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    Clinical Trial Results:
    A Randomized, Open-Label, Multi-Center, International Phase 2 Study of TAS-114 in Combination with S-1 in Patients with Advanced or Metastatic Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2016-001806-40
    Trial protocol
    		 ES   PL  
    Global end of trial date
    30 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Oct 2020
    First version publication date
    19 Oct 2020
    Other versions
    Summary report(s)
    		 2016-001806-40 - TAS-114-201 CSR Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    TO-TAS-114-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Taiho Oncology, Inc.
    Sponsor organisation address
    202 Carnegie Center, Suite 100, Princeton, United States, 08540
    Public contact
    Clinical Trials Information, Medpace Spain S.L, 0034 918534105, Spain.Regulatory@medpace.com
    Scientific contact
    Clinical Trials Information, Medpace Spain S.L, 0034 918534105, Spain.Regulatory@medpace.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
    30 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the progression-free survival (PFS) of patients with advanced or metastatic non-small cell lung cancer NSCLC, when treated with TAS-114/S-1 combination versus S-1 in patients with advanced solid tumor for which no standard therapy exists
    Protection of trial subjects
    All considerations regarding the protection of human subjects were carried out in accordance with the protocol, GCP, ICH Guidelines, the ethical principles that have their origin in the Declaration of Helsinki, and all applicable regulatory requirements. The investigator (according to applicable regulatory requirements) or a person designated by the investigator and under the investigator’s responsibility fully informed patients of all pertinent aspects of the clinical trial. All participants were informed to the fullest extent possible about the study in a language and in terms they are able to understand. Before participation in the trial, the written ICF were signed and personally dated by the patient or by the patient’s legal representative and by the person who conducted the ICF discussion. The study was approved by an appropriately constituted Institutional Review Board/Independent Ethics Committee (IRB/IEC), as required in Chapter 3 of the ICH E6 Guidelines, applicable local regulations, and, for studies conducted under an Investigational New Drug (IND) application, the United States (US) Code of Federal Regulations Title 21 part 56. Randomization took place once the consented patient completed all the necessary baseline procedures and was deemed eligible for study entry. Treatment assignment was done centrally using a dynamic allocation method (biased coin) via an interactive voice/web response system (IXRS) stratified by: 1) geographical region (Region 1: Asian; Region 2: Western); and 2) histological subtypes (non-squamous cell carcinoma [including mixed] and squamous cell carcinoma). Patients continued to receive study therapy until documentation of progressive disease (PD), intolerable toxicity, withdrawal of consent, or other discontinuation criteria were met.
    Background therapy
    		 -
    Evidence for comparator
    		 Chemotherapy regimens containing 5-fluorouracil (5-FU) drugs as the backbone are mainstays for the treatment of many cancers including breast, colorectal, and gastric cancer. Many combination chemotherapies employing 5-FU with chemical modulators such as leucovorin and other anti-malignant tumor agents have been investigated and have demonstrated efficacy against a variety of carcinomas to date. Oral fluoropyrimidines such as S-1, a fixed dose combination of tegafur, a prodrug of 5-FU, gimeracil, a dihydropyrimidine dehydrogenase (DPD) inhibitor that prevents degradation of 5-FU by the body and maintains 5-FU exposure, and oteracil potassium, an orotate phosphoribosyltransferase (OPRT) inhibitor that decreases the activity of 5-FU in normal gastrointestinal (GI) mucosa have been developed
    Actual start date of recruitment
    15 Aug 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: 25
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    Japan: 60
    Worldwide total number of subjects
    128
    EEA total number of subjects
    60
    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)
    61
    From 65 to 84 years
    67
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was planned to enroll approximately 124 patients with advanced or metastatic NSCLC. A total of 128 patients were randomized (64 to each study arm) at 26 study sites located in 5 countries and made up the intent-to-treat (ITT) population.

    Pre-assignment
    Screening details
    		 All patients completed the following study procedures prior to a confirmation of eligibility: Medical History, ECOG performance status , 12-lead electrocardiogram (ECG), Blood and urine sample assessment, Physical Examination, Baseline Signs and Symptoms, Height, Vital Signs, Weight, Pregnancy testing, CT scan and bone scan and so on...

    Pre-assignment period milestones
    Number of subjects started
    		 165 [1]
    Number of subjects completed
    		 128

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen Failure: 37
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 165 patients started screening and out of 165 patients, 37 patients screened failed and therefore 128 patients were randomized
    Period 1
    Period 1 title
    Baseline Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Baseline
    Arm description
    		 Baseline period; screening for participation in the study
    Arm type
    		 Screening

    Investigational medicinal product name
    TAS-114
    Investigational medicinal product code
    TAS-114
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAS-114, supplied as 100 mg tablets packaged in kits containing 20 tablets for Europe and the US and 120 tablets for Japan. TAS-114 (400 mg per dose) was administered to patients in the TAS-114/S-1 arm orally BID, with a glass of water within 1 hour after completion of morning and evening meals, for 14 days, followed by a 7-day rest period.

    Investigational medicinal product name
    S-1
    Investigational medicinal product code
    L01BC53
    Other name
    Tegafur/gimeracil/oteracil
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    S-1 is an immediate release dosage form contained in hard gelatin capsules in which tegafur (FT), gimeracil (CDHP), and oteracil as monopotassium salt (Oxo) are combined at a molar ratio of 1:0.4:1. Study drug was packaged in kits containing 28 capsules (15-mg or 20-mg capsules) for all regions. Patients in both arms received S-1 at a dose of 30 mg/m2 BID, with a glass of water within 1 hour after completion of morning and evening meals, for 14 days, followed by a 7-day rest period.

    Number of subjects in period 1
    		Baseline
    Started
    128
    Sign ICF
    128
    Inclusion/Exclusion
    128
    Assign Patient Number
    128
    Medical History
    128
    Baseline Signs and Symptoms
    128
    Physical Exam
    128
    Height
    128
    Vital Signs/Weight
    128
    Performance Status
    128
    ECG
    128
    Hematology
    128
    Serum Chemistry
    128
    Coagulation
    128
    Urinalysis
    128
    Pregnancy test
    128
    Concomitant Medications
    128
    Tumor Assessment
    128
    Completed
    128
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TAS-114/S-1
    Arm description
    		 Experimental arm, evaluating the efficacy, safety and tolerability of TAS-114 in combination with S-1 regimen in patients with advanced or metastatic non-small cell lung cancer (NSCLC).
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAS-114
    Investigational medicinal product code
    TAS-114
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAS-114, supplied as 100 mg tablets packaged in kits containing 20 tablets for Europe and the US and 120 tablets for Japan. TAS-114 (400 mg per dose) was administered to patients in the TAS-114/S-1 arm orally BID, with a glass of water within 1 hour after completion of morning and evening meals, for 14 days, followed by a 7-day rest period.

    Investigational medicinal product name
    S-1
    Investigational medicinal product code
    L01BC53
    Other name
    Tegafur/gimeracil/oteracil
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    S-1 is an immediate release dosage form contained in hard gelatin capsules in which tegafur (FT), gimeracil (CDHP), and oteracil as monopotassium salt (Oxo) are combined at a molar ratio of 1:0.4:1. Study drug was packaged in kits containing 28 capsules (15-mg or 20-mg capsules) for all regions. Patients in both arms received S-1 at a dose of 30 mg/m2 BID, with a glass of water within 1 hour after completion of morning and evening meals, for 14 days, followed by a 7-day rest period.

    Arm title
    		 S-1 control
    Arm description
    		 Control arm, evaluating the efficacy, safety and tolerability of the S-1 regimen in patients with advanced or metastatic non-small cell lung cancer (NSCLC).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    S-1
    Investigational medicinal product code
    L01BC53
    Other name
    Tegafur/gimeracil/oteracil
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    S-1 is an immediate release dosage form contained in hard gelatin capsules in which tegafur (FT), gimeracil (CDHP), and oteracil as monopotassium salt (Oxo) are combined at a molar ratio of 1:0.4:1. Study drug was packaged in kits containing 28 capsules (15-mg or 20-mg capsules) for all regions. Patients in both arms received S-1 at a dose of 30 mg/m2 BID, with a glass of water within 1 hour after completion of morning and evening meals, for 14 days, followed by a 7-day rest period.

    Number of subjects in period 2
    		TAS-114/S-1 S-1 control
    Started
    64
    64
    Inclusion/Exclusion
    64
    64
    Baseline Signs and Symptoms
    64
    64
    Physical Exam
    64
    64
    Vital Signs/Weight
    64
    64
    Performance Status
    64
    64
    Hematology
    64
    64
    Serum Chemistry
    64
    64
    Coagulation
    64
    64
    Concomitant Medications
    64
    64
    AE/Toxicity Assessment
    64
    64
    Tumor Assessment
    64
    64
    TAS-114/S-1 or S-1 treatment
    64
    64
    PGx Sampling
    64
    64
    Survival Status
    64
    64
    Completed
    64
    63
    Not completed
    0
    1
         Physician decision
    -
    1
    Period 3
    Period 3 title
    End of Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TAS-114/S-1
    Arm description
    		 End of Treatment/Study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 S-1 control
    Arm description
    		 End of Treatment/Study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		TAS-114/S-1 S-1 control
    Started
    64
    63
    Physical Exam
    64
    63
    Vital Signs/Weight
    64
    63
    Performance Status
    64
    63
    ECG
    64
    63
    Hematology
    64
    63
    Serum Chemistry
    64
    63
    Coagulation
    64
    63
    Urinalysis
    64
    63
    Concomitant Medications
    64
    63
    AE/Toxicity Assessment
    64
    63
    Tumor Assessment
    64
    63
    PGx Sampling
    64
    63
    Survival Status
    64
    63
    Completed
    9
    11
    Not completed
    55
    52
         Consent withdrawn by subject
    2
    2
         Physician decision
    1
    -
         Adverse event, non-fatal
    11
    7
         Lack of efficacy
    41
    43

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline Period
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Period Total
    Number of subjects
    		 128 128
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 61 61
        From 65-84 years
    		 67 67
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 63.2 (43 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 39 39
        Male
    		 89 89
    Race
    Units: Subjects
        Asian/Oriental
    		 60 60
        Caucasian/White
    		 42 42
        Not Collected
    		 24 24
        Other
    		 2 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 13 13
        Not Hispanic or Latino
    		 92 92
        Not Collected
    		 23 23
    Weight
    Units: kg
        arithmetic mean (full range (min-max))
    		 64.8 (38 to 104) -
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    		 165.6 (140 to 190) -
    Subject analysis sets

    Subject analysis set title
    Intention to treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population - patients who were randomized

    Subject analysis set title
    Intention to treat (ITT) - TAS-114/S-1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat (ITT) population for the TAS-114/S-1 group

    Subject analysis set title
    Intention to treat (ITT) - S-1 control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat (ITT) population for the S-1 control group

    Subject analysis sets values
    		 Intention to treat (ITT) Intention to treat (ITT) - TAS-114/S-1 Intention to treat (ITT) - S-1 control
    Number of subjects
    128
    64
    64
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    61
    28
    33
        From 65-84 years
    67
    36
    31
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    63.2 (43 to 80)
    63.8 (46 to 76)
    62.6 (43 to 80)
    Gender categorical
    Units: Subjects
        Female
    39
    23
    16
        Male
    89
    41
    48
    Race
    Units: Subjects
        Asian/Oriental
    60
    30
    30
        Caucasian/White
    42
    21
    21
        Not Collected
    24
    12
    12
        Other
    2
    1
    1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    13
    8
    5
        Not Hispanic or Latino
    92
    45
    47
        Not Collected
    23
    11
    12
    Weight
    Units: kg
        arithmetic mean (full range (min-max))
    64.8 (38 to 104)
    63.5 (39 to 92)
    66.0 (38 to 104)
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    165.6 (140 to 190)
    164.5 (148 to 180)
    168.0 (140 to 190)

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Baseline period; screening for participation in the study
    Reporting group title
    TAS-114/S-1
    Reporting group description
    		 Experimental arm, evaluating the efficacy, safety and tolerability of TAS-114 in combination with S-1 regimen in patients with advanced or metastatic non-small cell lung cancer (NSCLC).

    Reporting group title
    S-1 control
    Reporting group description
    		 Control arm, evaluating the efficacy, safety and tolerability of the S-1 regimen in patients with advanced or metastatic non-small cell lung cancer (NSCLC).
    Reporting group title
    TAS-114/S-1
    Reporting group description
    		 End of Treatment/Study

    Reporting group title
    S-1 control
    Reporting group description
    		 End of Treatment/Study

    Subject analysis set title
    Intention to treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population - patients who were randomized

    Subject analysis set title
    Intention to treat (ITT) - TAS-114/S-1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat (ITT) population for the TAS-114/S-1 group

    Subject analysis set title
    Intention to treat (ITT) - S-1 control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat (ITT) population for the S-1 control group

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Progression-Free Survival (PFS) was the primary endpoint of this study and was defined as the time from the day of randomization to the start of disease progression or death (any cause), whichever occurs first, based on the blinded radiological review assessment of response. PFS was compared between the 2 treatment groups using the stratified log-rank test with significance level of 1-sided 5%. The estimate of the hazard ratio and corresponding 90% and 95% confidence interval (CI) were provided using a Cox proportional hazards (CPH) model including treatment and the 2 stratification factors in the model; survival curves were estimated using the Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    Time from the day of randomization to the start of disease progression or death (any cause), whichever occurs first, based on the blinded radiological review assessment of response.
    End point values
    		 TAS-114/S-1 S-1 control
    Number of subjects analysed
    64
    64
    Units: months
        median (confidence interval 95%)
    3.65 (2.69 to 5.16)
    4.17 (2.60 to 6.60)
    Statistical analysis title
    		 Progression-Free Survival
    Statistical analysis description
    Progression-Free Survival (PFS) per central independent review in the Intent to Treat (ITT) population. PFS was compared between the 2 treatment groups using the stratified log-rank test with significance level of 1-sided 5%. The estimate of the hazard ratio and corresponding 90% and 95% confidence interval (CI) were provided using a Cox proportional hazards (CPH) model including treatment and the 2 stratification factors in the model.
    Comparison groups
    S-1 control v TAS-114/S-1
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2744
    Method
    		 t-test, 1-sided
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.88
    Variability estimate
    Standard deviation

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Survival (OS) was defined as the time from the day of randomization to the date of death by any cause. The estimate of the HR and corresponding 95% CI was provided using a univariate CPH model. Survival curves were estimated using the Kaplan-Meier method, and treatment arms were compared using an unstratified log-rank test.
    End point type
    Secondary
    End point timeframe
    Overall Survival (OS) was defined as the time from the day of randomization to the date of death by any cause.
    End point values
    		 TAS-114/S-1 S-1 control
    Number of subjects analysed
    64
    64
    Units: months
        median (confidence interval 95%)
    7.92 (6.28 to 10.78)
    9.82 (7.66 to 13.40)
    Statistical analysis title
    		 Overall Survival (months)
    Statistical analysis description
    Overall Survival (OS) in the Intent to Treat (ITT) population compared between the 2 treatment groups using an unstratified log-rank test.
    Comparison groups
    TAS-114/S-1 v S-1 control
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1431
    Method
    		 t-test, 2-sided
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 2.14
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded from the time a patient started receiving study treatment until 30 days after the last dose of study drug or until the start of new antitumor therapy, whichever was earlier.
    Adverse event reporting additional description
    Events were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. Safety assessments also included evaluation of laboratory test results, vital signs measurements, physical examination findings, and changes in ECOG performance status (ECOG PS).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    TAS-114/S-1 (As Treated Population)
    Reporting group description
    		 Adverse Events occurring in subjects within the TAS-114/S-1 (As Treated Population)

    Reporting group title
    S-1 (As Treated Population)
    Reporting group description
    		 Adverse Events occurring in subjects within the S-1 (As Treated Population)

    Serious adverse events
    		 TAS-114/S-1 (As Treated Population) S-1 (As Treated Population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 64 (46.88%)
    19 / 63 (30.16%)
         number of deaths (all causes)
    36
    29
         number of deaths resulting from adverse events
    5
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Chronic obstructive pulmonary
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Leptomeningeal carcinomatosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary-dependent Cushing's syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic alkalosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TAS-114/S-1 (As Treated Population) S-1 (As Treated Population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 64 (100.00%)
    61 / 63 (96.83%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    2 / 64 (3.13%)
    3 / 63 (4.76%)
         occurrences all number
    2
    3
    Tumour associated fever
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences all number
    3
    0
    Cancer pain
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    0
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 63 (0.00%)
         occurrences all number
    4
    0
    Hot flush
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Intermittent claudication
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Subclavian artery thrombosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Thrombophlebitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 64 (29.69%)
    14 / 63 (22.22%)
         occurrences all number
    19
    14
    Pyrexia
         subjects affected / exposed
    14 / 64 (21.88%)
    9 / 63 (14.29%)
         occurrences all number
    14
    9
    Fatigue
         subjects affected / exposed
    6 / 64 (9.38%)
    11 / 63 (17.46%)
         occurrences all number
    6
    11
    Malaise
         subjects affected / exposed
    10 / 64 (15.63%)
    5 / 63 (7.94%)
         occurrences all number
    10
    5
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 64 (9.38%)
    3 / 63 (4.76%)
         occurrences all number
    6
    3
    Oedema peripheral
         subjects affected / exposed
    5 / 64 (7.81%)
    4 / 63 (6.35%)
         occurrences all number
    5
    4
    Mucosal inflammation
         subjects affected / exposed
    4 / 64 (6.25%)
    3 / 63 (4.76%)
         occurrences all number
    4
    3
    Chills
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    Face oedema
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Gait disturbance
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Hyperthermia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Localised oedema
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Xerosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 64 (18.75%)
    10 / 63 (15.87%)
         occurrences all number
    12
    10
    Cough
         subjects affected / exposed
    8 / 64 (12.50%)
    7 / 63 (11.11%)
         occurrences all number
    8
    7
    Epistaxis
         subjects affected / exposed
    5 / 64 (7.81%)
    3 / 63 (4.76%)
         occurrences all number
    5
    3
    Haemoptysis
         subjects affected / exposed
    1 / 64 (1.56%)
    4 / 63 (6.35%)
         occurrences all number
    1
    4
    Oropharyngeal pain
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Hiccups
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Hypoxia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Lung disorder
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Pleural effusion
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Productive cough
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    0
    2
    Wheezing
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    0
    2
    Dysphonia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Hyperoxia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Lung infiltration
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Pulmonary pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 63 (1.59%)
         occurrences all number
    5
    1
    Anxiety
         subjects affected / exposed
    2 / 64 (3.13%)
    3 / 63 (4.76%)
         occurrences all number
    2
    3
    Depression
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Confusional state
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Hallucination
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    10 / 64 (15.63%)
    5 / 63 (7.94%)
         occurrences all number
    10
    5
    Platelet count decreased
         subjects affected / exposed
    8 / 64 (12.50%)
    6 / 63 (9.52%)
         occurrences all number
    8
    6
    Neutrophil count decreased
         subjects affected / exposed
    6 / 64 (9.38%)
    7 / 63 (11.11%)
         occurrences all number
    6
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 64 (6.25%)
    6 / 63 (9.52%)
         occurrences all number
    4
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 64 (4.69%)
    4 / 63 (6.35%)
         occurrences all number
    3
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 64 (4.69%)
    2 / 63 (3.17%)
         occurrences all number
    3
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 64 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    0
    5
    Weight decreased
         subjects affected / exposed
    5 / 64 (7.81%)
    0 / 63 (0.00%)
         occurrences all number
    5
    0
    Lymphocyte count decreased
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 63 (0.00%)
         occurrences all number
    4
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences all number
    3
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Blood albumin decreased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Blood bicarbonate increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Blood creatine increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Blood urine present
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Glucose urine present
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Protein total increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Protein urine
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 63 (4.76%)
         occurrences all number
    1
    3
    Contusion
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Accidental overdose
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Eschar
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Fracture
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Multiple lentigines syndrome
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences all number
    3
    0
    Atrial fibrillation
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Angina pectoris
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Cyanosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 64 (6.25%)
    3 / 63 (4.76%)
         occurrences all number
    4
    3
    Headache
         subjects affected / exposed
    4 / 64 (6.25%)
    3 / 63 (4.76%)
         occurrences all number
    4
    3
    Dysgeusia
         subjects affected / exposed
    2 / 64 (3.13%)
    4 / 63 (6.35%)
         occurrences all number
    2
    4
    Neuralgia
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences all number
    3
    0
    Syncope
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    0
    2
    Amnesia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Apraxia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Balance disorder
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Epilepsy
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Neurotoxicity
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    42 / 64 (65.63%)
    17 / 63 (26.98%)
         occurrences all number
    42
    17
    Neutropenia
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 63 (1.59%)
         occurrences all number
    5
    1
    Thrombocytopenia
         subjects affected / exposed
    4 / 64 (6.25%)
    2 / 63 (3.17%)
         occurrences all number
    4
    2
    Leukopenia
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 63 (1.59%)
         occurrences all number
    3
    1
    Leukocytosis
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Thrombocytosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 63 (4.76%)
         occurrences all number
    1
    3
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    5 / 64 (7.81%)
    5 / 63 (7.94%)
         occurrences all number
    5
    5
    Blepharitis
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Dry eye
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Eye discharge
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Eye pain
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Visual impairment
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Corneal disorder
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Dacryostenosis acquired
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Ocular icterus
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Retinal haemorrhage
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    20 / 64 (31.25%)
    23 / 63 (36.51%)
         occurrences all number
    20
    23
    Diarrhoea
         subjects affected / exposed
    19 / 64 (29.69%)
    18 / 63 (28.57%)
         occurrences all number
    19
    18
    Vomiting
         subjects affected / exposed
    12 / 64 (18.75%)
    13 / 63 (20.63%)
         occurrences all number
    12
    13
    Constipation
         subjects affected / exposed
    9 / 64 (14.06%)
    9 / 63 (14.29%)
         occurrences all number
    9
    9
    Stomatitis
         subjects affected / exposed
    10 / 64 (15.63%)
    4 / 63 (6.35%)
         occurrences all number
    10
    4
    Abdominal pain
         subjects affected / exposed
    3 / 64 (4.69%)
    5 / 63 (7.94%)
         occurrences all number
    3
    5
    Abdominal pain upper
         subjects affected / exposed
    4 / 64 (6.25%)
    3 / 63 (4.76%)
         occurrences all number
    4
    3
    Dry mouth
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Dyspepsia
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    0
    2
    Odynophagia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Oesophagitis
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Abdominal distension
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Ascites
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Colitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Dental caries
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Oral lichen planus
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Oral pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Peptic ulcer
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Tongue discolouration
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    0
    2
    Cholestasis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Skin hyperpigmentation
         subjects affected / exposed
    18 / 64 (28.13%)
    12 / 63 (19.05%)
         occurrences all number
    18
    12
    Rash maculo-papular
         subjects affected / exposed
    18 / 64 (28.13%)
    2 / 63 (3.17%)
         occurrences all number
    18
    2
    Rash
         subjects affected / exposed
    15 / 64 (23.44%)
    4 / 63 (6.35%)
         occurrences all number
    15
    4
    Pruritus
         subjects affected / exposed
    10 / 64 (15.63%)
    8 / 63 (12.70%)
         occurrences all number
    10
    8
    Dry skin
         subjects affected / exposed
    12 / 64 (18.75%)
    5 / 63 (7.94%)
         occurrences all number
    12
    5
    Erythema
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 63 (4.76%)
         occurrences all number
    1
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 63 (1.59%)
         occurrences all number
    3
    1
    Dermatitis acneiform
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Pigmentation disorder
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences all number
    3
    0
    Melanoderma
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Skin exfoliation
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Blister
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Erythema multiforme
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Intertrigo
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Nail disorder
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Pruritus generalised
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Rash erythematous
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Rash papular
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Proteinuria
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Acute kidney injury
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Cystitis noninfective
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Renal aneurysm
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Renal failure
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Hypopituitarism
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 64 (7.81%)
    6 / 63 (9.52%)
         occurrences all number
    5
    6
    Arthralgia
         subjects affected / exposed
    4 / 64 (6.25%)
    2 / 63 (3.17%)
         occurrences all number
    4
    2
    Muscle spasms
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 63 (1.59%)
         occurrences all number
    4
    1
    Myalgia
         subjects affected / exposed
    2 / 64 (3.13%)
    3 / 63 (4.76%)
         occurrences all number
    2
    3
    Pain in extremity
         subjects affected / exposed
    2 / 64 (3.13%)
    3 / 63 (4.76%)
         occurrences all number
    2
    3
    Bone pain
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Musculoskeletal pain
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    Neck pain
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Flank pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 64 (1.56%)
    5 / 63 (7.94%)
         occurrences all number
    1
    5
    Urinary tract infection
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 63 (1.59%)
         occurrences all number
    3
    1
    Conjunctivitis
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    Lung infection
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences all number
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Influenza
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Oral candidiasis
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Otitis externa
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    0
    2
    Pneumonia
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 63 (1.59%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Bronchitis haemophilus
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Erysipelas
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Gingivitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Hordeolum
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Oral infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis bacterial
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Sputum purulent
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Urethritis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 64 (45.31%)
    27 / 63 (42.86%)
         occurrences all number
    29
    27
    Hyperglycaemia
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 63 (1.59%)
         occurrences all number
    4
    1
    Hyperkalaemia
         subjects affected / exposed
    2 / 64 (3.13%)
    3 / 63 (4.76%)
         occurrences all number
    2
    3
    Hyponatraemia
         subjects affected / exposed
    3 / 64 (4.69%)
    2 / 63 (3.17%)
         occurrences all number
    3
    2
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 63 (1.59%)
         occurrences all number
    3
    1
    Hypophosphataemia
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 63 (1.59%)
         occurrences all number
    3
    1
    Dehydration
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Hypercalcaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    0
    3
    Hypocalcaemia
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    Diabetes mellitus
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    Folate deficiency
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Malnutrition
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2016
    Addition of the following exclusion criterion: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose/galactose malabsorption.
    08 Sep 2017
    Updated Appendix D - Supplemental Requirements for Japan Only

    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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