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    Clinical Trial Results:
    A randomised phase II trial of imatinib alternating with regorafenib compared to imatinib alone for the first line treatment of advanced gastrointestinal stromal tumour (GIST)

    Summary
    EudraCT number
    		 2015-001298-42
    Trial protocol
    		 SK   ES   NO   FI   GB   NL   FR   DK   IT  
    Global end of trial date
    08 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Aug 2025
    First version publication date
    01 Aug 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1321
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02365441
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NHMRC CTC Protocol number: CTC 0122/AGITG AG1013GST, SSG: ALT-GIST/SSG XXIII
    Sponsors
    Sponsor organisation name
    EORTC
    Sponsor organisation address
    Avenue E. Mounier 83, Bruxelles, Belgium,
    Public contact
    Head of Clinical Operations, EORTC, +32 27741035, regulatory@eortc.be
    Scientific contact
    Head of Clinical Operations, EORTC, +32 27741035, regulatory@eortc.be
    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
    28 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety to warrant further evaluation as a first line treatment for metastatic GIST.
    Protection of trial subjects
    The study investigator ensured that the study was conducted in agreement with the Declaration of Helsinki and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice, and the study protocol was approved by the competent authorities and ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2015
    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: 4
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Norway: 9
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    78
    EEA total number of subjects
    53
    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)
    45
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study originally aimed to recruit 240 patients. However, due to resource and study constraints, the design was amended to target a sample size of 76 patients. Between June 2015 and September 2018, a total of 76 eligible patients were recruited from 11 countries, including 8 in Europe.

    Pre-assignment
    Screening details
    		 Adults (over 18 years) with histologically confirmed, measurable metastatic GIST, who have received no prior treatment for metastatic disease. Patients who were taking, and did not have longer than 21 days of continuous treatment immediately prior to randomisation with 400mg daily of imatinib were eligible to participate in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Imatinib
    Arm description
    		 Imatinib 400mg daily ongoing until progression.
    Arm type
    		 Standard of Care

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg orally daily as standard of care

    Arm title
    		 Alternating
    Arm description
    		 Imatinib 400mg for 21 to 25 days with a 3‐7 day washout period followed by Regorafenib 160mg for 21 days followed by a 7 day washout period. Ongoing treatment until progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg orally daily as standard of care

    Investigational medicinal product name
    regorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Imatinib 400mg for 21 to 25 days with a 3‐7 day washout period followed by Regorafenib 160mg for 21 days followed by a 7 day washout period.

    Number of subjects in period 1 [1]
    		Imatinib Alternating
    Started
    36
    40
    Completed
    10
    9
    Not completed
    26
    31
         Treatment discontinuation
    26
    31
    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: Some randomized patients did not start the study treatment

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib 400mg daily ongoing until progression.

    Reporting group title
    Alternating
    Reporting group description
    		 Imatinib 400mg for 21 to 25 days with a 3‐7 day washout period followed by Regorafenib 160mg for 21 days followed by a 7 day washout period. Ongoing treatment until progression.

    Reporting group values
    		 Imatinib Alternating Total
    Number of subjects
    		 36 40 76
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 26 43
        From 65-84 years
    		 19 14 33
    Age continuous
    Units: years
        median (full range (min-max))
    		 65.4 (35.0 to 81.8) 58.4 (23.7 to 81.0) -
    Gender categorical
    Units: Subjects
        Female
    		 16 9 25
        Male
    		 20 31 51
    Primary tumour site
    Units: Subjects
        Colon/Rectum
    		 3 1 4
        Not possible to define
    		 7 6 13
        Pelvis
    		 1 1 2
        Peritoneum/Omentum/Mesentery
    		 2 2 4
        Small intestine
    		 9 16 25
        Stomach
    		 14 14 28
    Prior adjuvant Imatinib
    Units: Subjects
        No
    		 26 28 54
        Yes
    		 10 12 22
    Commenced Imatinib for Prior to Randomisation
    Units: Subjects
        No
    		 23 25 48
        Yes
    		 13 15 28

    End points

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    End points reporting groups
    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib 400mg daily ongoing until progression.

    Reporting group title
    Alternating
    Reporting group description
    		 Imatinib 400mg for 21 to 25 days with a 3‐7 day washout period followed by Regorafenib 160mg for 21 days followed by a 7 day washout period. Ongoing treatment until progression.

    Primary: Objective Tumour Response Rate (OTRR) at or before 9 months

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    End point title
    		 Objective Tumour Response Rate (OTRR) at or before 9 months
    End point description
    Objective Tumour Response (OTRR) was defined as the proportion of patients exhibiting complete or partial response (CR or PR) at or before 9 months as per the RECIST v1.1. The Objective Tumour Response Rate (OTRR) will be calculated by summing the number of participants assessed as having a complete or partial response within the first 9 months from the time from either: (i) Randomisation (if patients have not yet commenced treatment), or (ii) Commencement of therapy (if patients are randomized during the first cycle of Imatinib), and dividing this by the total number of participants evaluable for response.
    End point type
    Primary
    End point timeframe
    Imaging assessment was done every 8 weeks during the first 12 months
    End point values
    		 Imatinib Alternating
    Number of subjects analysed
    36
    40
    Units: % at 9 months
        number (confidence interval 95%)
    61 (45 to 75)
    60 (45 to 74)
    Statistical analysis title
    		 Objective Tumour Response Rate (OTRR)
    Comparison groups
    Alternating v Imatinib
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.92
    Method
    		 Chi-squared
    Parameter type
    		 Difference in proportions
    Confidence interval
    Notes
    [1] - Non-comparative

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival (PFS) was measured from date of patient randomisation to the study [or commencement of therapy if patients are randomized during the first cycle of Imatinib] to date of first evidence of disease progression or patient death from any cause. PFS will be reported in months from the date of randomisation. In patients who received study treatment without a progression date or death, PFS will be censored on the date of last clinical assessment or registration, whichever is later. Patients who do not receive study treatment and who have neither progressed nor died will be considered to be censored on the date of their last assessment.
    End point type
    Secondary
    End point timeframe
    Imaging assessment was performed every 8 weeks for the first year on trial, and then every 12 weeks until disease progression or death.
    End point values
    		 Imatinib Alternating
    Number of subjects analysed
    36
    40
    Units: PFS proportion at 12 months
        number (confidence interval 95%)
    83 (67 to 92)
    88 (73 to 95)
    Statistical analysis title
    		 Progression-free survival
    Comparison groups
    Imatinib v Alternating
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.71
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [2] - Non-comparative

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival (OS) is measured from the date a patient is randomized to the study [or commencement of therapy if patients are randomized during the first cycle of Imatinib] to the date of death from any cause. Patients remaining alive or lost to follow-up will be censored at the date of last follow-up.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the study.
    End point values
    		 Imatinib Alternating
    Number of subjects analysed
    36
    40
    Units: OS proportion at 12 months
        number (confidence interval 95%)
    97 (82 to 100)
    98 (84 to 100)
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    Imatinib v Alternating
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.31
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [3] - Non-comparative

    Secondary: Time to treatment failure

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    End point title
    		 Time to treatment failure
    End point description
    Treatment failure is defined as treatment discontinuation for any reason, including disease progression, treatment toxicity, patient/investigator's preference, non-protocol treatment or death. Only events in the first 12 months are considered. Patients not experiencing a treatment failure within 12 months were censored at 12 months.
    End point type
    Secondary
    End point timeframe
    From the start to the end of the protocol treatment
    End point values
    		 Imatinib Alternating
    Number of subjects analysed
    36
    40
    Units: Failure proportion at 12 months
        number (confidence interval 95%)
    83 (67 to 92)
    75 (59 to 86)
    Statistical analysis title
    		 Time to Treatment Failure
    Comparison groups
    Imatinib v Alternating
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.83
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [4] - Non-comparative

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The number of patients who experience specific adverse events in the period between randomization and 30 days (+/‐7 days) after the last dose of study treatment were reported.
    Adverse event reporting additional description
    The NCI Common Terminology Criteria for Adverse Events version 4 (NCI CTCAE v4.03) was used to classify and grade the intensity of adverse events after each treatment cycle.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Imatinib only
    Reporting group description
    		 All patients randomized to the Imatinib alone arm and received at least one dose of chemotherapy

    Reporting group title
    imatinib alternating with regorafenib
    Reporting group description
    		 All patients randomized to receive imatinib alternating with regorafenib and received at least one dose of chemotherapy

    Serious adverse events
    		 Imatinib only imatinib alternating with regorafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 36 (36.11%)
    14 / 40 (35.00%)
         number of deaths (all causes)
    11
    8
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular systolic dysfunction
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders - Other
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spleen disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (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
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders - Other
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal fistula
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jejunal perforation
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalized muscle weakness
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle weakness lower limb
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 40 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Imatinib only imatinib alternating with regorafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 36 (100.00%)
    40 / 40 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 40 (2.50%)
         occurrences all number
    3
    18
    Vascular disorders
    Hot flashes
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    6
    10
    Hypertension
         subjects affected / exposed
    7 / 36 (19.44%)
    24 / 40 (60.00%)
         occurrences all number
    50
    152
    Hypotension
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Lymphedema
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Lymphocele
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Thromboembolic event
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Surgical and medical procedures - Other
         subjects affected / exposed
    4 / 36 (11.11%)
    1 / 40 (2.50%)
         occurrences all number
    7
    2
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Edema face
         subjects affected / exposed
    5 / 36 (13.89%)
    1 / 40 (2.50%)
         occurrences all number
    20
    2
    Edema limbs
         subjects affected / exposed
    8 / 36 (22.22%)
    7 / 40 (17.50%)
         occurrences all number
    13
    25
    Edema trunk
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    3
    Fatigue
         subjects affected / exposed
    23 / 36 (63.89%)
    30 / 40 (75.00%)
         occurrences all number
    175
    193
    Fever
         subjects affected / exposed
    2 / 36 (5.56%)
    6 / 40 (15.00%)
         occurrences all number
    2
    9
    Flu like symptoms
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 40 (12.50%)
         occurrences all number
    2
    10
    Irritability
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    7
    Localized edema
         subjects affected / exposed
    4 / 36 (11.11%)
    1 / 40 (2.50%)
         occurrences all number
    36
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Pain
         subjects affected / exposed
    5 / 36 (13.89%)
    3 / 40 (7.50%)
         occurrences all number
    7
    8
    General disorders and administration site conditions - Other
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    20
    2
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Reproductive system and breast disorders
    Penile pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders - Other
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Testicular pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Uterine hemorrhage
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Vaginal discharge
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 40 (12.50%)
         occurrences all number
    5
    12
    Dyspnea
         subjects affected / exposed
    1 / 36 (2.78%)
    8 / 40 (20.00%)
         occurrences all number
    2
    18
    Hoarseness
         subjects affected / exposed
    1 / 36 (2.78%)
    9 / 40 (22.50%)
         occurrences all number
    14
    89
    Laryngeal inflammation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    Nasal congestion
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Pharyngeal mucositis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    Pharyngolaryngeal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    Respiratory failure
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders - Other
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 40 (10.00%)
         occurrences all number
    8
    6
    Sore throat
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Voice alteration
         subjects affected / exposed
    0 / 36 (0.00%)
    5 / 40 (12.50%)
         occurrences all number
    0
    13
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 40 (2.50%)
         occurrences all number
    24
    2
    Delirium
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    Insomnia
         subjects affected / exposed
    4 / 36 (11.11%)
    3 / 40 (7.50%)
         occurrences all number
    31
    3
    Psychiatric disorders - Other
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 36 (11.11%)
    8 / 40 (20.00%)
         occurrences all number
    9
    27
    Alkaline phosphatase increased
         subjects affected / exposed
    2 / 36 (5.56%)
    6 / 40 (15.00%)
         occurrences all number
    2
    21
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 36 (22.22%)
    7 / 40 (17.50%)
         occurrences all number
    20
    19
    Blood bilirubin increased
         subjects affected / exposed
    1 / 36 (2.78%)
    6 / 40 (15.00%)
         occurrences all number
    22
    15
    CPK increased
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Cholesterol high
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Creatinine increased
         subjects affected / exposed
    7 / 36 (19.44%)
    1 / 40 (2.50%)
         occurrences all number
    77
    3
    GGT increased
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 40 (5.00%)
         occurrences all number
    2
    22
    INR increased
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Investigations - Other
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 40 (10.00%)
         occurrences all number
    1
    8
    Lipase increased
         subjects affected / exposed
    2 / 36 (5.56%)
    7 / 40 (17.50%)
         occurrences all number
    19
    28
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 40 (7.50%)
         occurrences all number
    5
    8
    Neutrophil count decreased
         subjects affected / exposed
    5 / 36 (13.89%)
    2 / 40 (5.00%)
         occurrences all number
    17
    7
    Platelet count decreased
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    2
    4
    Weight gain
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 40 (0.00%)
         occurrences all number
    38
    0
    Weight loss
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 40 (12.50%)
         occurrences all number
    2
    9
    White blood cell decreased
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    14
    1
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Fall
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    5
    0
    Injury, poisoning and procedural complications - Other
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    14
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    Atrial fibrillation
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    1
    12
    Cardiac arrest
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Chest pain - cardiac
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    Heart failure
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    2
    Palpitations
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    3
    Sinus tachycardia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Cognitive disturbance
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    14
    0
    Concentration impairment
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    8
    2
    Dizziness
         subjects affected / exposed
    5 / 36 (13.89%)
    6 / 40 (15.00%)
         occurrences all number
    12
    15
    Dysesthesia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    4 / 36 (11.11%)
    3 / 40 (7.50%)
         occurrences all number
    12
    10
    Headache
         subjects affected / exposed
    6 / 36 (16.67%)
    13 / 40 (32.50%)
         occurrences all number
    13
    34
    Memory impairment
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    Nervous system disorders - Other
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Neuralgia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    30
    Paresthesia
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    5
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    8
    Presyncope
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    Tremor
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Vasovagal reaction
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    14 / 36 (38.89%)
    13 / 40 (32.50%)
         occurrences all number
    96
    39
    Blood and lymphatic system disorders - Other
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    10
    1
    Lymph node pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Ear pain
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    External ear pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Hearing impaired
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    10
    3
    Vertigo
         subjects affected / exposed
    4 / 36 (11.11%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Eye disorders
    Blurred vision
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    8
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    Dry eye
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 40 (5.00%)
         occurrences all number
    22
    4
    Eye disorders - Other
         subjects affected / exposed
    6 / 36 (16.67%)
    1 / 40 (2.50%)
         occurrences all number
    27
    1
    Eye pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Papilledema
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Retinal detachment
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Scleral disorder
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Watering eyes
         subjects affected / exposed
    4 / 36 (11.11%)
    0 / 40 (0.00%)
         occurrences all number
    7
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    5 / 36 (13.89%)
    1 / 40 (2.50%)
         occurrences all number
    9
    2
    Abdominal pain
         subjects affected / exposed
    15 / 36 (41.67%)
    17 / 40 (42.50%)
         occurrences all number
    40
    62
    Anal fistula
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Anal hemorrhage
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Anal mucositis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Anal pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    10
    0
    Anal ulcer
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Ascites
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    7
    1
    Bloating
         subjects affected / exposed
    7 / 36 (19.44%)
    1 / 40 (2.50%)
         occurrences all number
    13
    1
    Cheilitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Colitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    8 / 36 (22.22%)
    9 / 40 (22.50%)
         occurrences all number
    23
    28
    Diarrhea
         subjects affected / exposed
    21 / 36 (58.33%)
    19 / 40 (47.50%)
         occurrences all number
    128
    87
    Dry mouth
         subjects affected / exposed
    2 / 36 (5.56%)
    9 / 40 (22.50%)
         occurrences all number
    4
    18
    Dyspepsia
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 40 (7.50%)
         occurrences all number
    19
    6
    Flatulence
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 40 (5.00%)
         occurrences all number
    7
    3
    Gastric fistula
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Gastric hemorrhage
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Gastritis
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    6
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 40 (7.50%)
         occurrences all number
    3
    5
    Gastrointestinal disorders - Other
         subjects affected / exposed
    3 / 36 (8.33%)
    5 / 40 (12.50%)
         occurrences all number
    18
    9
    Gastrointestinal fistula
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal pain
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 40 (7.50%)
         occurrences all number
    5
    4
    Gastroparesis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Hemorrhoids
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Mucositis oral
         subjects affected / exposed
    4 / 36 (11.11%)
    20 / 40 (50.00%)
         occurrences all number
    7
    98
    Nausea
         subjects affected / exposed
    23 / 36 (63.89%)
    17 / 40 (42.50%)
         occurrences all number
    69
    69
    Oral hemorrhage
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Oral pain
         subjects affected / exposed
    0 / 36 (0.00%)
    5 / 40 (12.50%)
         occurrences all number
    0
    39
    Proctitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Rectal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Stomach pain
         subjects affected / exposed
    1 / 36 (2.78%)
    5 / 40 (12.50%)
         occurrences all number
    2
    18
    Toothache
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Upper gastrointestinal hemorrhage
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    11 / 36 (30.56%)
    5 / 40 (12.50%)
         occurrences all number
    37
    33
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 36 (8.33%)
    7 / 40 (17.50%)
         occurrences all number
    8
    28
    Bullous dermatitis
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Dry skin
         subjects affected / exposed
    4 / 36 (11.11%)
    11 / 40 (27.50%)
         occurrences all number
    11
    47
    Erythema multiforme
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Erythroderma
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    5
    4
    Hypohidrosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Nail ridging
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Pain of skin
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    31
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    1 / 36 (2.78%)
    31 / 40 (77.50%)
         occurrences all number
    4
    288
    Periorbital edema
         subjects affected / exposed
    13 / 36 (36.11%)
    10 / 40 (25.00%)
         occurrences all number
    117
    44
    Pruritus
         subjects affected / exposed
    5 / 36 (13.89%)
    6 / 40 (15.00%)
         occurrences all number
    14
    28
    Rash acneiform
         subjects affected / exposed
    4 / 36 (11.11%)
    3 / 40 (7.50%)
         occurrences all number
    8
    9
    Rash maculo-papular
         subjects affected / exposed
    6 / 36 (16.67%)
    9 / 40 (22.50%)
         occurrences all number
    12
    23
    Scalp pain
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders - Other
         subjects affected / exposed
    7 / 36 (19.44%)
    11 / 40 (27.50%)
         occurrences all number
    14
    18
    Skin ulceration
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    7
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 40 (0.00%)
         occurrences all number
    7
    0
    Proteinuria
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Renal and urinary disorders - Other
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Renal calculi
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Renal colic
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Urinary retention
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Urinary tract pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 40 (5.00%)
         occurrences all number
    5
    4
    Hypothyroidism
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    2
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 36 (19.44%)
    5 / 40 (12.50%)
         occurrences all number
    35
    12
    Back pain
         subjects affected / exposed
    7 / 36 (19.44%)
    5 / 40 (12.50%)
         occurrences all number
    13
    12
    Bone pain
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Buttock pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Chest wall pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Generalized muscle weakness
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorder - Other
         subjects affected / exposed
    14 / 36 (38.89%)
    18 / 40 (45.00%)
         occurrences all number
    60
    69
    Myalgia
         subjects affected / exposed
    4 / 36 (11.11%)
    4 / 40 (10.00%)
         occurrences all number
    28
    16
    Neck pain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    6
    1
    Pain in extremity
         subjects affected / exposed
    5 / 36 (13.89%)
    5 / 40 (12.50%)
         occurrences all number
    11
    12
    Infections and infestations
    Bladder infection
         subjects affected / exposed
    4 / 36 (11.11%)
    1 / 40 (2.50%)
         occurrences all number
    5
    1
    Enterocolitis infectious
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Infections and infestations - Other
         subjects affected / exposed
    7 / 36 (19.44%)
    6 / 40 (15.00%)
         occurrences all number
    10
    6
    Lip infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Lung infection
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Mucosal infection
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Otitis externa
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Sepsis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Skin infection
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Tooth infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Upper respiratory infection
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 40 (10.00%)
         occurrences all number
    8
    7
    Urinary tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 40 (5.00%)
         occurrences all number
    2
    4
    Vaginal infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    6 / 36 (16.67%)
    11 / 40 (27.50%)
         occurrences all number
    14
    21
    Dehydration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Hyperglycemia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Hyperkalemia
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Hypermagnesemia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    4
    Hypernatremia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Hypoalbuminemia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    9
    0
    Hypocalcemia
         subjects affected / exposed
    5 / 36 (13.89%)
    6 / 40 (15.00%)
         occurrences all number
    37
    9
    Hypoglycemia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Hypokalemia
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    Hypomagnesemia
         subjects affected / exposed
    5 / 36 (13.89%)
    5 / 40 (12.50%)
         occurrences all number
    26
    17
    Hyponatremia
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    3
    3
    Hypophosphatemia
         subjects affected / exposed
    6 / 36 (16.67%)
    10 / 40 (25.00%)
         occurrences all number
    27
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2017
    Change in study design including primary endpoint and sample size

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

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