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    Clinical Trial Results:
    PHASE II STUDY OF EVEROLIMUS IN PATIENTS WITH THYMOMA AND THYMIC CARCINOMA PREVIOUSLY TREATED WITH CHEMOTHERAPY

    Summary
    EudraCT number
    		 2010-019683-37
    Trial protocol
    		 IT  
    Global end of trial date
    05 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2020
    First version publication date
    05 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ONC-2010-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ISTITUTO CLINICO HUMANITAS
    Sponsor organisation address
    Via Manzoni 56 , Rozzano (MI), Italy, 20089
    Public contact
    Armando Santoro, Istituto Clinico Humanitas, +39 02 82244080, armando.santoro@humanitas.it
    Scientific contact
    Armando Santoro, Istituto Clinico Humanitas, +39 02 82244080, armando.santoro@humanitas.it
    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
    27 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the activity of Everolimus in patients with advanced or recurrent thymoma or thymic carcinoma by the determination of disease control rate (DCR), considered as complete response (CR) plus partial response (PR) plus stable disease (SD).
    Protection of trial subjects
    Therapies considered necessary for patients' well being were given at the discretion of the Investigator, i.e chronic treatment for concomitant medical conditions, as well as agents required for life-threatening medical problems.
    Background therapy
    		 -
    Evidence for comparator
    		 Not Applicable
    Actual start date of recruitment
    17 Feb 2011
    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
    Italy: 51
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    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)
    43
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients with pathologically confirmed, advanced (ie, unresectable or metastatic) thymoma (T) or thymic carcinoma (TC) were eligible after failure of at least one previous line of platinum-based chemotherapy. 51 patients were enrolled between 17 February 2011 and 21 October 2013. One patient decided to leave the study before starting the treatment.

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

    Arms
    Arm title
    		 Arm 1
    Arm description
    		 All patients treated with everolimus 10 mg once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was orally administered at the dosage of 10 mg once daily. Each cycle was considered as 21 days of treatment.

    Number of subjects in period 1 [1]
    		Arm 1
    Started
    50
    Completed
    20
    Not completed
    30
         Adverse event, serious fatal
    7
         Consent withdrawn by subject
    2
         Physician decision
    1
         Adverse event, non-fatal
    11
         Not reported
    9
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 51 patients were initially enrolled but one patient decided to leave the study before starting the treatment. Then 50 patients were treated and considered in the analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 All patients treated with everolimus 10 mg once daily.

    Reporting group values
    		 Arm 1 Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 42 42
        From 65-84 years
    		 8 8
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 55 (36 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 22 22
        Male
    		 28 28
    ECOG PS
    Units: Subjects
        0-1
    		 50 50
        =2
    		 0 0
    Myastenia gravis
    Units: Subjects
        Yes
    		 10 10
        No
    		 40 40
    Histologic type
    Units: Subjects
        Thymoma
    		 32 32
        Thymic carcinoma
    		 18 18
    Stage of disease
    Units: Subjects
        Recurrent
    		 9 9
        Metastatic
    		 41 41
    No. of previous treatment lines
    Units: Subjects
        < or =2
    		 33 33
        > or = 3
    		 17 17
    Type of previous line before everolimus
    Units: Subjects
        Platinum-based chemotherapy
    		 34 34
        Other chemotherapy
    		 10 10
        Target therapy
    		 6 6
    Best response to previous line before everolimus
    Units: Subjects
        CR (complete response)
    		 2 2
        PR (partial response)
    		 10 10
        SD (stable disease)
    		 17 17
        PD (progressive disease)
    		 11 11
        UK (unknown)
    		 10 10

    End points

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    End points reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 All patients treated with everolimus 10 mg once daily.

    Subject analysis set title
    All patient treated with everolimus 10 mg once daily
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patient treated with everolimus 10 mg once daily

    Subject analysis set title
    Responder patients
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients that showed completed or partial tumor response.

    Subject analysis set title
    p4E-BP1 low intensity
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with low intratumoral expression levels of 4E-BP1 (translational regulator eukaryotic factor).

    Subject analysis set title
    p4E-BP1 high intensity
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patiients with high intratumoral expression levels of 4E-BP1 (translational regulator eukaryotic factor).

    Subject analysis set title
    IGF-1R low intensity
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with low intratumoral expression levels of IGF-1R (insulin-like growth farctor receptor).

    Subject analysis set title
    IGF-1R high intensity
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patiients with high intratumoral expression levels of IGF-1R (insulin-like growth farctor receptor).

    Primary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR) [1]
    End point description
    Disease control rate was considered as proportion of patients who achieved complete response (CR) plus partial response (PR) plus stable disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
    End point type
    Primary
    End point timeframe
    During the entire study
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A Disease Control Rate (CR, PR or SD) ≤40% was considered clinically irrelevant whereas a proportion ≥ 60% was assumed to be of potential interest. Exact binomial 95% confidence intervals were calculated.
    End point values
    		 All patient treated with everolimus 10 mg once daily
    Number of subjects analysed
    50
    Units: percent
        number (confidence interval 95%)
    88 (75.7 to 95.5)
    No statistical analyses for this end point

    Secondary: median Progression Free Survival (mPFS)

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    End point title
    		 median Progression Free Survival (mPFS)
    End point description
    PSF is calculated as the time from start of treatment until disease progression or death from any cause. Patients alive without any evidence of progressive disease were censored on the date of the last visit.
    End point type
    Secondary
    End point timeframe
    Time from start of treatment until disease progression or death, whichever comes first.
    End point values
    		 All patient treated with everolimus 10 mg once daily
    Number of subjects analysed
    50
    Units: Months
        median (confidence interval 95%)
    10.1 (6.0 to 14.2)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) 1 year

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    End point title
    		 Overall Survival (OS) 1 year
    End point description
    OS was was evaluated from the date of treatment start until the date of death from any cause. Patients alive were censored at last contact date. It is here reported the 1 year OS rate (95% CI) .
    End point type
    Secondary
    End point timeframe
    From the start of treatment until death.
    End point values
    		 All patient treated with everolimus 10 mg once daily
    Number of subjects analysed
    50
    Units: percent
        number (confidence interval 95%)
    72 (57.4 to 82.4)
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    Duration of response is the length of time that a tumor continues to respond to treatment without the cancer growing or spreading. Data are reported as median and range.
    End point type
    Secondary
    End point timeframe
    From the first treatment to disease progression.
    End point values
    		 Responder patients
    Number of subjects analysed
    6
    Units: months
        median (full range (min-max))
    7.1 (1.2 to 25.9)
    No statistical analyses for this end point

    Secondary: Relationship between p4E-BP1 tumor biomarker intensity and Progression Free Survival rate at 1 year

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    End point title
    		 Relationship between p4E-BP1 tumor biomarker intensity and Progression Free Survival rate at 1 year
    End point description
    The percentage of patients progression free survival at 1 year from tretment start by biomarker expression.
    End point type
    Secondary
    End point timeframe
    From the start of treatment to 1 year from the first treatment.
    End point values
    		 p4E-BP1 low intensity p4E-BP1 high intensity
    Number of subjects analysed
    20
    6
    Units: percent
    number (not applicable)
        p4E-BP1
    72.3
    16.7
    Statistical analysis title
    		 Survival curve comparison
    Statistical analysis description
    Survival based on biomarker distribution: 4E-BP1 (translational regulator eukaryotic factor)
    Comparison groups
    p4E-BP1 high intensity v p4E-BP1 low intensity
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.09
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Log-rank test

    Secondary: Relationship between IGF-1R tumor biomarker intensity and Progression Free Survival rate at 1 year

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    End point title
    		 Relationship between IGF-1R tumor biomarker intensity and Progression Free Survival rate at 1 year
    End point description
    The percentage of patients progression free survival at 1 year from tretment start by biomarker expression.
    End point type
    Secondary
    End point timeframe
    From the start of treatment to 1 year from the first treatment.
    End point values
    		 IGF-1R low intensity IGF-1R high intensity
    Number of subjects analysed
    17
    7
    Units: percent
    number (not applicable)
        IGF-1R
    66.3
    35.7
    Statistical analysis title
    		 Survival Curve Comparison
    Statistical analysis description
    Survival based on biomarker distribution: IGF-1R (insulin-like growth factor receptor)
    Comparison groups
    IGF-1R low intensity v IGF-1R high intensity
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.241
    Method
    		 Logrank
    Confidence interval

    Secondary: Relationship between p4E-BP1 tumor biomarker intensity and Overal Survival rate at 2 years

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    End point title
    		 Relationship between p4E-BP1 tumor biomarker intensity and Overal Survival rate at 2 years
    End point description
    The percentage of overall survival at 2 years from tretment start by biomarker expression.
    End point type
    Secondary
    End point timeframe
    From the start of treatment to 2 years from the first treatment.
    End point values
    		 p4E-BP1 low intensity p4E-BP1 high intensity
    Number of subjects analysed
    20
    6
    Units: percent
    number (not applicable)
        p4E-BP1
    94.7
    33.3
    Statistical analysis title
    		 Survival Curve Comparison
    Statistical analysis description
    Survival based on biomarker distribution: 4E-BP1 (translational regulator eukaryotic factor).
    Comparison groups
    p4E-BP1 low intensity v p4E-BP1 high intensity
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Confidence interval

    Secondary: Relationship between IGF-1R tumor biomarker intensity and Overall Survival rate at 2 years

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    End point title
    		 Relationship between IGF-1R tumor biomarker intensity and Overall Survival rate at 2 years
    End point description
    Relationship between IGF-1R tumor biomarker intensity and Overall Survival rate at 2 years.
    End point type
    Secondary
    End point timeframe
    From the start of treatment to 2 years from the first treatment.
    End point values
    		 IGF-1R low intensity IGF-1R high intensity
    Number of subjects analysed
    17
    7
    Units: percent
    number (not applicable)
        IGF-1R
    84.4
    57.1
    Statistical analysis title
    		 Survival Curve Comparison
    Statistical analysis description
    Survival based on biomarker distribution: IGF-1R (insulin-like growth factor receptor).
    Comparison groups
    IGF-1R low intensity v IGF-1R high intensity
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the Informed Consent signature to 30 days after the last dose of treatment, or until every ongoing drug-related toxicities and serious AEs had resolved or the investigator assessed them as “chronic” or “stable” or patient started a new therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    All patient treated
    Reporting group description
    		 -

    Serious adverse events
    		 All patient treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 50 (38.00%)
         number of deaths (all causes)
    24
         number of deaths resulting from adverse events
    10
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Oedema peripheral
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 2
    Pneumonitis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory failure
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 4
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 2
    Lung infection
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    2 / 3
    Pneumonia influenzal
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Anorexia nervosa
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 All patient treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 50 (96.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    27 / 50 (54.00%)
         occurrences all number
    53
    Chest pain
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    11
    Chills
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    8
    Mucosal inflammation
         subjects affected / exposed
    23 / 50 (46.00%)
         occurrences all number
    51
    Oedema peripheral
         subjects affected / exposed
    9 / 50 (18.00%)
         occurrences all number
    10
    Pyrexia
         subjects affected / exposed
    18 / 50 (36.00%)
         occurrences all number
    51
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 50 (32.00%)
         occurrences all number
    35
    Dyspnoea
         subjects affected / exposed
    16 / 50 (32.00%)
         occurrences all number
    22
    Epistaxis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Pneumonitis
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    11
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    9
    Blood glucose increased
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    9
    Blood triglycerides increased
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    7
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    8
    Haemoglobin decreased
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    9
    Neutrophil count decreased
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    10
    Platelet count decreased
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    10
    Weight decreased
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Dysgeusia
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    9
    Headache
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    23
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    7
    Abdominal pain upper
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    10
    Constipation
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    14 / 50 (28.00%)
         occurrences all number
    32
    Dyspepsia
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    Haemorrhoids
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    10
    Stomatitis
         subjects affected / exposed
    17 / 50 (34.00%)
         occurrences all number
    36
    Vomiting
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Nail disorder
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    6
    Rash
         subjects affected / exposed
    16 / 50 (32.00%)
         occurrences all number
    21
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    7
    Muscle spasms
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    Musculoskeletal pain
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    6
    Cystitis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    Folliculitis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    13
    Localised infection
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    Nail infection
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    7
    Onychomycosis
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    Oral herpes
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    17
    Paronychia
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Pneumonia
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    6
    Rhinitis
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    Tooth abscess
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Anorexia nervosa
         subjects affected / exposed
    10 / 50 (20.00%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29240542
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