of time from the first dose of study drug (Day 1) to the earlier of death or disease progression by RECIST v1.1, as assessed by the independent centralized radiological review committee.
    End point type
    Secondary
    End point timeframe
    up to 50.17 months
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Number of subjects analysed
    108
    20
    17
    0 [15]
    Units: months
        median (confidence interval 95%)
    7.03 (6.08 to 10.48)
    2.10 (1.18 to 4.86)
    1.51 (1.38 to 1.84)
    ( to )
    Notes
    [15] - Analysis was not conducted in this treatment group.
    No statistical analyses for this end point

    Secondary: Duration of response (DOR)

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    End point title
    Duration of response (DOR)
    End point description
    DOR was defined as the time from the first overall response contributing to an objective response (CR or PR) as assessed by an independent centralized radiological review committee to the earlier of death or first overall response of PD occurring after the first overall response contributing to the objective response. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion.
    End point type
    Secondary
    End point timeframe
    up to 47.11 months
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Number of subjects analysed
    40
    0 [16]
    0 [17]
    0 [18]
    Units: months
        median (confidence interval 95%)
    9.13 (6.01 to 14.49)
    ( to )
    ( to )
    ( to )
    Notes
    [16] - Analysis was conducted in those participants with a CR or PR.
    [17] - Analysis was conducted in those participants with a CR or PR.
    [18] - Analysis was not conducted in this treatment group.
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR)

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    End point title
    Disease control rate (DCR)
    End point description
    DCR was defined as the proportion of participants with an overall response of CR, PR, or stable disease (SD), per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD.
    End point type
    Secondary
    End point timeframe
    up to 1527 days
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Number of subjects analysed
    108
    20
    17
    0 [19]
    Units: percentage of participants
        number (confidence interval 95%)
    82.4 (73.9 to 89.1)
    40.0 (19.1 to 63.9)
    17.6 (3.8 to 43.4)
    ( to )
    Notes
    [19] - Analysis was not conducted in this treatment group.
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall survival was defined as the length of time from the first dose of study drug (Day 1) until the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    up to 51.32 months
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Number of subjects analysed
    108
    20
    17
    0 [20]
    Units: months
        median (confidence interval 95%)
    17.48 (14.36 to 22.93)
    6.70 (2.10 to 10.55)
    3.98 (1.97 to 4.60)
    ( to )
    Notes
    [20] - Analysis was not conducted in this treatment group.
    No statistical analyses for this end point

    Secondary: Number of participants with any treatment-emergent adverse event (TEAE)

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    End point title
    Number of participants with any treatment-emergent adverse event (TEAE)
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any adverse event either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and within 30 days of the last dose of study drug.
    End point type
    Secondary
    End point timeframe
    up to 1584 days
    End point values
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other
    Number of subjects analysed
    108
    20
    17
    2
    Units: participants
    108
    20
    17
    2
    No statistical analyses for this end point

    Secondary: First-order absorption rate constant (ka) of pemigatinib

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    End point title
    First-order absorption rate constant (ka) of pemigatinib
    End point description
    First-order absorption rate constant is defined as the rate at which a drug enters into the system.
    End point type
    Secondary
    End point timeframe
    Predose; 1-2 hours post-dose; 4-12 hours post-dose
    End point values
    All cohorts
    Number of subjects analysed
    136
    Units: 1/hour
        arithmetic mean (standard deviation)
    1.29 ± 0.827
    No statistical analyses for this end point

    Secondary: CL/F of pemigatinib

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    End point title
    CL/F of pemigatinib
    End point description
    CL/F is defined as apparent oral clearance.
    End point type
    Secondary
    End point timeframe
    Predose; 1-2 hours post-dose; 4-12 hours post-dose
    End point values
    All cohorts
    Number of subjects analysed
    136
    Units: Liters/hour
        arithmetic mean (standard deviation)
    12.2 ± 5.28
    No statistical analyses for this end point

    Secondary: Vc/F of pemigatinib

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    End point title
    Vc/F of pemigatinib
    End point description
    Vc/F is defined as the apparent volume of distribution for the central compartment of pemigatinib.
    End point type
    Secondary
    End point timeframe
    Predose; 1-2 hours post-dose; 4-12 hours post-dose
    End point values
    All cohorts
    Number of subjects analysed
    136
    Units: Liters
        arithmetic mean (standard deviation)
    144 ± 55.7
    No statistical analyses for this end point

    Secondary: Vp/F of pemigatinib

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    End point title
    Vp/F of pemigatinib
    End point description
    Vp/F is defined as the apparent volume of distribution for the tissue (peripheral) compartment.
    End point type
    Secondary
    End point timeframe
    Predose; 1-2 hours post-dose; 4-12 hours post-dose
    End point values
    All cohorts
    Number of subjects analysed
    136
    Units: Liters
        arithmetic mean (standard deviation)
    85.6 ± 30.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 1584 days
    Adverse event reporting additional description
    Treatment-emergent adverse events, defined as adverse events either reported for the first time or the worsening of pre-existing events after the first dose of study drug and within 30 days of the last dose of study drug, have been reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Cohort A: FGFR2 rearrangements or fusions
    Reporting group description
    Participants with fibroblast growth factor (FGF) receptor 2 (FGFR2) rearrangements or fusions self-administered oral pemigatinib at a starting dose of 13.5 milligrams (mg) once daily (QD) on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Cohort B: Other FGF/FGFR alterations
    Reporting group description
    Participants with all other FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Cohort C: negative for FGF/FGFR alterations
    Reporting group description
    Participants with no FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles (United States only). Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Other
    Reporting group description
    Participants with an FGF/FGFR status for whom the local laboratory FGF/FGFR results could not be confirmed centrally self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a 2-weeks-on therapy/1-week-off schedule in 21-day cycles. Pemigatinib was administered until documented disease progression or unacceptable toxicity.

    Reporting group title
    Total
    Reporting group description
    Total

    Serious adverse events
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 108 (42.59%)
    10 / 20 (50.00%)
    12 / 17 (70.59%)
    0 / 2 (0.00%)
    68 / 147 (46.26%)
         number of deaths (all causes)
    76
    18
    15
    2
    111
         number of deaths resulting from adverse events
    3
    2
    1
    0
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 108 (4.63%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 1
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 108 (1.85%)
    2 / 20 (10.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    5 / 147 (3.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device leakage
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
    0 / 2
    0 / 0
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Biloma
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    5 / 108 (4.63%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 1
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Jaundice
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant biliary obstruction
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Typhoid fever
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Hypercalcaemia
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 108 (0.93%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort A: FGFR2 rearrangements or fusions Cohort B: Other FGF/FGFR alterations Cohort C: negative for FGF/FGFR alterations Other Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    108 / 108 (100.00%)
    20 / 20 (100.00%)
    17 / 17 (100.00%)
    2 / 2 (100.00%)
    147 / 147 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Malignant ascites
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Malignant pleural effusion
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Tumour associated fever
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Hypertension
         subjects affected / exposed
    9 / 108 (8.33%)
    3 / 20 (15.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    12 / 147 (8.16%)
         occurrences all number
    11
    4
    0
    0
    15
    Hypotension
         subjects affected / exposed
    5 / 108 (4.63%)
    2 / 20 (10.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    9 / 147 (6.12%)
         occurrences all number
    9
    2
    3
    0
    14
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 108 (13.89%)
    4 / 20 (20.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    20 / 147 (13.61%)
         occurrences all number
    34
    9
    1
    0
    44
    Chills
         subjects affected / exposed
    6 / 108 (5.56%)
    0 / 20 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    8 / 147 (5.44%)
         occurrences all number
    8
    0
    2
    0
    10
    Fatigue
         subjects affected / exposed
    50 / 108 (46.30%)
    5 / 20 (25.00%)
    9 / 17 (52.94%)
    0 / 2 (0.00%)
    64 / 147 (43.54%)
         occurrences all number
    60
    6
    9
    0
    75
    Gait disturbance
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    6 / 108 (5.56%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    7
    0
    0
    0
    7
    Malaise
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    5 / 147 (3.40%)
         occurrences all number
    3
    2
    1
    0
    6
    Oedema peripheral
         subjects affected / exposed
    16 / 108 (14.81%)
    4 / 20 (20.00%)
    6 / 17 (35.29%)
    0 / 2 (0.00%)
    26 / 147 (17.69%)
         occurrences all number
    21
    4
    6
    0
    31
    Pain
         subjects affected / exposed
    4 / 108 (3.70%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    5 / 147 (3.40%)
         occurrences all number
    4
    0
    1
    0
    5
    Performance status decreased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    11 / 108 (10.19%)
    3 / 20 (15.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    16 / 147 (10.88%)
         occurrences all number
    20
    3
    2
    0
    25
    Thirst
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    3
    1
    0
    0
    4
    Gynaecomastia
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Penile pain
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Cough
         subjects affected / exposed
    10 / 108 (9.26%)
    0 / 20 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    12 / 147 (8.16%)
         occurrences all number
    12
    0
    2
    0
    14
    Dysphonia
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    2
    0
    1
    0
    3
    Dyspnoea
         subjects affected / exposed
    10 / 108 (9.26%)
    3 / 20 (15.00%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
    16 / 147 (10.88%)
         occurrences all number
    12
    3
    3
    0
    18
    Dyspnoea exertional
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    3
    0
    1
    0
    4
    Epistaxis
         subjects affected / exposed
    19 / 108 (17.59%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    20 / 147 (13.61%)
         occurrences all number
    24
    1
    0
    0
    25
    Laryngeal inflammation
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Nasal congestion
         subjects affected / exposed
    8 / 108 (7.41%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    11 / 147 (7.48%)
         occurrences all number
    9
    1
    2
    0
    12
    Nasal dryness
         subjects affected / exposed
    13 / 108 (12.04%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    13 / 147 (8.84%)
         occurrences all number
    14
    0
    0
    0
    14
    Oropharyngeal pain
         subjects affected / exposed
    11 / 108 (10.19%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    13 / 147 (8.84%)
         occurrences all number
    13
    2
    0
    0
    15
    Pulmonary embolism
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    0
    2
    0
    0
    2
    Rhinitis allergic
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Sinus pain
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Stridor
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    2
    0
    1
    0
    3
    Depression
         subjects affected / exposed
    6 / 108 (5.56%)
    2 / 20 (10.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    9 / 147 (6.12%)
         occurrences all number
    6
    2
    1
    0
    9
    Hallucination
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Insomnia
         subjects affected / exposed
    13 / 108 (12.04%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    15 / 147 (10.20%)
         occurrences all number
    13
    2
    0
    0
    15
    Nervousness
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    4 / 147 (2.72%)
         occurrences all number
    3
    0
    0
    1
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 108 (11.11%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    13 / 147 (8.84%)
         occurrences all number
    16
    0
    1
    0
    17
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 108 (8.33%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    12 / 147 (8.16%)
         occurrences all number
    16
    3
    2
    0
    21
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood 1,25-dihydroxycholecalciferol decreased
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    4
    1
    0
    0
    5
    Blood 1,25-dihydroxycholecalciferol increased
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    3
    1
    0
    0
    4
    Blood 25-hydroxycholecalciferol decreased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    12 / 108 (11.11%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    15 / 147 (10.20%)
         occurrences all number
    16
    1
    2
    0
    19
    Blood bilirubin increased
         subjects affected / exposed
    6 / 108 (5.56%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    9
    0
    1
    0
    10
    Blood chloride decreased
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    4
    0
    0
    5
    Blood creatinine increased
         subjects affected / exposed
    9 / 108 (8.33%)
    2 / 20 (10.00%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
    15 / 147 (10.20%)
         occurrences all number
    12
    2
    4
    0
    18
    Blood parathyroid hormone decreased
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    4
    2
    0
    0
    6
    Blood urea increased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    2
    1
    0
    0
    3
    Lipase increased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    5
    2
    1
    0
    8
    Platelet count decreased
         subjects affected / exposed
    8 / 108 (7.41%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    10 / 147 (6.80%)
         occurrences all number
    15
    1
    0
    1
    17
    Transaminases increased
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 20 (15.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    1
    5
    0
    0
    6
    Tri-iodothyronine free increased
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    20 / 108 (18.52%)
    4 / 20 (20.00%)
    1 / 17 (5.88%)
    1 / 2 (50.00%)
    26 / 147 (17.69%)
         occurrences all number
    23
    4
    1
    1
    29
    Weight increased
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    5 / 147 (3.40%)
         occurrences all number
    7
    2
    0
    0
    9
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Fall
         subjects affected / exposed
    8 / 108 (7.41%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    9 / 147 (6.12%)
         occurrences all number
    13
    0
    1
    0
    14
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    3 / 147 (2.04%)
         occurrences all number
    2
    0
    0
    1
    3
    Sinus tachycardia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    4
    0
    1
    0
    5
    Nervous system disorders
    Coma
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Dizziness
         subjects affected / exposed
    19 / 108 (17.59%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    21 / 147 (14.29%)
         occurrences all number
    23
    1
    1
    0
    25
    Dysgeusia
         subjects affected / exposed
    45 / 108 (41.67%)
    3 / 20 (15.00%)
    3 / 17 (17.65%)
    2 / 2 (100.00%)
    53 / 147 (36.05%)
         occurrences all number
    49
    5
    3
    2
    59
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Headache
         subjects affected / exposed
    20 / 108 (18.52%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    23 / 147 (15.65%)
         occurrences all number
    32
    1
    2
    0
    35
    Neuropathy peripheral
         subjects affected / exposed
    7 / 108 (6.48%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    9 / 147 (6.12%)
         occurrences all number
    8
    2
    0
    0
    10
    Seizure
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Somnolence
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    1
    1
    1
    0
    3
    Taste disorder
         subjects affected / exposed
    7 / 108 (6.48%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    9
    0
    0
    0
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 108 (14.81%)
    2 / 20 (10.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    20 / 147 (13.61%)
         occurrences all number
    27
    2
    2
    0
    31
    Febrile neutropenia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Lymphopenia
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    3
    1
    0
    0
    4
    Eye disorders
    Cataract
         subjects affected / exposed
    7 / 108 (6.48%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    10
    0
    0
    0
    10
    Chorioretinal scar
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Dry eye
         subjects affected / exposed
    38 / 108 (35.19%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    1 / 2 (50.00%)
    41 / 147 (27.89%)
         occurrences all number
    45
    1
    1
    1
    48
    Episcleritis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Eye discharge
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Eye pain
         subjects affected / exposed
    6 / 108 (5.56%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    6
    0
    0
    0
    6
    Growth of eyelashes
         subjects affected / exposed
    8 / 108 (7.41%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    8 / 147 (5.44%)
         occurrences all number
    8
    0
    0
    0
    8
    Keratitis
         subjects affected / exposed
    4 / 108 (3.70%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    5 / 147 (3.40%)
         occurrences all number
    4
    0
    0
    1
    5
    Lacrimation increased
         subjects affected / exposed
    7 / 108 (6.48%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    12
    0
    0
    0
    12
    Ocular hyperaemia
         subjects affected / exposed
    6 / 108 (5.56%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    6
    0
    0
    0
    6
    Presbyopia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Punctate keratitis
         subjects affected / exposed
    8 / 108 (7.41%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    10 / 147 (6.80%)
         occurrences all number
    8
    1
    0
    1
    10
    Subretinal fluid
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Trichiasis
         subjects affected / exposed
    11 / 108 (10.19%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    13 / 147 (8.84%)
         occurrences all number
    11
    2
    0
    0
    13
    Trichomegaly
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    3 / 147 (2.04%)
         occurrences all number
    2
    0
    0
    1
    3
    Vitreous floaters
         subjects affected / exposed
    5 / 108 (4.63%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    6
    1
    0
    0
    7
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    9 / 108 (8.33%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    10 / 147 (6.80%)
         occurrences all number
    10
    0
    1
    0
    11
    Abdominal pain
         subjects affected / exposed
    22 / 108 (20.37%)
    3 / 20 (15.00%)
    3 / 17 (17.65%)
    1 / 2 (50.00%)
    29 / 147 (19.73%)
         occurrences all number
    39
    3
    3
    1
    46
    Abdominal pain upper
         subjects affected / exposed
    11 / 108 (10.19%)
    2 / 20 (10.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    14 / 147 (9.52%)
         occurrences all number
    16
    2
    1
    0
    19
    Ascites
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    5 / 147 (3.40%)
         occurrences all number
    4
    1
    0
    0
    5
    Constipation
         subjects affected / exposed
    46 / 108 (42.59%)
    5 / 20 (25.00%)
    2 / 17 (11.76%)
    1 / 2 (50.00%)
    54 / 147 (36.73%)
         occurrences all number
    68
    6
    2
    1
    77
    Diarrhoea
         subjects affected / exposed
    58 / 108 (53.70%)
    5 / 20 (25.00%)
    6 / 17 (35.29%)
    1 / 2 (50.00%)
    70 / 147 (47.62%)
         occurrences all number
    169
    15
    6
    1
    191
    Dry mouth
         subjects affected / exposed
    42 / 108 (38.89%)
    5 / 20 (25.00%)
    1 / 17 (5.88%)
    2 / 2 (100.00%)
    50 / 147 (34.01%)
         occurrences all number
    49
    5
    1
    2
    57
    Dyspepsia
         subjects affected / exposed
    14 / 108 (12.96%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    16 / 147 (10.88%)
         occurrences all number
    17
    2
    0
    0
    19
    Dysphagia
         subjects affected / exposed
    5 / 108 (4.63%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    5
    1
    0
    0
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    13 / 108 (12.04%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    16 / 147 (10.88%)
         occurrences all number
    14
    1
    2
    0
    17
    Haemorrhoids
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    0
    1
    0
    2
    Nausea
         subjects affected / exposed
    45 / 108 (41.67%)
    7 / 20 (35.00%)
    7 / 17 (41.18%)
    1 / 2 (50.00%)
    60 / 147 (40.82%)
         occurrences all number
    71
    10
    7
    2
    90
    Retching
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Stomatitis
         subjects affected / exposed
    46 / 108 (42.59%)
    6 / 20 (30.00%)
    3 / 17 (17.65%)
    1 / 2 (50.00%)
    56 / 147 (38.10%)
         occurrences all number
    74
    10
    3
    1
    88
    Vomiting
         subjects affected / exposed
    35 / 108 (32.41%)
    3 / 20 (15.00%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
    42 / 147 (28.57%)
         occurrences all number
    55
    3
    5
    0
    63
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    4
    1
    0
    0
    5
    Hyperbilirubinaemia
         subjects affected / exposed
    9 / 108 (8.33%)
    2 / 20 (10.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    12 / 147 (8.16%)
         occurrences all number
    9
    2
    1
    0
    12
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    64 / 108 (59.26%)
    4 / 20 (20.00%)
    3 / 17 (17.65%)
    2 / 2 (100.00%)
    73 / 147 (49.66%)
         occurrences all number
    66
    4
    3
    2
    75
    Decubitus ulcer
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    2
    1
    0
    0
    3
    Dry skin
         subjects affected / exposed
    30 / 108 (27.78%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    2 / 2 (100.00%)
    32 / 147 (21.77%)
         occurrences all number
    33
    0
    0
    2
    35
    Erythema
         subjects affected / exposed
    8 / 108 (7.41%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    8 / 147 (5.44%)
         occurrences all number
    9
    0
    0
    0
    9
    Hypertrichosis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    0
    1
    1
    Nail discolouration
         subjects affected / exposed
    12 / 108 (11.11%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    14 / 147 (9.52%)
         occurrences all number
    12
    1
    0
    1
    14
    Nail disorder
         subjects affected / exposed
    6 / 108 (5.56%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    6
    0
    0
    0
    6
    Nail dystrophy
         subjects affected / exposed
    11 / 108 (10.19%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    12 / 147 (8.16%)
         occurrences all number
    14
    1
    0
    0
    15
    Onychoclasis
         subjects affected / exposed
    9 / 108 (8.33%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    9 / 147 (6.12%)
         occurrences all number
    10
    0
    0
    0
    10
    Onycholysis
         subjects affected / exposed
    10 / 108 (9.26%)
    2 / 20 (10.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    13 / 147 (8.84%)
         occurrences all number
    10
    2
    1
    0
    13
    Onychomadesis
         subjects affected / exposed
    13 / 108 (12.04%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    14 / 147 (9.52%)
         occurrences all number
    14
    1
    0
    0
    15
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    23 / 108 (21.30%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    24 / 147 (16.33%)
         occurrences all number
    34
    2
    0
    0
    36
    Pruritus
         subjects affected / exposed
    13 / 108 (12.04%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    15 / 147 (10.20%)
         occurrences all number
    15
    1
    1
    0
    17
    Psoriasis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    0
    1
    0
    2
    Rash
         subjects affected / exposed
    12 / 108 (11.11%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    13 / 147 (8.84%)
         occurrences all number
    14
    0
    1
    0
    15
    Rash maculo-papular
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    2
    1
    0
    0
    3
    Skin disorder
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    6 / 108 (5.56%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    6
    1
    0
    0
    7
    Skin fissures
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    5 / 147 (3.40%)
         occurrences all number
    4
    1
    0
    0
    5
    Skin mass
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Skin ulcer
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    2
    0
    0
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 108 (4.63%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    8 / 147 (5.44%)
         occurrences all number
    6
    1
    2
    0
    9
    Chronic kidney disease
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    2
    1
    0
    0
    3
    Dysuria
         subjects affected / exposed
    2 / 108 (1.85%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    2
    2
    0
    0
    4
    Haematuria
         subjects affected / exposed
    0 / 108 (0.00%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    0
    2
    0
    0
    2
    Micturition urgency
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Pollakiuria
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    4
    1
    0
    0
    5
    Urinary tract pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    2
    0
    1
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    37 / 108 (34.26%)
    5 / 20 (25.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    44 / 147 (29.93%)
         occurrences all number
    52
    8
    3
    0
    63
    Back pain
         subjects affected / exposed
    27 / 108 (25.00%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    30 / 147 (20.41%)
         occurrences all number
    34
    1
    2
    0
    37
    Flank pain
         subjects affected / exposed
    5 / 108 (4.63%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    5
    2
    0
    0
    7
    Muscle spasms
         subjects affected / exposed
    11 / 108 (10.19%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    13 / 147 (8.84%)
         occurrences all number
    12
    1
    1
    0
    14
    Muscular weakness
         subjects affected / exposed
    5 / 108 (4.63%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    6
    1
    0
    0
    7
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Myalgia
         subjects affected / exposed
    15 / 108 (13.89%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    18 / 147 (12.24%)
         occurrences all number
    19
    1
    2
    0
    22
    Neck pain
         subjects affected / exposed
    5 / 108 (4.63%)
    0 / 20 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    5
    0
    2
    0
    7
    Osteoporotic fracture
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    26 / 108 (24.07%)
    3 / 20 (15.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    29 / 147 (19.73%)
         occurrences all number
    41
    4
    0
    0
    45
    Infections and infestations
    Acinetobacter bacteraemia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Bacterial vaginosis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    3
    1
    0
    0
    4
    Candida infection
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    0
    1
    0
    2
    Cellulitis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    0
    1
    1
    0
    2
    Conjunctivitis
         subjects affected / exposed
    7 / 108 (6.48%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    9 / 147 (6.12%)
         occurrences all number
    9
    1
    1
    0
    11
    Cystitis
         subjects affected / exposed
    5 / 108 (4.63%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    6
    1
    0
    0
    7
    Device related infection
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Klebsiella infection
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    6 / 108 (5.56%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    6 / 147 (4.08%)
         occurrences all number
    8
    0
    0
    0
    8
    Oral candidiasis
         subjects affected / exposed
    5 / 108 (4.63%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    6 / 147 (4.08%)
         occurrences all number
    6
    0
    0
    1
    7
    Oral herpes
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    0
    1
    0
    2
    Paronychia
         subjects affected / exposed
    9 / 108 (8.33%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    10 / 147 (6.80%)
         occurrences all number
    9
    1
    0
    0
    10
    Peritonitis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Peritonitis bacterial
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Pharyngitis
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    2
    1
    1
    0
    4
    Pneumonia
         subjects affected / exposed
    1 / 108 (0.93%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 147 (1.36%)
         occurrences all number
    1
    1
    0
    0
    2
    Rash pustular
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Trichomoniasis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 108 (6.48%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    8
    0
    0
    0
    8
    Urinary tract infection
         subjects affected / exposed
    21 / 108 (19.44%)
    2 / 20 (10.00%)
    2 / 17 (11.76%)
    1 / 2 (50.00%)
    26 / 147 (17.69%)
         occurrences all number
    33
    3
    2
    1
    39
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    34 / 108 (31.48%)
    7 / 20 (35.00%)
    7 / 17 (41.18%)
    1 / 2 (50.00%)
    49 / 147 (33.33%)
         occurrences all number
    39
    10
    8
    2
    59
    Dehydration
         subjects affected / exposed
    16 / 108 (14.81%)
    1 / 20 (5.00%)
    3 / 17 (17.65%)
    1 / 2 (50.00%)
    21 / 147 (14.29%)
         occurrences all number
    17
    2
    4
    1
    24
    Hypercalcaemia
         subjects affected / exposed
    16 / 108 (14.81%)
    4 / 20 (20.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    21 / 147 (14.29%)
         occurrences all number
    18
    5
    2
    0
    25
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    2
    1
    0
    0
    3
    Hyperglycaemia
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    4
    1
    0
    0
    5
    Hyperkalaemia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Hyperphosphataemia
         subjects affected / exposed
    60 / 108 (55.56%)
    13 / 20 (65.00%)
    12 / 17 (70.59%)
    1 / 2 (50.00%)
    86 / 147 (58.50%)
         occurrences all number
    109
    14
    13
    1
    137
    Hyperuricaemia
         subjects affected / exposed
    4 / 108 (3.70%)
    3 / 20 (15.00%)
    1 / 17 (5.88%)
    1 / 2 (50.00%)
    9 / 147 (6.12%)
         occurrences all number
    5
    3
    1
    1
    10
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 108 (1.85%)
    2 / 20 (10.00%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
    7 / 147 (4.76%)
         occurrences all number
    2
    2
    3
    0
    7
    Hypocalcaemia
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    3
    1
    1
    0
    5
    Hypokalaemia
         subjects affected / exposed
    9 / 108 (8.33%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    10 / 147 (6.80%)
         occurrences all number
    10
    0
    1
    0
    11
    Hyponatraemia
         subjects affected / exposed
    6 / 108 (5.56%)
    4 / 20 (20.00%)
    4 / 17 (23.53%)
    0 / 2 (0.00%)
    14 / 147 (9.52%)
         occurrences all number
    10
    6
    6
    0
    22
    Hypophosphataemia
         subjects affected / exposed
    28 / 108 (25.93%)
    4 / 20 (20.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    34 / 147 (23.13%)
         occurrences all number
    49
    6
    2
    0
    57
    Hypovitaminosis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Malnutrition
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    10 / 108 (9.26%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    12 / 147 (8.16%)
         occurrences all number
    10
    1
    0
    1
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Sep 2016
    The primary purpose of this amendment was to amend the language regarding participants to whom the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-BIL21 was to be administered.
    05 Dec 2016
    The primary purpose of this amendment was to update language based on Regulatory Agencies comments. Updates included but were not limited to clarification of inclusion and exclusion criteria, the addition of updated clinical experience data, and guidance for dose reductions.
    18 Jan 2017
    The primary purpose of this amendment was to update the text in the Protocol based on the European Union Voluntary Harmonisation Procedure (VHP) request, to clarify requirements for human immunodeficiency virus (HIV) screening and enrollment parameters for Cohort C.
    21 Mar 2017
    The primary purpose of this amendment was to provide new language to allow participants to enroll under local genomic testing results. Updated clinical experience data were added as well.
    03 Oct 2017
    The primary purpose of this amendment was to increase the total number of participants enrolled into the study.
    15 Feb 2018
    The primary purpose of this amendment was to ensure the study population was clearly identified, to provide guidelines for dose reductions, and to provide additional language for ophthalmologic testing and hyperphosphatemia grading.
    02 Apr 2020
    The primary purpose of this amendment was to incorporate previous administrative changes and include updated language for comprehensive eye examination, per Food and Drug Administration (FDA) feedback.

    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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