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    Clinical Trial Results:
    INTERIM: a randomised phase II feasibility study of INTERmittent versus continuous dosing of oral targeted combination therapy In patients with BRAFV600 mutant stage 3 unresectable or metastatic Melanoma

    Summary
    EudraCT number
    		 2016-005228-27
    Trial protocol
    		 GB  
    Global end of trial date
    27 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INTERIM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03352947
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust
    Sponsor organisation address
    Hills Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Mrs Carrie Bayliss, Cambridge University Hospitals NHS Foundation Trust, Cambridge Clinical Trials Unit, 44 01223 348158, cctu@addenbrookes.nhs.uk
    Scientific contact
    Dr Pippa Corrie, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, 44 01223 216083, pippa.corrie@addenbrookes.nhs.uk
    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
    25 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary: •Assess recruitment rate and treatment compliance of the intermittent dosing schedule as a measure of acceptance of intermittent dosing to patients and physicians •Evaluate the impact on overall quality of life with intermittent dosing using European Organisation for Research and Treatment of Cancer QLQ-C30 •Estimate the size of clinical efficacy of intermittent dosing compared to continuous dosing, measured by progression-free survival Secondary: •Evaluate safety, objective response rate, time to treatment failure and overall survival •Evaluate skin toxicity as assessed by clinicans and patients using patient reported outcome measures •Assess factors which influence patients’ decision to enter/decline entering the trial •Evaluate patient experience of participation in this trial (using mixed methods) •Determine the QoL and cost-effectiveness of intermittent dosing compared with standard continuous dosing in a subset of patients, explore pharmacokinetics of dosing
    Protection of trial subjects
    The study was approved by a Research Ethics Committee and received authorisation from the Medicine and Healthcare Product Regulatory Authority. Patients received verbal and written information prior to consenting to the trial, and had time to consider their participation and had an opportunity to ask questions. Consenting patients had a series of screening tests to ensure they were suitable for the study and it was safe to proceed. On registration to the trial the participants were allocated a unique trial identification number which was used on all data forms and samples sent to the Sponsor. This allowed their personal data to remain anonymous. Only the participant's direct care team had access to their recruited participants personal/identifiable information during the trial. All participant related information shared was anonymised, with only reference to the participant's trial identification number being included.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    03 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 79
    Worldwide total number of subjects
    79
    EEA total number of subjects
    0
    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)
    35
    From 65 to 84 years
    43
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The INTERIM trial planned to recruit approximately 100 patients (50 patients in each arm) with a minimum of 9 months follow up per patient. Recruitment commenced on the 03 November 2017 and closed on the 30 March 2020. 79 patients were randomised into the trial across 19 sites in the UK.

    Pre-assignment
    Screening details
    		 A total of 86 patients were assessed for eligibility, 7 patients did not give informed consent. The remaining 79 patients were sucessfully screened for eligibility and randomised (39 experimental and 40 standard arms) from 20/12/2017 to 28/02/2020 from 19 sites. The cut-off date for the last patient last visit was the 27th of November 2020.

    Pre-assignment period milestones
    Number of subjects started
    		 79
    Number of subjects completed
    		 79

    Period 1
    Period 1 title
    On Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard arm (continuous schedule)
    Arm description
    		 Patients with BRAFV600 mutant stage 3 unresectable or metastatic melanoma who met the trial eligibility criteria were randomised to one trial arm. Participants self-administered both dabrafenib and trametinib. Dabrafenib was taken orally 150mg twice daily 12 hours apart, on days 1 – 28 of a 28 day cycle. Trametinib was taken orally 2mg once daily, on days 1 – 28 of a 28 day cycle. Treatment was continued until disease progression or beyond, at the investigator’s discretion.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    L01XE23
    Other name
    Tafinlar
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150mg twice daily, 12 hours apart, on days 1 – 28 of a 28 day cycle.

    Investigational medicinal product name
    Tramitinib
    Investigational medicinal product code
    L01XE25
    Other name
    Mekinist
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg once daily, on days 1 – 28 of a 28 day cycle

    Arm title
    		 Experimental arm (intermittent schedule)
    Arm description
    		 Patients with BRAFV600 mutant stage 3 unresectable or metastatic melanoma who met the trial eligibility criteria were randomised to one trial arm. Participants self-administered both dabrafenib and trametinib. Dabrafenib was taken orally 150mg twice daily 12 hours apart, on days 1 – 21 of a 28 day cycle. Trametinib was taken orally 2mg once daily, on days 1 – 14 of a 28 day cycle. Treatment was continued until disease progression or beyond, at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    L01XE23
    Other name
    Tafinlar
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150mg twice daily, 12 hours apart, on days 1 – 21 of a 28 day cycle.

    Investigational medicinal product name
    Tramitinib
    Investigational medicinal product code
    L01XE25
    Other name
    Mekinist
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg once daily, on days 1 – 14 of a 28 day cycle

    Number of subjects in period 1
    		Standard arm (continuous schedule) Experimental arm (intermittent schedule)
    Started
    40
    39
    Completed
    40
    39

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard arm (continuous schedule)
    Reporting group description
    		 Patients with BRAFV600 mutant stage 3 unresectable or metastatic melanoma who met the trial eligibility criteria were randomised to one trial arm. Participants self-administered both dabrafenib and trametinib. Dabrafenib was taken orally 150mg twice daily 12 hours apart, on days 1 – 28 of a 28 day cycle. Trametinib was taken orally 2mg once daily, on days 1 – 28 of a 28 day cycle. Treatment was continued until disease progression or beyond, at the investigator’s discretion.

    Reporting group title
    Experimental arm (intermittent schedule)
    Reporting group description
    		 Patients with BRAFV600 mutant stage 3 unresectable or metastatic melanoma who met the trial eligibility criteria were randomised to one trial arm. Participants self-administered both dabrafenib and trametinib. Dabrafenib was taken orally 150mg twice daily 12 hours apart, on days 1 – 21 of a 28 day cycle. Trametinib was taken orally 2mg once daily, on days 1 – 14 of a 28 day cycle. Treatment was continued until disease progression or beyond, at the investigator’s discretion.

    Reporting group values
    		 Standard arm (continuous schedule) Experimental arm (intermittent schedule) Total
    Number of subjects
    		 40 39 79
    Age categorical
    The median patient age was 67 (ranging from 34 to 85) years old with 54.4% (43 out of 79) female.
    Units: Subjects
        Adults (18-64 years)
    		 23 12 35
        From 65-84 years
    		 17 26 43
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 61.3 (38.0 to 78.0) 66.2 (34.0 to 85.0) -
    Gender categorical
    Units: Subjects
        Female
    		 21 22 43
        Male
    		 19 17 36
    ECOG performance status
    Units: Subjects
        Grade 0
    		 19 19 38
        Grade 1
    		 17 15 32
        Grade 2
    		 4 5 9
    AJCC stage at baseline
    Units: Subjects
        IIIc
    		 1 2 3
        IVM1a
    		 6 5 11
        IVM1b
    		 8 6 14
        IVM1c
    		 25 26 51
    Presence of brain metastases
    Units: Subjects
        No
    		 40 39 79
    LDH relative to ULN
    Units: Subjects
        ≤ ULN
    		 22 21 43
        > ULN and ≤ 2 x ULN
    		 14 13 27
        > 2 x ULN
    		 4 5 9
    Subject analysis sets

    Subject analysis set title
    Full analysis population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis population includes all randomised subjects who gave informed consent, met all eligibility criteria and received treatment on the trial.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all patients randomised and received at least one dose of trial treatment.

    Subject analysis sets values
    		 Full analysis population Safety population
    Number of subjects
    78
    78
    Age categorical
    The median patient age was 67 (ranging from 34 to 85) years old with 54.4% (43 out of 79) female.
    Units: Subjects
        Adults (18-64 years)
    35
    35
        From 65-84 years
    43
    42
        85 years and over
    1
    1
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    63.7 (34.0 to 85.0)
    Gender categorical
    Units: Subjects
        Female
    43
    43
        Male
    36
    36
    ECOG performance status
    Units: Subjects
        Grade 0
    38
    38
        Grade 1
    32
    31
        Grade 2
    9
    9
    AJCC stage at baseline
    Units: Subjects
        IIIc
    3
    3
        IVM1a
    11
    11
        IVM1b
    14
    14
        IVM1c
    51
    50
    Presence of brain metastases
    Units: Subjects
        No
    56
    56
    LDH relative to ULN
    Units: Subjects
        ≤ ULN
    43
    42
        > ULN and ≤ 2 x ULN
    27
    27
        > 2 x ULN
    9
    9

    End points

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    End points reporting groups
    Reporting group title
    Standard arm (continuous schedule)
    Reporting group description
    		 Patients with BRAFV600 mutant stage 3 unresectable or metastatic melanoma who met the trial eligibility criteria were randomised to one trial arm. Participants self-administered both dabrafenib and trametinib. Dabrafenib was taken orally 150mg twice daily 12 hours apart, on days 1 – 28 of a 28 day cycle. Trametinib was taken orally 2mg once daily, on days 1 – 28 of a 28 day cycle. Treatment was continued until disease progression or beyond, at the investigator’s discretion.

    Reporting group title
    Experimental arm (intermittent schedule)
    Reporting group description
    		 Patients with BRAFV600 mutant stage 3 unresectable or metastatic melanoma who met the trial eligibility criteria were randomised to one trial arm. Participants self-administered both dabrafenib and trametinib. Dabrafenib was taken orally 150mg twice daily 12 hours apart, on days 1 – 21 of a 28 day cycle. Trametinib was taken orally 2mg once daily, on days 1 – 14 of a 28 day cycle. Treatment was continued until disease progression or beyond, at the investigator’s discretion.

    Subject analysis set title
    Full analysis population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis population includes all randomised subjects who gave informed consent, met all eligibility criteria and received treatment on the trial.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all patients randomised and received at least one dose of trial treatment.

    Primary: Recruitment rate

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    End point title
    		 Recruitment rate [1]
    End point description
    End point type
    Primary
    End point timeframe
    On 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: There are no statistical analyses for these endpoints.
    End point values
    		 Full analysis population
    Number of subjects analysed
    79
    Units: per site per 2 months
        number (not applicable)
    0.31
    No statistical analyses for this end point

    Primary: Overall QoL

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    End point title
    		 Overall QoL
    End point description
    This is defined as the global health status score derived from the standard EORTC QLQ-C30 questionnaire at 6 months from date of randomisation
    End point type
    Primary
    End point timeframe
    On Study
    End point values
    		 Standard arm (continuous schedule) Experimental arm (intermittent schedule) Safety population
    Number of subjects analysed
    30
    21
    51
    Units: mean
        least squares mean (confidence interval 95%)
    11.43 (3.91 to 18.96)
    -1.16 (-10.32 to 7.99)
    -13.25 (-26.13 to -0.36)
    Statistical analysis title
    		 Overall QoL change from baseline
    Statistical analysis description
    The analysis of changes from baseline of the mean score over time and difference between groups will be carried out with repeated measures ANCOVA, adjusting for baseline level, treatment arm, timepoint, interaction between treatment group and time. Time treated as repeated variable within subjects, and the analysis was performed with unstructured or AR(1) covariance matrix mixed model with PROC MIXED. Restricted maximum likelihood will be used in estimation of parameters.
    Comparison groups
    Experimental arm (intermittent schedule) v Standard arm (continuous schedule) v Safety population
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    This is calculated as the duration from date of randomisation to the date of first progression or death from any cause, whichever occurs first.
    End point type
    Primary
    End point timeframe
    On Study
    End point values
    		 Standard arm (continuous schedule) Experimental arm (intermittent schedule) Safety population
    Number of subjects analysed
    40
    38
    78
    Units: number
        Disease progressed
    23
    25
    48
    Attachments
    		 Progression free survival (PFS) over time
    Statistical analysis title
    		 K-M plot
    Comparison groups
    Standard arm (continuous schedule) v Experimental arm (intermittent schedule)
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.45

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective response is based on overall best objective response.
    End point type
    Secondary
    End point timeframe
    On Study, until a disease progression.
    End point values
    		 Standard arm (continuous schedule) Experimental arm (intermittent schedule)
    Number of subjects analysed
    35 [2]
    37 [3]
    Units: percent
    number (confidence interval 95%)
        Yes
    77.14 (59.86 to 89.58)
    56.76 (39.49 to 72.9)
    Notes
    [2] - 5 patients missing, 27 patients has an objective response out of 35.
    [3] - 1 patients missing, 21 patients has an objective response out of 37.
    No statistical analyses for this end point

    Secondary: Time to treatment failure

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    End point title
    		 Time to treatment failure
    End point description
    End point type
    Secondary
    End point timeframe
    On Study
    End point values
    		 Standard arm (continuous schedule) Experimental arm (intermittent schedule)
    Number of subjects analysed
    40
    38
    Units: percent
    number (not applicable)
        Yes
    26
    28
    Attachments
    		 KM-plot of Time to treatment failure
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    On Study
    End point values
    		 Standard arm (continuous schedule) Experimental arm (intermittent schedule)
    Number of subjects analysed
    40
    38
    Units: percent
    number (not applicable)
        Death
    15
    21
    Attachments
    		 KM-plot of of overall survival
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE collected during the treatment period and at disease progression.
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Experimental intermittent
    Reporting group description
    		 -

    Reporting group title
    Standard continuous
    Reporting group description
    		 -

    Serious adverse events
    		 Experimental intermittent Standard continuous
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 38 (52.63%)
    18 / 39 (46.15%)
         number of deaths (all causes)
    21
    15
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
    Additional description: Thromboembolic event
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
    Additional description: Chills
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
    Additional description: Fever
         subjects affected / exposed
    9 / 38 (23.68%)
    7 / 39 (17.95%)
         occurrences causally related to treatment / all
    9 / 9
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu like symptoms
    Additional description: Flu like symptoms
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
    Additional description: Dyspnea
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders - Other, Asthma
    Additional description: Other, Asthma
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
    Additional description: Productive cough
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
    Additional description: Confusion
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
    Additional description: Alanine aminotransferase increased
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
    Additional description: Neutrophil count decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Injury, poisoning and procedural complications
    Fall
    Additional description: Fall
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
    Additional description: Supraventricular tachycardia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dysphasia
    Additional description: Dysphasia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Edema cerebral
    Additional description: Edema cerebral
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
    Additional description: Headache
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head pain
    Additional description: Other, Head pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Spinal cord compression
    Additional description: Other, Spinal cord compression
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
    Additional description: Seizure
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
    Additional description: Syncope
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Chorioretinitis
    Additional description: Other, Chorioretinitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
    Additional description: Diarrhea
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophageal hemorrhage
    Additional description: Esophageal hemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophageal varices hemorrhage
    Additional description: Esophageal varices hemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
    Additional description: Pancreatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
    Additional description: Urinary incontinence
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (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
    Muscle weakness lower limb
    Additional description: Muscle weakness lower limb
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
    Additional description: Lung infection
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, Infection
    Additional description: Other, Infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    Additional description: Sepsis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
    Additional description: Skin infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
    Additional description: Anorexia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
    Additional description: Dehydration
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
    Additional description: Hyponatremia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphatemia
    Additional description: Hypophosphatemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Experimental intermittent Standard continuous
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 38 (78.95%)
    36 / 39 (92.31%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Seborrhoea
    Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Seborrhoea
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Cysts
    Additional description: Other, Cysts
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Papilloma
    Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Papilloma
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Seborrheic keratosis
    Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Seborrheic keratosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Vascular disorders
    Flushing
    Additional description: Flushing
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Hot flashes
    Additional description: Hot flashes
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 39 (2.56%)
         occurrences all number
    4
    1
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 39 (10.26%)
         occurrences all number
    1
    4
    Lymphedema
    Additional description: Lymphedema
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    1
    2
    Thromboembolic event
    Additional description: Thromboembolic event
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 39 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Chills
    Additional description: Chills
         subjects affected / exposed
    13 / 38 (34.21%)
    12 / 39 (30.77%)
         occurrences all number
    13
    12
    Edema face
    Additional description: Edema face
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Edema limbs
    Additional description: Edema limbs
         subjects affected / exposed
    3 / 38 (7.89%)
    5 / 39 (12.82%)
         occurrences all number
    3
    5
    Facial pain
    Additional description: Facial pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    13 / 38 (34.21%)
    23 / 39 (58.97%)
         occurrences all number
    13
    25
    Fever
    Additional description: Fever
         subjects affected / exposed
    11 / 38 (28.95%)
    22 / 39 (56.41%)
         occurrences all number
    11
    24
    Flu like symptoms
    Additional description: Flu like symptoms
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 39 (10.26%)
         occurrences all number
    1
    5
    Non-cardiac chest pain
    Additional description: Non-cardiac chest pain
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    1
    2
    General disorders and administration site conditions - Other, Night sweats
    Additional description: Other, Night sweats
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Pain
    Additional description: Pain
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 39 (7.69%)
         occurrences all number
    1
    3
    Immune system disorders
    Immune system disorders - Other, Erythema nodusum
    Additional description: Other, Erythema nodusum
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Cough
         subjects affected / exposed
    4 / 38 (10.53%)
    5 / 39 (12.82%)
         occurrences all number
    4
    5
    Dyspnea
    Additional description: Dyspnea
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 39 (0.00%)
         occurrences all number
    4
    0
    Hoarseness
    Additional description: Hoarseness
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
    Additional description: Nasal congestion
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    1
    2
    Pneumothorax
    Additional description: Pneumothorax
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders - Other, Asthma
    Additional description: Respiratory, thoracic and mediastinal disorders - Other, Asthma
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Sore throat
    Additional description: Sore throat
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Confusion
    Additional description: Confusion
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 39 (5.13%)
         occurrences all number
    4
    2
    Depression
    Additional description: Depression
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Psychiatric disorders - Other, Low mood
    Additional description: Other, Low mood
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Restlessness
    Additional description: Restlessness
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
    Additional description: Alanine aminotransferase increased
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    Alkaline phosphatase increased
    Additional description: Alkaline phosphatase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    0
    3
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Blood bilirubin increased
    Additional description: Blood bilirubin increased
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Creatinine increased
    Additional description: Creatinine increased
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 39 (2.56%)
         occurrences all number
    3
    1
    Ejection fraction decreased
    Additional description: Ejection fraction decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 39 (10.26%)
         occurrences all number
    0
    4
    GGT increased
    Additional description: GGT increased
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 39 (10.26%)
         occurrences all number
    0
    4
    Investigations - Other, Lactate dehydrogenase increased
    Additional description: Investigations - Other, Lactate dehydrogenase increased
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 39 (5.13%)
         occurrences all number
    2
    1
    Investigations - Other, TSH increased
    Additional description: Investigations - Other, TSH increased
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Lymphocyte count decreased
    Additional description: Lymphocyte count decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Neutrophil count decreased
    Additional description: Neutrophil count decreased
         subjects affected / exposed
    2 / 38 (5.26%)
    7 / 39 (17.95%)
         occurrences all number
    2
    8
    Investigations - Other, Cortisol low
    Additional description: Investigations - Other, Cortisol low
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Investigations - Other, Urea increased
    Additional description: Other, Urea increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Platelet count decreased
    Additional description: Platelet count decreased
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 39 (7.69%)
         occurrences all number
    1
    3
    Serum amylase increased
    Additional description: Serum amylase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Weight loss
    Additional description: Weight loss
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    White blood cell decreased
    Additional description: White blood cell decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    6 / 39 (15.38%)
         occurrences all number
    0
    6
    Injury, poisoning and procedural complications
    Fall
    Additional description: Fall
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Fracture
    Additional description: Fracture
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications - Other, Head injury
    Additional description: Other, Head injury
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Cardiac disorders
    Acute coronary syndrome
    Additional description: Acute coronary syndrome
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Palpitations
    Additional description: Palpitations
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Amnesia
    Additional description: Amnesia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Depressed level of consciousness
    Additional description: Depressed level of consciousness
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 39 (10.26%)
         occurrences all number
    3
    4
    Dysarthria
    Additional description: Dysarthria
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Dysphasia
    Additional description: Dysphasia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Edema cerebral
    Additional description: Edema cerebral
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Headache
    Additional description: Headache
         subjects affected / exposed
    7 / 38 (18.42%)
    11 / 39 (28.21%)
         occurrences all number
    7
    12
    Lethargy
    Additional description: Lethargy
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 39 (10.26%)
         occurrences all number
    1
    4
    Memory impairment
    Additional description: Memory impairment
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Neuralgia
    Additional description: Neuralgia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders - Other, Peripheral neuropathy
    Additional description: Other, Peripheral neuropathy
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Paresthesia
    Additional description: Paresthesia
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 39 (10.26%)
         occurrences all number
    2
    4
    Peripheral sensory neuropathy
    Additional description: Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Presyncope
    Additional description: Presyncope
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Seizure
    Additional description: Seizure
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Spasticity
    Additional description: Spasticity
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Stroke
    Additional description: Stroke
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anemia
    Additional description: Anemia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    Lymph node pain
    Additional description: Lymph node pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other, Blocked ear
    Additional description: Other, blocked ear
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
    Additional description: Tinnitus
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Vertigo
    Additional description: Vertigo
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Blurred vision
    Additional description: Blurred vision
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 39 (10.26%)
         occurrences all number
    1
    4
    Cataract
    Additional description: Cataract
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Eye pain
    Additional description: Eye pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Floaters
    Additional description: Floaters
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Eye disorders - Other, Red eye
    Additional description: Other, Red eye
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Eye disorders - Other, Swollen eyes
    Additional description: Swollen eyes
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Eye disorders - Other, Visual acuity reduced
    Additional description: Other, Visual acuity reduced
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Eye Disorders - Other, Worsening eye sight
    Additional description: Other, Worsening eye sight
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Uveitis
    Additional description: Uveitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 39 (7.69%)
         occurrences all number
    3
    4
    Ascites
    Additional description: Ascites
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Bloating
    Additional description: Bloating
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    3
    0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    4 / 38 (10.53%)
    10 / 39 (25.64%)
         occurrences all number
    4
    11
    Dental caries
    Additional description: Dental caries
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Diarrhoea
    Additional description: Diarrhea
         subjects affected / exposed
    8 / 38 (21.05%)
    9 / 39 (23.08%)
         occurrences all number
    8
    10
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 39 (7.69%)
         occurrences all number
    1
    3
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    1
    2
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Fecal incontinence
    Additional description: Fecal incontinence
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Flatulence
    Additional description: Flatulence
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Gastroesophageal reflux disease
    Additional description: Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Mucositis oral
    Additional description: Mucositis oral
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 39 (7.69%)
         occurrences all number
    1
    3
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    7 / 38 (18.42%)
    13 / 39 (33.33%)
         occurrences all number
    7
    16
    Oral pain
    Additional description: Oral pain
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Periodontal disease
    Additional description: Periodontal disease
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Rectal pain
    Additional description: Rectal pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Toothache
    Additional description: Toothache
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    9 / 38 (23.68%)
    4 / 39 (10.26%)
         occurrences all number
    9
    4
    Hepatobiliary disorders
    Cholecystitis
    Additional description: Cholecystitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Bullous dermatitis
    Additional description: Bullous dermatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Dry skin
    Additional description: Dry skin
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 39 (10.26%)
         occurrences all number
    4
    4
    Erythema multiforme
    Additional description: Erythema multiforme
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Erythroderma
    Additional description: Erythroderma
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders - Other, Skin patches
    Additional description: Other, Skin patches
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous disorders - Other, Dermatitis
    Additional description: Other, Dermatitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous disorders - Other, Eczema
    Additional description: Skin and subcutaneous disorders - Other, Eczema
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Skin and subcutaneous disorders - Other, Papilloma neck
    Additional description: Skin and subcutaneous disorders - Other, Papilloma neck
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous disorders - Other, Rash on left hand
    Additional description: Skin and subcutaneous disorders - Other, Rash on left hand
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders - Other, Seborrheic keratosis
    Additional description: Other, Seborrheic keratosis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders - Other, Skin tissue disorder
    Additional description: Other, Skin tissue disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous skin disorders - Other, Transient rash
    Additional description: other, transient rash
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Palmar-plantar erythrodysesthesia syndrome
    Additional description: Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    2
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 39 (10.26%)
         occurrences all number
    1
    4
    Purpura
    Additional description: Purpura
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Rash acneiform
    Additional description: Rash acneiform
         subjects affected / exposed
    3 / 38 (7.89%)
    7 / 39 (17.95%)
         occurrences all number
    3
    7
    Rash maculo-papular
    Additional description: Rash maculo-papular
         subjects affected / exposed
    1 / 38 (2.63%)
    6 / 39 (15.38%)
         occurrences all number
    1
    6
    Skin and subcutaneous tissue disorders - Other, Hyperkeratosis
    Additional description: Skin and subcutaneous tissue disorders - Other, Hyperkeratosis
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 39 (10.26%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders - Other, Rash
    Additional description: Skin and subcutaneous tissue disorders - Other, Rash
         subjects affected / exposed
    8 / 38 (21.05%)
    4 / 39 (10.26%)
         occurrences all number
    8
    4
    Skin and subcutaneous tissue disorders - Other, Skin lesion
    Additional description: Skin and subcutaneous tissue disorders - Other, Skin lesion
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    2
    2
    Skin hyperpigmentation
    Additional description: Skin hyperpigmentation
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Skin hypopigmentation
    Additional description: Skin hypopigmentation
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 39 (10.26%)
         occurrences all number
    0
    4
    Skin ulceration
    Additional description: Skin ulceration
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Urticaria
    Additional description: Urticaria
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Chronic kidney disease
    Additional description: Chronic kidney disease
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
    Additional description: Urinary incontinence
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    5 / 38 (13.16%)
    13 / 39 (33.33%)
         occurrences all number
    6
    15
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 39 (2.56%)
         occurrences all number
    3
    1
    Muscle weakness lower limb
    Additional description: Muscle weakness lower limb
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Muscle weakness right-sided
    Additional description: Muscle weakness right-sided
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    5 / 38 (13.16%)
    5 / 39 (12.82%)
         occurrences all number
    5
    7
    Neck pain
    Additional description: Neck pain
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    5 / 38 (13.16%)
    2 / 39 (5.13%)
         occurrences all number
    5
    2
    Infections and infestations
    Eye infection
    Additional description: Eye infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Gum infection
    Additional description: Gum infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, Oral thrush
    Additional description: Infections and infestations - Other, Oral thrush
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 39 (5.13%)
         occurrences all number
    2
    2
    Infections and infestations - Other, Toe infection
    Additional description: Infections and infestations - Other, Toe infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Lung infection
    Additional description: Lung infection
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 39 (10.26%)
         occurrences all number
    0
    4
    Nail infection
    Additional description: Nail infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Infections and infestations - Other, Finger infection
    Additional description: Other, Finger infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Infection and infestations - Other, Leg infection
    Additional description: Other, Leg infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Infections and infestations - Other, Thrush vaginal
    Additional description: Other, Thrush vaginal
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Papulopustular rash
    Additional description: Papulopustular rash
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Penile infection
    Additional description: Penile infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Pharyngitis
    Additional description: Pharyngitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Sepsis
    Additional description: Sepsis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Skin infection
    Additional description: Skin infection
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    Soft tissue infection
    Additional description: Soft tissue infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Tooth infection
    Additional description: Tooth infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory infection
    Additional description: Upper respiratory infection
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 39 (7.69%)
         occurrences all number
    2
    3
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 39 (5.13%)
         occurrences all number
    2
    2
    Metabolism and nutrition disorders
    Anorexia
    Additional description: Anorexia
         subjects affected / exposed
    7 / 38 (18.42%)
    6 / 39 (15.38%)
         occurrences all number
    7
    7
    Dehydration
    Additional description: Dehydration
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Hypercalcemia
    Additional description: Hypercalcemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Hyperglycemia
    Additional description: Hyperglycemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Hypernatremia
    Additional description: Hypernatremia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Hypoalbuminemia
    Additional description: Hypoalbuminemia
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 39 (10.26%)
         occurrences all number
    0
    4
    Hypoglycemia
    Additional description: Hypoglycemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Hypokalemia
    Additional description: Hypokalemia
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 39 (5.13%)
         occurrences all number
    3
    2
    Hyponatremia
    Additional description: Hyponatremia
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    0
    4
    Hypophosphatemia
    Additional description: Hypophosphatemia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jan 2018
    To allow patients to be randomised before RECIST measurements are available. To clarify the both MRI and CT scans can be used to measure disease.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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