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    Clinical Trial Results:
    APPLE trial: Feasibility and activity of AZD9291 (osimertinib) treatment on Positive PLasma T790M in EGFR mutant NSCLC patients

    Summary
    EudraCT number
    		 2016-001834-82
    Trial protocol
    		 SI   ES   PL  
    Global end of trial date
    06 May 2022

    Results information
    Results version number
    		 v1
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    1613-LCG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02856893
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    EORTC
    Sponsor organisation address
    Avenue Emmanuel Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Regulatory Affairs Department, European Organisation for Research and Treatment of Cancer (EORTC), +32 2774 13 53, regulatory@eortc.org
    Scientific contact
    Regulatory Affairs Department, European Organisation for Research and Treatment of Cancer (EORTC), +32 2774 13 53, regulatory@eortc.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the best strategy for delivering osimertinib (AZD9291) in NSCLC patients with EGFR mutation. The objective is assessed by Progression Free Survival rate at 18 months (PFSR-18).
    Protection of trial subjects
    Safety data were reviewed within the EORTC Headquarters on a regular basis as part of the Medical Review process. Safety information was included in trial status reports which served as a basis of discussion during EORTC Group meetings.
    Background therapy
    		 In treatment arm B, patients received Gefitinib until RECIST-based progressive disease, before switching to Osimertinib. In treatment arm C, patients received Gefitinib until RECIST-based progressive disease, before switching to Osimertinib.
    Evidence for comparator
    		 No Prior studies have indicated that Gefitinib improves the response rate (RR), progression-free survival (PFS) and quality of life over standard first-line platinum-doublet chemotherapy in several randomized phase III trials in EGFR mutant advanced NSCLC patients
    Actual start date of recruitment
    01 Sep 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
    Spain: 74
    Country: Number of subjects enrolled
    France: 63
    Country: Number of subjects enrolled
    Jordan: 15
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Poland: 1
    Worldwide total number of subjects
    156
    EEA total number of subjects
    141
    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)
    72
    From 65 to 84 years
    78
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study intended to randomize 156 patients (52 patients per arm). It was expected that 156 patients would be randomized within 2 years and 2 months from the first patient randomized into the study. In total, 156 patients have been randomized. ECOG performance status of 0 or 1

    Pre-assignment
    Screening details
    		 Main eligibility criteria: Stage IV NSCLC common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R) EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI If brain metastases, only stable allowed Adequate hepatic, renal and bone marrow function

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: first-line treatment with Osimertinib until RECIST pro
    Arm description
    		 Osimertinib until PD according to RECIST 1.1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Osimertinib
    Investigational medicinal product code
    DM09330
    Other name
    AZD9291 (Tagrisso)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    orally taken, beige, filmcoated tablet containing 40 mg or 80 mg of Osimertinib expressed as free base (equivalent of 47.7 mg or 95.4 mg of Osimertinib mesalate). Osimertinib (TAGRISSO ™1, laboratory code AZD9291) is an oral, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor activating mutation (EGFRm) and the resistance mutation (T790M) specifically

    Arm title
    		 Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib
    Arm description
    		 If patients have RECIST 1.1 progression without cfDNA T790M positive test, they will be switched to osimertinib. Note that that after protocol amendement 4, the T790M tests no longer needed to be performed for patients still on gefitinib. These patients should continue on gefitinib until progression by RECIST 1.1 (as in Arm C) .
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gefinitib
    Investigational medicinal product code
    DM00317
    Other name
    ZD1839 (IRESSA™, laboratory code)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    orally taken, brown, round, biconvex tablets containing 250 mg of gefitinib Gefitinib (IRESSA™, laboratory code) is an oral, reversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor activating mutation (EGFRm). Dose: Once a day (QD)

    Investigational medicinal product name
    Osimertinib
    Investigational medicinal product code
    DM09330
    Other name
    AZD9291 (Tagrisso)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    orally taken, beige, filmcoated tablet containing 40 mg or 80 mg of Osimertinib expressed as free base (equivalent of 47.7 mg or 95.4 mg of Osimertinib mesalate). Osimertinib (TAGRISSO ™1, laboratory code AZD9291) is an oral, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor activating mutation (EGFRm) and the resistance mutation (T790M) specifically

    Arm title
    		 Arm C: Gefitinib until PD followed by Osimertinib
    Arm description
    		 Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 .
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gefinitib
    Investigational medicinal product code
    DM00317
    Other name
    ZD1839 (IRESSA™, laboratory code)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    orally taken, brown, round, biconvex tablets containing 250 mg of gefitinib Gefitinib (IRESSA™, laboratory code) is an oral, reversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor activating mutation (EGFRm). Dose: Once a day (QD)

    Investigational medicinal product name
    Osimertinib
    Investigational medicinal product code
    DM09330
    Other name
    AZD9291 (Tagrisso)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    orally taken, beige, filmcoated tablet containing 40 mg or 80 mg of Osimertinib expressed as free base (equivalent of 47.7 mg or 95.4 mg of Osimertinib mesalate). Osimertinib (TAGRISSO ™1, laboratory code AZD9291) is an oral, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor activating mutation (EGFRm) and the resistance mutation (T790M) specifically

    Number of subjects in period 1
    		Arm A: first-line treatment with Osimertinib until RECIST pro Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib Arm C: Gefitinib until PD followed by Osimertinib
    Started
    53
    52
    51
    Completed
    47
    34
    37
    Not completed
    6
    18
    14
         death not due to malignant disease or tox
    1
    1
    1
         Investigator's decision
    -
    2
    5
         Adverse event, non-fatal
    2
    5
    5
         Other malignancy
    2
    -
    -
         Patient's decision
    1
    2
    1
         other
    -
    4
    2
         Missing
    -
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: first-line treatment with Osimertinib until RECIST pro
    Reporting group description
    		 Osimertinib until PD according to RECIST 1.1

    Reporting group title
    Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib
    Reporting group description
    		 If patients have RECIST 1.1 progression without cfDNA T790M positive test, they will be switched to osimertinib. Note that that after protocol amendement 4, the T790M tests no longer needed to be performed for patients still on gefitinib. These patients should continue on gefitinib until progression by RECIST 1.1 (as in Arm C) .

    Reporting group title
    Arm C: Gefitinib until PD followed by Osimertinib
    Reporting group description
    		 Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 .

    Reporting group values
    		 Arm A: first-line treatment with Osimertinib until RECIST pro Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib Arm C: Gefitinib until PD followed by Osimertinib Total
    Number of subjects
    		 53 52 51 156
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 21 20 31 72
        From 65-84 years
    		 29 32 17 78
        85 years and over
    		 3 0 3 6
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68 (60 to 76) 69 (61.5 to 75.5) 61 (54 to 68) -
    Gender categorical
    Units: Subjects
        Female
    		 30 39 33 102
        Male
    		 23 13 18 54
    Prior neo-adjuvant therapy
    Was Prior neo-adjuvant therapy given?
    Units: Subjects
        yes
    		 0 2 1 3
        no
    		 53 50 50 153
    Prior adjuvant therapy
    Was prior adjuvant therapy given?
    Units: Subjects
        yes
    		 2 0 1 3
        no
    		 51 52 50 153
    T790M
    Stratification factor used for randomization
    Units: Subjects
        Mutation
    		 0 0 0 0
        No mutation
    		 53 52 51 156
    EGFR mutation
    Stratification factor used for randomization
    Units: Subjects
        Del19
    		 35 33 33 101
        L858R
    		 18 19 18 55
    Presence of brain metastases
    Stratification factor used for randomisation
    Units: Subjects
        yes
    		 10 16 14 40
        no
    		 43 36 37 116
    Smoking history
    Smoking history
    Units: Subjects
        Never smoked
    		 35 37 30 102
        Ex-smoker
    		 17 12 17 46
        Current smoker
    		 1 3 3 7
        missing
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Arm A: first-line treatment with Osimertinib until RECIST pro
    Reporting group description
    		 Osimertinib until PD according to RECIST 1.1

    Reporting group title
    Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib
    Reporting group description
    		 If patients have RECIST 1.1 progression without cfDNA T790M positive test, they will be switched to osimertinib. Note that that after protocol amendement 4, the T790M tests no longer needed to be performed for patients still on gefitinib. These patients should continue on gefitinib until progression by RECIST 1.1 (as in Arm C) .

    Reporting group title
    Arm C: Gefitinib until PD followed by Osimertinib
    Reporting group description
    		 Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 .

    Primary: Progression Free Survival at 18 months (PFSR-OSI-18)

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    End point title
    		 Progression Free Survival at 18 months (PFSR-OSI-18)
    End point description
    The primary endpoint in this study is Progression Free Survival rate according to RECIST 1.1 “while receiving Osimertinib” at 18 months (PFSR-OSI-18). This endpoint is evaluated in arm B and C. In arm A (osimertinib alone), the endpoint is assessed to simply provide a point estimate for PFSR-OSI-18 and the corresponding confidence interval. The primary endpoint is defined as the proportion of patients at 18 months who are alive and did not experience an event for PFS-OSI according to the definition below. Practically, the time point of disease evaluation corresponding to the primary endpoint is 18 months after randomization. Therefore, disease evaluation at 18 months (+/- 14 days) is required for all patients who are still alive and without an event for PFS-OSI at the 18th month. Disease evaluation done within a window of +/- 2 weeks will be taken into account for the 18-month assessment.
    End point type
    Primary
    End point timeframe
    18 months after randomization
    End point values
    		 Arm A: first-line treatment with Osimertinib until RECIST pro Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib Arm C: Gefitinib until PD followed by Osimertinib
    Number of subjects analysed
    45 [1]
    47 [2]
    44 [3]
    Units: events per 1.5 years
        number (confidence interval 95%)
    51.1 (35.8 to 64.5)
    67.2 (51.5 to 78.8)
    53.5 (37.7 to 67.0)
    Notes
    [1] - per-protocol patient population
    [2] - per-protocol patient population
    [3] - per-protocol patient population
    Statistical analysis title
    		 Progression-free survival rate at 18 months Arm B
    Statistical analysis description
    analysis of progression free survival rate at 18 months while on osimertinib. The decision rule is based on the lower bound of the 84% confidence interval: If it above 40% (null hypothesis), the arm will be declared worthwhile of further investigation, if below the arm should be rejected from further exploration
    Comparison groups
    Arm A: first-line treatment with Osimertinib until RECIST pro v Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib v Arm C: Gefitinib until PD followed by Osimertinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 PFSR-OSI-18 rate
    Point estimate
    67.2
    Confidence interval
         level
    		 84%
         sides
    2-sided
         lower limit
    		 56.4
         upper limit
    		 75.9
    Notes
    [4] - derivation of 84% confidence intervals was done using the Kaplan-Meier technique.
    Statistical analysis title
    		 Progression free survival rate at 18 months Arm C
    Statistical analysis description
    analysis of progression free survival rate at 18 months while on osimertinib. The decision rule is based on the lower bound of the 84% confidence interval: If it above 40% (null hypothesis), the arm will be declared worthwhile of further investigation, if below the arm should be rejected from further exploration
    Comparison groups
    Arm C: Gefitinib until PD followed by Osimertinib v Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib v Arm A: first-line treatment with Osimertinib until RECIST pro
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 PFSR-OSI-18 rate
    Point estimate
    53.5
    Confidence interval
         level
    		 84%
         sides
    2-sided
         lower limit
    		 42.3
         upper limit
    		 63.5
    Notes
    [5] - derivation of 84% confidence intervals was done using the Kaplan-Meier technique.

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival time is computed from date of registration until date of death from any cause. If no death has been observed, then the patient is censored at the last date known to be alive.
    End point values
    		 Arm A: first-line treatment with Osimertinib until RECIST pro Arm B: Gefitinib until (cfDNA) PD followed by Osimertinib Arm C: Gefitinib until PD followed by Osimertinib
    Number of subjects analysed
    45 [6]
    47 [7]
    44 [8]
    Units: Months
        median (confidence interval 95%)
    84.4 (70.1 to 92.3)
    87.0 (73.3 to 93.9)
    77.3 (61.9 to 87.1)
    Notes
    [6] - Per protocol set
    [7] - Per protocol set
    [8] - Per protocol set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The number of patients who had specific adverse events in the period between the randomization and time of treatment discontinuation was reported
    Adverse event reporting additional description
    Adverse events are evaluated using CTC grading. Serious adverse events were defined following the Good Clinical Practice Guideline. Adverse events are reported as belonging to the treatment period if the adverse event start date falls on the first day of treatment and up till the date of last treatment administration + 30 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 -

    Reporting group title
    Arm B
    Reporting group description
    		 for the Serious adverse events and deaths, no distinction is made between between the GEFITINIB and OSIMERITINIB period.

    Reporting group title
    Arm C
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A Arm B Arm C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 53 (26.42%)
    10 / 52 (19.23%)
    22 / 51 (43.14%)
         number of deaths (all causes)
    20
    20
    20
         number of deaths resulting from adverse events
    2
    1
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoma in situ
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular dyskinesia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Splenic infarction
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal infarct
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Diverticulitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypophagia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A Arm B Arm C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 53 (98.11%)
    51 / 52 (98.08%)
    50 / 51 (98.04%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Neoplasms Other
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Hot Flashes
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Hypertension
         subjects affected / exposed
    7 / 53 (13.21%)
    8 / 52 (15.38%)
    5 / 51 (9.80%)
         occurrences all number
    7
    8
    5
    Hypotension
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Thromboembolic Event
         subjects affected / exposed
    7 / 53 (13.21%)
    2 / 52 (3.85%)
    2 / 51 (3.92%)
         occurrences all number
    7
    2
    2
    Vascular Other
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 52 (7.69%)
    0 / 51 (0.00%)
         occurrences all number
    1
    4
    0
    oedema limbs
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 52 (3.85%)
    4 / 51 (7.84%)
         occurrences all number
    2
    2
    4
    Facial pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Fatigue
         subjects affected / exposed
    18 / 53 (33.96%)
    17 / 52 (32.69%)
    15 / 51 (29.41%)
         occurrences all number
    18
    17
    15
    Fever
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 52 (3.85%)
    3 / 51 (5.88%)
         occurrences all number
    3
    2
    3
    Flu Like Symptoms
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
         occurrences all number
    1
    1
    3
    Gait disturbance
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Multi-Organ Failure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 53 (11.32%)
    2 / 52 (3.85%)
    7 / 51 (13.73%)
         occurrences all number
    6
    2
    7
    Pain
         subjects affected / exposed
    5 / 53 (9.43%)
    4 / 52 (7.69%)
    7 / 51 (13.73%)
         occurrences all number
    5
    4
    7
    GENERAL Other
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Immune system disorders
    Allergic Reaction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Reproductive system and breast disorders
    Irregular menstruation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Menorrhagia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginal inflammation
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Adult Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Allergic Rhinitis
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Bronchospasm
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    10 / 53 (18.87%)
    9 / 52 (17.31%)
    10 / 51 (19.61%)
         occurrences all number
    10
    9
    10
    Dyspnoea
         subjects affected / exposed
    10 / 53 (18.87%)
    3 / 52 (5.77%)
    6 / 51 (11.76%)
         occurrences all number
    10
    3
    6
    Epistaxis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    1
    0
    4
    Hoarseness
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Laryngeal mucositis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Pharyngeal haemorrhage
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    pharyngeal mucositis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngolaryngeal Pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Pleuratic pain
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    1
    1
    0
    Pneumonitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Pneumothorax
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0
    Postnasal Drip
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Productive cough
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 52 (3.85%)
    2 / 51 (3.92%)
         occurrences all number
    2
    2
    2
    Sore Throat
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 52 (3.85%)
    2 / 51 (3.92%)
         occurrences all number
    1
    2
    2
    Voice Alteration
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory Other
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 52 (5.77%)
    2 / 51 (3.92%)
         occurrences all number
    2
    3
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    6 / 51 (11.76%)
         occurrences all number
    0
    1
    6
    Confusion
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    2
    Depression
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
         occurrences all number
    2
    3
    0
    Insomnia
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
         occurrences all number
    4
    1
    3
    Psychosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 53 (13.21%)
    14 / 52 (26.92%)
    15 / 51 (29.41%)
         occurrences all number
    7
    14
    15
    Alkaline Phosphatase Increased
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 52 (5.77%)
    5 / 51 (9.80%)
         occurrences all number
    4
    3
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 53 (9.43%)
    12 / 52 (23.08%)
    13 / 51 (25.49%)
         occurrences all number
    5
    12
    13
    Blood bilirubin increased
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    4 / 51 (7.84%)
         occurrences all number
    0
    2
    4
    Cholesterol High
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 52 (5.77%)
    2 / 51 (3.92%)
         occurrences all number
    2
    3
    2
    Cpk Increased
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
         occurrences all number
    2
    1
    3
    Creatinine Increased
         subjects affected / exposed
    3 / 53 (5.66%)
    5 / 52 (9.62%)
    3 / 51 (5.88%)
         occurrences all number
    3
    5
    3
    Electrocardiogram Qt Corrected Interval
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 52 (5.77%)
    2 / 51 (3.92%)
         occurrences all number
    4
    3
    2
    Ggt Increased
         subjects affected / exposed
    6 / 53 (11.32%)
    3 / 52 (5.77%)
    4 / 51 (7.84%)
         occurrences all number
    6
    3
    4
    Haemoglobin increased
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    1
    Neutrophil count decreased
         subjects affected / exposed
    5 / 53 (9.43%)
    9 / 52 (17.31%)
    4 / 51 (7.84%)
         occurrences all number
    5
    9
    4
    Platelet count decreased
         subjects affected / exposed
    12 / 53 (22.64%)
    7 / 52 (13.46%)
    2 / 51 (3.92%)
         occurrences all number
    12
    7
    2
    Weight gain
         subjects affected / exposed
    5 / 53 (9.43%)
    4 / 52 (7.69%)
    10 / 51 (19.61%)
         occurrences all number
    5
    4
    10
    Weight loss
         subjects affected / exposed
    19 / 53 (35.85%)
    15 / 52 (28.85%)
    19 / 51 (37.25%)
         occurrences all number
    19
    15
    19
    White blood cell decreased
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
         occurrences all number
    3
    3
    0
    INV other
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 52 (5.77%)
    6 / 51 (11.76%)
         occurrences all number
    2
    3
    6
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Hip fracture
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0
    Injury to carotid artery
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Spinal fracture
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    1
    1
    0
    Injury Other
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    0
    3
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Acute coronary syndrome
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    heart failure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 52 (5.77%)
    1 / 51 (1.96%)
         occurrences all number
    1
    3
    1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Atrial flutter
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Mitral valve disease
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Pericardial Tamponade
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Cardiac OTHER
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    2
    Concentration impairment
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 53 (3.77%)
    8 / 52 (15.38%)
    4 / 51 (7.84%)
         occurrences all number
    2
    8
    4
    Dysaesthesia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    7 / 53 (13.21%)
    2 / 52 (3.85%)
    4 / 51 (7.84%)
         occurrences all number
    7
    2
    4
    Dysphagia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema cerebral
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Facial nerve disorder
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    1
    1
    0
    Headache
         subjects affected / exposed
    1 / 53 (1.89%)
    10 / 52 (19.23%)
    11 / 51 (21.57%)
         occurrences all number
    1
    10
    11
    Memory impairment
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    1
    Neuralgia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Oculomotor nerve disorder
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Paresthesia
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 52 (5.77%)
    3 / 51 (5.88%)
         occurrences all number
    4
    3
    3
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Radiculitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Recurrent Laryngeal Nerve Palsy
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Seizure
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Spasticity
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Stroke
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    2
    Transient ischaemic attack
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Nervous Other
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 52 (5.77%)
    2 / 51 (3.92%)
         occurrences all number
    0
    3
    2
    Blood and lymphatic system disorders
    anemia
         subjects affected / exposed
    10 / 53 (18.87%)
    10 / 52 (19.23%)
    5 / 51 (9.80%)
         occurrences all number
    10
    10
    5
    Leukocytosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Bood OTHER
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    0
    1
    Vertigo
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    2
    1
    2
    EAR OTHER
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    External ear inflammation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Hearing disability
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Cataract
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    1
    Conjunctivitis
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 52 (5.77%)
    3 / 51 (5.88%)
         occurrences all number
    2
    3
    3
    Dry eye
         subjects affected / exposed
    1 / 53 (1.89%)
    6 / 52 (11.54%)
    7 / 51 (13.73%)
         occurrences all number
    1
    6
    7
    Papilloedema
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Watering Eyes
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    0
    1
    EYES OTHER
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 52 (7.69%)
    3 / 51 (5.88%)
         occurrences all number
    1
    4
    3
    Eye pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Keratitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    2
    Glaucoma
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 53 (7.55%)
    6 / 52 (11.54%)
    6 / 51 (11.76%)
         occurrences all number
    4
    6
    6
    Anal ulcer
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    7 / 53 (13.21%)
    6 / 52 (11.54%)
    5 / 51 (9.80%)
         occurrences all number
    7
    6
    5
    Dental caries
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    27 / 53 (50.94%)
    30 / 52 (57.69%)
    28 / 51 (54.90%)
         occurrences all number
    27
    30
    28
    Dry mouth
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 52 (5.77%)
    3 / 51 (5.88%)
         occurrences all number
    3
    3
    3
    Gastritis
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    2
    0
    Gastroesophageal Reflux Disease
         subjects affected / exposed
    2 / 53 (3.77%)
    5 / 52 (9.62%)
    6 / 51 (11.76%)
         occurrences all number
    2
    5
    6
    Abdominal distension
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Anal haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Colitis
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspepsia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    2
    Dysphagia
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 52 (5.77%)
    1 / 51 (1.96%)
         occurrences all number
    0
    3
    1
    Enterocolitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Esophagitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    2
    Gastrointestinal pain
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    1
    0
    Gingival pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    4
    0
    1
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Mucositis Oral
         subjects affected / exposed
    7 / 53 (13.21%)
    9 / 52 (17.31%)
    6 / 51 (11.76%)
         occurrences all number
    7
    9
    6
    Nausea
         subjects affected / exposed
    4 / 53 (7.55%)
    8 / 52 (15.38%)
    8 / 51 (15.69%)
         occurrences all number
    4
    8
    8
    Oral dysaesthesia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Oral Hemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Oral pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Periodontal disease
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Salivary duct inflammation
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    stomach pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Toothache
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    1
    Vomiting
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 52 (7.69%)
    4 / 51 (7.84%)
         occurrences all number
    2
    4
    4
    GASTRO Other
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    4
    2
    1
    Hepatobiliary disorders
    HEPATO Other
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    5 / 51 (9.80%)
         occurrences all number
    0
    0
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 53 (5.66%)
    5 / 52 (9.62%)
    1 / 51 (1.96%)
         occurrences all number
    3
    5
    1
    Bullous Dermatitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Dry skin
         subjects affected / exposed
    22 / 53 (41.51%)
    18 / 52 (34.62%)
    17 / 51 (33.33%)
         occurrences all number
    22
    18
    17
    Erythema multiforme
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
         occurrences all number
    3
    1
    3
    Hirsutism
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    1
    1
    0
    Hypertrichosis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    3
    Nail discolouration
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Nail Loss
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    3
    1
    2
    Nail ridging
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Pain of skin
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    1
    Periorbital oedema
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Photosensitivity
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    7 / 53 (13.21%)
    10 / 52 (19.23%)
    10 / 51 (19.61%)
         occurrences all number
    7
    10
    10
    Rash acneiform
         subjects affected / exposed
    11 / 53 (20.75%)
    24 / 52 (46.15%)
    19 / 51 (37.25%)
         occurrences all number
    11
    24
    19
    Rash maculo-papular
         subjects affected / exposed
    4 / 53 (7.55%)
    7 / 52 (13.46%)
    5 / 51 (9.80%)
         occurrences all number
    4
    7
    5
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Skin ulceration
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    2 / 51 (3.92%)
         occurrences all number
    0
    2
    2
    Skin Other
         subjects affected / exposed
    9 / 53 (16.98%)
    11 / 52 (21.15%)
    6 / 51 (11.76%)
         occurrences all number
    9
    11
    6
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
         occurrences all number
    2
    3
    0
    Chronic kidney disease
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Cystitis noninfective
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    5 / 51 (9.80%)
         occurrences all number
    1
    1
    5
    Haematuria
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    2
    Renal colic
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    1
    2
    1
    Urinary frequency
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    1
    2
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    2
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
         occurrences all number
    0
    1
    3
    Urinary urgency
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Urine discoloration
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Renal Other
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 53 (9.43%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
         occurrences all number
    5
    1
    3
    Arthritis
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    1
    0
    Back pain
         subjects affected / exposed
    9 / 53 (16.98%)
    8 / 52 (15.38%)
    10 / 51 (19.61%)
         occurrences all number
    9
    8
    10
    Bone pain
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 52 (5.77%)
    6 / 51 (11.76%)
         occurrences all number
    4
    3
    6
    Chest wall pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 53 (0.00%)
    5 / 52 (9.62%)
    1 / 51 (1.96%)
         occurrences all number
    0
    5
    1
    Generalized Muscle Weakness
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    0
    Muscle Weakness Upper Limb
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 52 (3.85%)
    6 / 51 (11.76%)
         occurrences all number
    4
    2
    6
    Myositis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Neck pain
         subjects affected / exposed
    5 / 53 (9.43%)
    2 / 52 (3.85%)
    5 / 51 (9.80%)
         occurrences all number
    5
    2
    5
    Osteoporosis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 52 (5.77%)
    5 / 51 (9.80%)
         occurrences all number
    2
    3
    5
    Muscoskeletal Other
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    1
    0
    2
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchial Infection
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 52 (3.85%)
    2 / 51 (3.92%)
         occurrences all number
    2
    2
    2
    Gum Infection
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatitis viral
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Lip infection
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Lung Infection
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 52 (5.77%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    3
    Meningitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Mucosal infection
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Nail infection
         subjects affected / exposed
    4 / 53 (7.55%)
    4 / 52 (7.69%)
    3 / 51 (5.88%)
         occurrences all number
    4
    4
    3
    Otitis media
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    Papulopustular Rash
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 52 (5.77%)
    2 / 51 (3.92%)
         occurrences all number
    0
    3
    2
    Paronychia
         subjects affected / exposed
    7 / 53 (13.21%)
    7 / 52 (13.46%)
    8 / 51 (15.69%)
         occurrences all number
    7
    7
    8
    Pharyngitis
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    2
    Rhinitis Infective
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    0
    Sepsis
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 52 (3.85%)
    2 / 51 (3.92%)
         occurrences all number
    1
    2
    2
    Skin infection
         subjects affected / exposed
    2 / 53 (3.77%)
    5 / 52 (9.62%)
    2 / 51 (3.92%)
         occurrences all number
    2
    5
    2
    Tooth infection
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    Upper respiratory infection
         subjects affected / exposed
    2 / 53 (3.77%)
    6 / 52 (11.54%)
    5 / 51 (9.80%)
         occurrences all number
    2
    6
    5
    Urinary tract infection
         subjects affected / exposed
    3 / 53 (5.66%)
    7 / 52 (13.46%)
    5 / 51 (9.80%)
         occurrences all number
    3
    7
    5
    Infections Other
         subjects affected / exposed
    8 / 53 (15.09%)
    5 / 52 (9.62%)
    4 / 51 (7.84%)
         occurrences all number
    8
    5
    4
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Anorexia
         subjects affected / exposed
    12 / 53 (22.64%)
    11 / 52 (21.15%)
    9 / 51 (17.65%)
         occurrences all number
    12
    11
    9
    Hypercalcaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
         occurrences all number
    3
    3
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 52 (7.69%)
    0 / 51 (0.00%)
         occurrences all number
    1
    4
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    1
    2
    1
    Hypocalcaemia
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    2
    2
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 52 (5.77%)
    2 / 51 (3.92%)
         occurrences all number
    0
    3
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    5 / 52 (9.62%)
    1 / 51 (1.96%)
         occurrences all number
    0
    5
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 52 (3.85%)
    0 / 51 (0.00%)
         occurrences all number
    2
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 52 (5.77%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    3
    Metbabolism Other
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    1
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2022
    Due to a funding gap in the study budget driven by the cost of the T790M testing in all arms as well as by some patients being long term responders to the both study treatments, the study team had prepared different scenarios for HBM collection of varying cost with the aim of mitigating the budget gap. The least costly of these scenarios involved only keeping the T790M testing for patients in arm B still under gefitinib, while also providing the study drugs to all patients still under treatment. These scenario were presented and discussed with Astra Zeneca during a TC on the 8th of December 2021, who agreed to keep providing study drugs to long term responders but declined to continue paying for the sample testing in all arms, arguing that only 2 patients were still under gefitinib treatment in arm B and interrupting the sample testing at the time would not influence the results since we were already past the clinical cut off date for the primary analysis. This required that the protocol be modified to indicate that blood samples for this T790M analysis will not be required nay more in all arms. This implies that patients in arm B no longer switch from gefitinib to Osimertinib based on the result of the T790M mutation status, but switch based on RECIST progression as in arm C.

    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.
    Regarding the reported of adverse events: for treatment arms B and C, the adverse events experienced during Gefitinib and Osimeritinib were grouped together.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36863484
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