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    Clinical Trial Results:
    A randomized phase 2 study comparing different dose-approaches of induction treatment (first cycle) of regorafenib in metastatic colorectal cancer (mCRC) patients

    Summary
    EudraCT number
    		 2016-000640-34
    Trial protocol
    		 ES   FR   IT  
    Global end of trial date
    24 Sep 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    TTD-16-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    TTD
    Sponsor organisation address
    Téllez 30, Madrid, Spain, 28007
    Public contact
    Inmaculada Ruiz de Mena, Grupo de Tratamiento de los Tumores Digestivos (TTD), +34 91378 82 75, ttd@ttdgroup.org
    Scientific contact
    Inmaculada Ruiz de Mena, Grupo de Tratamiento de los Tumores Digestivos (TTD), +34 91378 82 75, ttd@ttdgroup.org
    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
    13 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of different dose-escalation approaches of regorafenib in mCRC patients.
    Protection of trial subjects
    Any medication that patients needed for their correct clinical control (except prohibited therapies), according to investigator’s criteria were allowed.
    Background therapy
    		 Standard therapies for concurrent medical conditions. Prophylactic anti-emetics could be administered according to standard practice. Treatment with non-conventional therapies (eg, herbs or acupuncture) or vitamin/mineral supplements was acceptable provided that such agents did not interfere, in the opinion of the investigator, with the study endpoints. Bisphosphonates. Subjects taking narrow therapeutic index medications, such as warfarin, quinidine, cyclosporine, and digoxin, were monitored proactively. Contrast agents used in CT or MRI. G-CSF and other hematopoietic growth factors could be used during the study for the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator; however, there could not be substituted for a required dose reduction. Long-term administration of erythropoietin was permitted.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2016
    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
    Spain: 277
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Italy: 12
    Worldwide total number of subjects
    299
    EEA total number of subjects
    299
    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)
    159
    From 65 to 84 years
    140
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 299
    Number of subjects completed
    		 299

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Control arm: 160 mg regorafenib/day 3 weeks every 4 weeks
    Arm type
    		 Control

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Regorafenib 160 mg/day 3weeks / 4 weeks

    Arm title
    		 Arm B
    Arm description
    		 120 mg/day 3 weeks every 4 weeks (first cycle), 160 mg/day 3 weeks/4 weeks if no limiting toxicities
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg/day 3 weeks every 4 weeks 1st cycle, 160 mg/day 3 weeks every 4 weeks if no limiting toxicities

    Arm title
    		 Arm C
    Arm description
    		 160 mg/day 1 week on, 1 week off during the first cycle, Dose escalation to the standard dose of 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks followed by 1 week off therapy from cycle 2 onwards if no limiting toxicities
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg/day, 1 week on/1 week off 1st cycle: 160 mg/day 3 weeks on/1week off 2nd cycle on

    Number of subjects in period 1
    		Arm A Arm B Arm C
    Started
    101
    99
    99
    Completed
    100
    98
    99
    Not completed
    1
    1
    0
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Control arm: 160 mg regorafenib/day 3 weeks every 4 weeks

    Reporting group title
    Arm B
    Reporting group description
    		 120 mg/day 3 weeks every 4 weeks (first cycle), 160 mg/day 3 weeks/4 weeks if no limiting toxicities

    Reporting group title
    Arm C
    Reporting group description
    		 160 mg/day 1 week on, 1 week off during the first cycle, Dose escalation to the standard dose of 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks followed by 1 week off therapy from cycle 2 onwards if no limiting toxicities

    Reporting group values
    		 Arm A Arm B Arm C Total
    Number of subjects
    		 101 99 99 299
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 50 56 53 159
        From 65-84 years
    		 51 43 46 140
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.2 ( 9.08 ) 62.34 ( 9.86 ) 62.56 ( 9.92 ) -
    Gender categorical
    Units: Subjects
        Female
    		 42 46 47 135
        Male
    		 59 53 52 164
    ECOG
    Units: Subjects
        ECOG 0
    		 36 33 35 104
        ECOG 1
    		 65 66 64 195
    Cancer history-Location
    Units: Subjects
        Rectum
    		 31 22 39 92
        Colon
    		 53 59 49 161
        Colon and rectum
    		 17 18 11 46
    Histology
    Units: Subjects
        Adenocarcinoma
    		 89 90 91 270
        Missing
    		 6 5 7 18
        Carcinoma not otherwise specified
    		 0 1 0 1
        Mucinous carcinoma
    		 3 0 0 3
        UK
    		 3 2 1 6
        ND
    		 0 1 0 1
    Histological Grade
    Units: Subjects
        G1: Well-differentiated
    		 15 16 21 52
        G2: Moderately differentiated
    		 31 30 38 99
        G3: Poorly differentiated
    		 10 7 5 22
        Gx: Grade cannot assessed
    		 4 3 4 11
        Missing
    		 1 0 0 1
        Unknown
    		 40 43 31 114
    Previous radiotherapy
    Units: Subjects
        YES
    		 28 22 27 77
        NO
    		 73 77 72 222
    Number of prior treatment lines
    Units: Treatment lines
        arithmetic mean (standard deviation)
    		 4.12 ( 1.81 ) 4.21 ( 4.00 ) 3.85 ( 3.00 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Control arm: 160 mg regorafenib/day 3 weeks every 4 weeks

    Reporting group title
    Arm B
    Reporting group description
    		 120 mg/day 3 weeks every 4 weeks (first cycle), 160 mg/day 3 weeks/4 weeks if no limiting toxicities

    Reporting group title
    Arm C
    Reporting group description
    		 160 mg/day 1 week on, 1 week off during the first cycle, Dose escalation to the standard dose of 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks followed by 1 week off therapy from cycle 2 onwards if no limiting toxicities

    Primary: • Percentage of patients with G3/G4 treatment-related AEs in each arm according to CTCAE v4.03 criteria.

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    End point title
    		 • Percentage of patients with G3/G4 treatment-related AEs in each arm according to CTCAE v4.03 criteria.
    End point description
    End point type
    Primary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    100
    98
    99
    Units: percentage
    60
    55
    54
    Statistical analysis title
    		 % of pt with G3/G4 treat-rel AEs in each arm
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7262
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Confidence interval

    Secondary: Percentage of total administrated dose over the planned dose received

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    End point title
    		 Percentage of total administrated dose over the planned dose received
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    100
    98
    99
    Units: dosage form
        arithmetic mean (standard deviation)
    82.25 ( 29.51 )
    67.30 ( 26.93 )
    71.81 ( 25.14 )
    Statistical analysis title
    		 % of total adm dose over the plan dose received
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0217
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Dose intensity during the whole treatment

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    End point title
    		 Dose intensity during the whole treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    100
    98
    99
    Units: dosage form
        arithmetic mean (standard deviation)
    68.54 ( 24.60 )
    66.42 ( 24.83 )
    74.92 ( 23.65 )
    Statistical analysis title
    		 Dose intensity dur whole treatment
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0002
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Percentage of dose reductions in each arm.

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    End point title
    		 Percentage of dose reductions in each arm.
    End point description
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    100
    98
    99
    Units: Percentage
    39
    38
    25
    Statistical analysis title
    		 % of dose red in each arm
    Comparison groups
    Arm B v Arm C v Arm A
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    34.3434
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 28.9549
         upper limit
    		 40.0479

    Secondary: Percentage of dose delays in each arm

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    End point title
    		 Percentage of dose delays in each arm
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    100
    98
    99
    Units: Percentage
    35
    33
    29
    Statistical analysis title
    		 Percentage of dose delays in each arm
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    32.6599
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 27.3549
         upper limit
    		 38.3151

    Secondary: Dose intensity during the first two cycles

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    End point title
    		 Dose intensity during the first two cycles
    End point description
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    100
    98
    99
    Units: dosage form
        arithmetic mean (standard deviation)
    90.77 ( 27.91 )
    77.09 ( 24.94 )
    79.99 ( 22.41 )
    Statistical analysis title
    		 Dose intensity during the first 2 cycles
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.001
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Disease control rate

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    End point title
    		 Disease control rate
    End point description
    Number of patients with complete response, partial response or stable disease
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    101
    99
    99
    Units: Subjects
        Complete response
    0
    0
    0
        Partial response
    2
    2
    3
        Stable disease
    31
    34
    32
    Statistical analysis title
    		 Disease control rate
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8515
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    Time from randomization until the date of the first disease progression, observed radiologically, or death (whichever comes first). Subjects who have shown no progression while in the study and who did not die in the study were censored at the date of their last evaluable disease assessment.
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    101
    99
    99
    Units: months
        median (confidence interval 95%)
    1.94 (1.84 to 2.07)
    2 (1.87 to 2.86)
    1.97 (1.87 to 2.2)
    Statistical analysis title
    		 Progression free survival
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3795
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to treatment failure (TTF)

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    End point title
    		 Time to treatment failure (TTF)
    End point description
    Time from randomization until the date the decision is made to end the treatment period, for any reason. For subjects who remained in the treatment period at the time of the analysis, time to treatment failure was censored at the date of their last evaluable disease assessment.
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    101
    99
    99
    Units: months
        median (confidence interval 95%)
    1.87 (1.81 to 2.04)
    1.94 (1.84 to 2.07)
    1.94 (1.84 to 2.14)
    Statistical analysis title
    		 Time to treatment failure
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2114
    Method
    		 Logrank
    Parameter type
    		 Logrank
    Confidence interval

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Time from randomization until the date of death due to any cause. Subjects who were lost to follow-up or who did not die by the end of the study were censored at the last contact date.
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    101
    99
    99
    Units: months
        median (confidence interval 95%)
    7.39 (5.98 to 9.34)
    8.58 (5.78 to 10.13)
    7.13 (5.85 to 8.22)
    Statistical analysis title
    		 Overall survival
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7222
    Method
    		 Logrank
    Parameter type
    		 Logrank
    Confidence interval

    Secondary: Proportion of patients who complete 2 cycles and who intend to initiate cycle 3

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    End point title
    		 Proportion of patients who complete 2 cycles and who intend to initiate cycle 3
    End point description
    Proportion of patients in each arm who completed 2 cycles of treatment and who intended to initiate cycle 3 if no progression was noted on the planned 8-week scan.
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    100
    98
    99
    Units: Percentage
    39
    43
    45
    Statistical analysis title
    		 Prop of pt who complet 2 cyc
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6309
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Confidence interval

    Secondary: Proportion of patients who stopped the trial due to disease progression at planned 8-week scan

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    End point title
    		 Proportion of patients who stopped the trial due to disease progression at planned 8-week scan
    End point description
    Proportion of patients who stopped the trial due to disease progression in each arm at the planned 8-week scan
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    61
    55
    54
    Units: Percentage
    63
    63
    61
    Statistical analysis title
    		 Prop pt who stop trial at 8-week scan
    Comparison groups
    Arm A v Arm B v Arm C
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.9442
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 -

    Reporting group title
    Arm B
    Reporting group description
    		 -

    Reporting group title
    Arm C
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A Arm B Arm C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 100 (29.00%)
    29 / 98 (29.59%)
    24 / 99 (24.24%)
         number of deaths (all causes)
    80
    78
    83
         number of deaths resulting from adverse events
    6
    6
    8
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 98 (1.02%)
    4 / 99 (4.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    pyrexia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Performance status decreased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 98 (1.02%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 98 (1.02%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    blood glycaemia decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Acute coronary syndrome
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Leukoencephalopathy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    diarrhoea
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 98 (2.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 98 (1.02%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Oesophegal varices haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 98 (3.06%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    Jaundice cholestatic
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 98 (2.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ulcer
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 100 (5.00%)
    2 / 98 (2.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Enterocolitis infectious
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B Arm C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    100 / 100 (100.00%)
    98 / 98 (100.00%)
    99 / 99 (100.00%)
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    24 / 100 (24.00%)
    20 / 98 (20.41%)
    25 / 99 (25.25%)
         occurrences all number
    24
    20
    25
    Hyperbilirubinaemia
         subjects affected / exposed
    20 / 100 (20.00%)
    25 / 98 (25.51%)
    19 / 99 (19.19%)
         occurrences all number
    20
    25
    19
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 100 (12.00%)
    20 / 98 (20.41%)
    10 / 99 (10.10%)
         occurrences all number
    12
    20
    10
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 100 (6.00%)
    15 / 98 (15.31%)
    8 / 99 (8.08%)
         occurrences all number
    6
    15
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 100 (7.00%)
    13 / 98 (13.27%)
    8 / 99 (8.08%)
         occurrences all number
    7
    13
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 100 (5.00%)
    9 / 98 (9.18%)
    5 / 99 (5.05%)
         occurrences all number
    5
    9
    5
    Amylase increased
         subjects affected / exposed
    6 / 100 (6.00%)
    6 / 98 (6.12%)
    6 / 99 (6.06%)
         occurrences all number
    6
    6
    6
    Vascular disorders
    Hypertension
         subjects affected / exposed
    46 / 100 (46.00%)
    41 / 98 (41.84%)
    48 / 99 (48.48%)
         occurrences all number
    46
    41
    48
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 100 (11.00%)
    4 / 98 (4.08%)
    13 / 99 (13.13%)
         occurrences all number
    11
    4
    13
    Aphonia
         subjects affected / exposed
    8 / 100 (8.00%)
    11 / 98 (11.22%)
    3 / 99 (3.03%)
         occurrences all number
    8
    11
    3
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    22 / 100 (22.00%)
    14 / 98 (14.29%)
    14 / 99 (14.14%)
         occurrences all number
    22
    14
    14
    Anaemia
         subjects affected / exposed
    13 / 100 (13.00%)
    9 / 98 (9.18%)
    19 / 99 (19.19%)
         occurrences all number
    13
    9
    19
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    67 / 100 (67.00%)
    63 / 98 (64.29%)
    68 / 99 (68.69%)
         occurrences all number
    67
    63
    68
    Mucosal inflammation
         subjects affected / exposed
    25 / 100 (25.00%)
    22 / 98 (22.45%)
    23 / 99 (23.23%)
         occurrences all number
    25
    22
    23
    pyrexia
         subjects affected / exposed
    24 / 100 (24.00%)
    20 / 98 (20.41%)
    16 / 99 (16.16%)
         occurrences all number
    24
    20
    16
    Fatigue
         subjects affected / exposed
    11 / 100 (11.00%)
    11 / 98 (11.22%)
    15 / 99 (15.15%)
         occurrences all number
    11
    11
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    47 / 100 (47.00%)
    34 / 98 (34.69%)
    41 / 99 (41.41%)
         occurrences all number
    47
    34
    41
    Abdominal pain
         subjects affected / exposed
    22 / 100 (22.00%)
    20 / 98 (20.41%)
    17 / 99 (17.17%)
         occurrences all number
    22
    20
    17
    Constipation
         subjects affected / exposed
    18 / 100 (18.00%)
    17 / 98 (17.35%)
    18 / 99 (18.18%)
         occurrences all number
    18
    17
    18
    Nausea
         subjects affected / exposed
    17 / 100 (17.00%)
    14 / 98 (14.29%)
    19 / 99 (19.19%)
         occurrences all number
    17
    14
    19
    Vomiting
         subjects affected / exposed
    13 / 100 (13.00%)
    16 / 98 (16.33%)
    14 / 99 (14.14%)
         occurrences all number
    13
    16
    14
    Abdominal pain upper
         subjects affected / exposed
    12 / 100 (12.00%)
    13 / 98 (13.27%)
    6 / 99 (6.06%)
         occurrences all number
    12
    13
    6
    Dry mouth
         subjects affected / exposed
    7 / 100 (7.00%)
    6 / 98 (6.12%)
    4 / 99 (4.04%)
         occurrences all number
    7
    6
    4
    Stomatitis
         subjects affected / exposed
    6 / 100 (6.00%)
    4 / 98 (4.08%)
    6 / 99 (6.06%)
         occurrences all number
    6
    4
    6
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    51 / 100 (51.00%)
    43 / 98 (43.88%)
    44 / 99 (44.44%)
         occurrences all number
    51
    43
    44
    Cough
         subjects affected / exposed
    9 / 100 (9.00%)
    12 / 98 (12.24%)
    4 / 99 (4.04%)
         occurrences all number
    9
    12
    4
    Dyspnoea
         subjects affected / exposed
    7 / 100 (7.00%)
    4 / 98 (4.08%)
    7 / 99 (7.07%)
         occurrences all number
    7
    4
    7
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    40 / 100 (40.00%)
    52 / 98 (53.06%)
    41 / 99 (41.41%)
         occurrences all number
    40
    52
    41
    Rash
         subjects affected / exposed
    19 / 100 (19.00%)
    13 / 98 (13.27%)
    15 / 99 (15.15%)
         occurrences all number
    19
    13
    15
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    10 / 100 (10.00%)
    10 / 98 (10.20%)
    9 / 99 (9.09%)
         occurrences all number
    10
    10
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 100 (16.00%)
    15 / 98 (15.31%)
    12 / 99 (12.12%)
         occurrences all number
    16
    15
    12
    Musculoskeletal pain
         subjects affected / exposed
    10 / 100 (10.00%)
    6 / 98 (6.12%)
    8 / 99 (8.08%)
         occurrences all number
    10
    6
    8
    Myalgia
         subjects affected / exposed
    6 / 100 (6.00%)
    6 / 98 (6.12%)
    11 / 99 (11.11%)
         occurrences all number
    6
    6
    11
    Arthralgia
         subjects affected / exposed
    4 / 100 (4.00%)
    5 / 98 (5.10%)
    9 / 99 (9.09%)
         occurrences all number
    4
    5
    9
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    11 / 100 (11.00%)
    9 / 98 (9.18%)
    4 / 99 (4.04%)
         occurrences all number
    11
    9
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    45 / 100 (45.00%)
    47 / 98 (47.96%)
    37 / 99 (37.37%)
         occurrences all number
    45
    47
    37

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jul 2018
    The substantial amendment was done in order to update the analysis section. The following changes were made from Protocol v1.0 (15-Feb-2016) to protocol v2.0 (9-Jul-18).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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