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    Clinical Trial Results:
    Open-label first line, single-arm phase II study of CisGem combined with pembrolizumab in patients with advanced or metastatic biliary tract cancer

    Summary
    EudraCT number
    		 2017-003323-30
    Trial protocol
    		 GB   ES  
    Global end of trial date
    31 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Sep 2024
    First version publication date
    25 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EORTC-1607-GITCG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03260712
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NCRI-UK Upper GI CSG (HB): ABC-09
    Sponsors
    Sponsor organisation name
    European Organisation for the Research and treatment of Cancer (EORTC)
    Sponsor organisation address
    Avenue Emmanuel Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Regulatory Affairs Department, European Organisation for the Research and treatment of Cancer (EORTC), +32 27741072, murielle.mauer@gmail.com
    Scientific contact
    Regulatory Affairs Department, European Organisation for the Research and treatment of Cancer (EORTC), 0471693363 27741072, murielle.mauer@gmail.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this single-arm phase II trial is to detect an increase in progression-free survival (PFS) rate at 6 months (according to RECIST version 1.1) in patients with BTC treated with CisGem combined with pembrolizumab as compared to historical controls when treated with standard chemotherapy approach.
    Protection of trial subjects
    The responsible investigator had to ensure that this study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol had been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinicalpractice_en.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 No control arm is available in this study. Historical controls treated with standard CisGem chemotherapy are used as benchmark. All patients will receive CisGem [25mg/m2 intravenous (IV) cisplatin + 1000mg/m2 IV gemcitabine, on days 1 and 8 of a 21-day cycle] as backbone chemotherapy regimen plus 200 mg intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle up to 2 years from enrolment until disease progression or the early occurrence of a withdrawal.
    Evidence for comparator
    		 Valle et al. conducted randomized phase III study, the ABC-02 trial with a total of 410 patients (including the ABC-01 cohort) with locally advanced or metastatic CCA, GBC, or ampullary cancer randomly assigned to treatment either with cisplatin (25 mg/m2 on days 1 and 8), followed by gemcitabine (1000 mg/m2 on days 1 and 8 every 3 weeks) or gemcitabine (1000 mg/m2 on days 1, 8 and 15 every 4 weeks) alone (Ref. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281). With a median overall survival of 11.7 months in the CisGem group, as compared to 8.1 months in the gemcitabine group (hazard ratio, 0.64; 95% confidence interval (CI), 0.52 to 0.80; P<0.001), the CisGem combination demonstrated a significant survival benefit.
    Actual start date of recruitment
    07 Jan 2020
    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: 9
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Germany: 10
    Worldwide total number of subjects
    50
    EEA total number of subjects
    19
    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)
    26
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 07/01/2020 and 27/04/2021, 50 patients with advanced or metastatic biliary tract cancer were enrolled at 7 medical centres in 3 countries (Germany, Spain and UK).

    Pre-assignment
    Screening details
    		 Upon signing the informed consent and after verification of eligibility, patients were centrally enrolled using the electronic platform available on the EORTC website. Patients were not randomized as this was a single arm study.

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

    Arms
    Arm title
    		 Experimental arm
    Arm description
    		 CisGem [25mg/m² intravenous (IV) cisplatin + 1000mg/m² IV gemcitabine, on days 1 and 8 of a 21-day cycle] plus 200 mg intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle up to 2 years from enrolment until progressive disease or the early occurrence of a withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25mg/m2 intravenous (IV) cisplatin, on days 1 and 8 of a 21-day cycle up to 2 years from enrolment until progressive disease or the early occurrence of a withdrawal.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m² IV gemcitabine, on days 1 and 8 of a 21-day cycle up to 2 years from enrolment until progressive disease or the early occurrence of a withdrawal.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK 3475
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    On day 1 of each cycle, pembrolizumab will be administered before the chemotherapies. All patients will receive 200 mg intravenous pembrolizumab on day 1 of a 21-day cycle up to 2 years from enrolment until progressive disease or the early occurrence of a withdrawal.

    Number of subjects in period 1
    		Experimental arm
    Started
    50
    Completed
    3
    Not completed
    47
         Adverse event, serious fatal
    2
         Adverse event, non-fatal
    3
         Death not due to malignant disease or toxicity
    2
         Other malignancy
    1
         Patient's or investigator's decision (no AE)
    3
         Progression of disease/death due to PD
    32
         Deterioration of health status/clinical PD
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    From enrollment
    Reporting group description
    		 -

    Reporting group values
    		 From enrollment Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 63 (52 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 31 31
        Male
    		 19 19
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 32 32
        ECOG 1
    		 18 18
    Histopathological diagnosis of BTC
    Units: Subjects
        Intra-hepatic biliary tract cancer
    		 29 29
        Extra-hepatic biliary tract cancer
    		 8 8
        Both intra- and extra-hepatic biliary tract cancer
    		 2 2
        Gallbladder carcinoma
    		 11 11
    Type of biliary tract cancer
    Units: Subjects
        Non-resectable biliary tract cancer
    		 21 21
        Recurrent/metastatic biliary tract cancer
    		 18 18
        Missing
    		 11 11
    Measurable disease by CT/MRI (RECIST 1.1)
    Units: Subjects
        Yes
    		 50 50
    Lead ECG
    Units: Subjects
        Normal
    		 36 36
        Abnormal, not clinically significant
    		 14 14
    Any prior systemic chemotherapy for locally advanced or metastatic disease
    Units: Subjects
        No
    		 50 50
    Prior adjuvant therapy
    Units: Subjects
        No
    		 48 48
        Yes, without Cisplatin or Gemcitabine
    		 2 2
    Prior adjuvant therapy
    Units: Subjects
        No
    		 48 48
        Yes, stopped for more than 6 months
    		 2 2
    Prior non-curative surgery for disease under study
    Units: Subjects
        No
    		 48 48
        Yes, R2 resection
    		 2 2
    Prior curative surgery with clear evidence of non-resectable disease relapse after surgery
    Units: Subjects
        No
    		 46 46
        Yes
    		 4 4
    Prior radiotherapy for localised disease with PD/relapse after radiotherapy
    Units: Subjects
        No
    		 48 48
        Yes
    		 2 2
    Primary site
    Units: Subjects
        Intrahepatic bile duct cancer
    		 30 30
        Distal bile duct cancer
    		 2 2
        Ampulla of Vater cancer
    		 2 2
        Proximal or perihilar bile duct cancer
    		 3 3
        Gallbladder cancer
    		 11 11
        Extrahepatic cholangiocarcinoma
    		 1 1
        Hilar cholangiocarcinoma
    		 1 1
    AJCC stage at initial diagnosis
    Units: Subjects
        Stage II
    		 4 4
        Stage IIIA
    		 3 3
        Stage IIIB
    		 11 11
        Stage IV
    		 27 27
        Stage IVB
    		 4 4
        Missing
    		 1 1
    AJCC stage at study entry
    Units: Subjects
        Stage II
    		 1 1
        Stage IIIA
    		 1 1
        Stage IIIB
    		 9 9
        Stage IV
    		 33 33
        Stage IVB
    		 5 5
        Missing
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Experimental arm
    Reporting group description
    		 CisGem [25mg/m² intravenous (IV) cisplatin + 1000mg/m² IV gemcitabine, on days 1 and 8 of a 21-day cycle] plus 200 mg intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle up to 2 years from enrolment until progressive disease or the early occurrence of a withdrawal.

    Primary: Progression free survival rate at 6 months according to RECIST 1.1

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    End point title
    		 Progression free survival rate at 6 months according to RECIST 1.1 [1]
    End point description
    In this single-arm phase II trial, the primary objective was to detect an increase in PFS rate at 6 months (according to RECIST 1.1) from 60% (assumption based on historical controls) to 75% in patients with BTC when treated with CT combined with pembrolizumab using a one-sided type I error of 10%. PFS rate at 6 months and its two-sided 80% confidence interval was estimated using the log-log transformation of the Kaplan-Meier estimate and the standard deviation of the Kaplan Meier estimate based on the Greenwood formula. If the lower bound of the two-sided 80% CI was above 60%, the null hypothesis of a PFS rate at 6 months equal or lower than 60% in the experimental arm could be rejected. Given that the lower bound of the two-sided 80% CI is 51.7% and therefore below 60% and the two-sided 80% CI includes 60%, the hypothesis testing could not reject a PFS rate at 6 months equal or lower than 60%.
    End point type
    Primary
    End point timeframe
    Progression free survival (PFS) rate at 6 months was defined as the rate of patients alive and progression free at 6 months. PFS rate at 6 months was estimated using the Kaplan Meier technique to take into account possible loss to follow-up
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a single-arm early phase II study with an hypothesis testing in the experimental arm to reject a PFS rate at 6 months equal to or lower than 60% (assumption based on historical controls) using a one-sided type I error of 10%. No formal comparative statistical analysis was foreseen and no comparison groups could be specified.
    End point values
    		 Experimental arm
    Number of subjects analysed
    49 [2]
    Units: Percentage
        number (confidence interval 80%)
    61.2 (51.7 to 69.5)
    Notes
    [2] - 1 patient was not evaluable for efficacy as WBC was very high and considered as active infection.
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) according to RECIST 1.1.

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    End point title
    		 Progression free survival (PFS) according to RECIST 1.1.
    End point description
    Progression free survival (PFS) according to RECIST 1.1 was computed from the date of enrollment to the date of first progression according to the RECIST criteria (version 1.1) or death, whatever came first. Patients alive and free of progression prior to the analysis cut-off date are censored at the date of the most recent assessment.
    End point type
    Secondary
    End point timeframe
    Disease evaluation was to be performed every 12 weeks (within 7 days prior to dosing) during treatment and every 3 months ± 7days after the end of treatment (in the absence of progression) until progression or 2 years after start of treatment.
    End point values
    		 Experimental arm
    Number of subjects analysed
    49 [3]
    Units: Months
        median (confidence interval 95%)
    8.28 (5.59 to 10.58)
    Attachments
    		 Progression free survival according to RECIST v1.1
    Notes
    [3] - 1 patient was not evaluable for efficacy as WBC was very high and considered as active infection.
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) according to iRECIST

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    End point title
    		 Progression free survival (PFS) according to iRECIST
    End point description
    Progression free survival (iPFS) according to iRECIST was computed from the date of enrollment to the date of first progression according to the iRECIST criteria or death, whatever came first. Patients alive and free of progression prior to the analysis cut-off date were censored at the date of the most recent assessment.
    End point type
    Secondary
    End point timeframe
    Disease evaluation was to be performed every 12 weeks (within 7 days prior to dosing) during treatment and every 3 months ± 7days after the end of treatment (in the absence of progression) until progression or 2 years after start of treatment.
    End point values
    		 Experimental arm
    Number of subjects analysed
    49 [4]
    Units: Months
        median (confidence interval 95%)
    8.34 (5.62 to 11.10)
    Attachments
    		 Progression free survival according to iRECIST
    Notes
    [4] - 1 patient was not evaluable for efficacy as WBC was very high and considered as active infection.
    No statistical analyses for this end point

    Secondary: Overall response rate according to RECIST 1.1

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    End point title
    		 Overall response rate according to RECIST 1.1
    End point description
    Overall response rate according to RECIST v1.1 was computed as the rate of complete response (CR) or partial response (PR) as best overall response according to the RECIST v1.1 criteria.
    End point type
    Secondary
    End point timeframe
    All patients had their BEST OVERALL RESPONSE assessed according to RECIST 1.1 from the start of study treatment until progression or the start of further anticancer therapy or maximum 2 years after the start of study treatment whatever came first.
    End point values
    		 Experimental arm
    Number of subjects analysed
    49 [5]
    Units: Patients
        Complete response (CR)
    0
        Partial response (PR)
    20
        Stable disease (SD)
    18
        Progressive disease (PD)
    6
        Early death
    5
    Notes
    [5] - 1 patient was not evaluable for efficacy as WBC was very high and considered as active infection.
    No statistical analyses for this end point

    Secondary: Overall response rate according to iRECIST

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    End point title
    		 Overall response rate according to iRECIST
    End point description
    Overall response rate according to iRECIST was computed as the rate of complete response (iCR) or partial response (iPR) as best overall response according to the iRECIST criteria.
    End point type
    Secondary
    End point timeframe
    All patients had their BEST OVERALL IMMUNE RESPONSE assessed from the start of study treatment until confirmed progression according to iRECIST or the start of further anticancer therapy or maximum 2 years after start of treatment whatever came first.
    End point values
    		 Experimental arm
    Number of subjects analysed
    49 [6]
    Units: Patients
        Complete response (iCR)
    0
        Partial response (iPR)
    20
        Stable disease (iSD)
    18
        Progressive disease (iUPD/iCPD)
    6
        Early death
    5
    Notes
    [6] - 1 patient was not evaluable for efficacy as WBC was very high and considered as active infection.
    No statistical analyses for this end point

    Secondary: Progression free survival rate at 6 months according to iRECIST

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    End point title
    		 Progression free survival rate at 6 months according to iRECIST
    End point description
    This was a supportive analysis for the primary endpoint PFS rate at 6 months according to RECIST v1.1 in which PFS rate at 6 months was evaluated using the iRECIST criteria instead of the RECIST v1.1 criteria. Given that the lower bound of the two-sided 80% CI is 53.7% and therefore below 60% and the two-sided 80% CI includes 60%, the hypothesis testing could not reject a PFS rate at 6 months equal or lower than 60%.
    End point type
    Secondary
    End point timeframe
    Progression free survival (PFS) rate at 6 months was defined as the rate of patients alive and progression free at 6 months. PFS rate at 6 months was estimated using the Kaplan Meier technique to take into account possible loss to follow-up.
    End point values
    		 Experimental arm
    Number of subjects analysed
    49 [7]
    Units: Percentage
        number (confidence interval 80%)
    63.3 (53.7 to 71.4)
    Notes
    [7] - 1 patient was not evaluable for efficacy as WBC was very high and considered as active infection.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from day 1 of study treatment (after the "screening" period) till then end of the follow-up period for safety.
    Adverse event reporting additional description
    AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs has not been collected specifically, all AEs will be reported in non-SAE section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Experimental Arm
    Reporting group description
    		 CisGem [25mg/m² intravenous (IV) cisplatin + 1000mg/m² IV gemcitabine, on days 1 and 8 of a 21-day cycle] plus 200 mg intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle up to 2 years from enrolment until progressive disease or the early occurrence of a withdrawal.

    Serious adverse events
    		 Experimental Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 50 (50.00%)
         number of deaths (all causes)
    37
         number of deaths resulting from adverse events
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    METASTASES TO CENTRAL NERVOUS SYSTEM
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vascular disorders
    EMBOLISM
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    PYREXIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    CONDITION AGGRAVATED
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    CHILLS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY HYPERTENSION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPOXIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    COUGH
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    BLOOD CREATININE INCREASED
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PLATELET COUNT DECREASED
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    FALL
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HUMERUS FRACTURE
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SUBDURAL HAEMATOMA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    ATRIAL SEPTAL DEFECT
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    CARDIOVASCULAR DISORDER
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    ATRIAL FIBRILLATION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    LEFT VENTRICULAR FAILURE
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PERICARDITIS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MYOCARDIAL INFARCTION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    HEADACHE
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    PERIPHERAL SENSORY NEUROPATHY
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    SYNCOPE
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    ANAEMIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    ASCITES
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    ABDOMINAL PAIN UPPER
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    OESOPHAGEAL VARICES HAEMORRHAGE
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MELAENA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    LARGE INTESTINAL HAEMORRHAGE
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    INTESTINAL OBSTRUCTION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    CONSTIPATION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    GALLBLADDER RUPTURE
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    CHOLESTASIS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    CHOLECYSTITIS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    CHOLANGITIS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    TUBULOINTERSTITIAL NEPHRITIS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    AUTOIMMUNE NEPHRITIS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    ACUTE KIDNEY INJURY
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    HYPERTHYROIDISM
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    FLANK PAIN
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    JOINT EFFUSION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    ABSCESS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    BILIARY SEPSIS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    BILIARY TRACT INFECTION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PERITONITIS BACTERIAL
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    INFECTION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    HEPATOBILIARY INFECTION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    COVID-19 PNEUMONIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    COVID-19
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SEPSIS
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    5 / 7
         deaths causally related to treatment / all
    0 / 1
    URINARY TRACT INFECTION
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    HYPERCALCAEMIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    HYPONATRAEMIA
    alternative dictionary used: MedDRA 25
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Experimental Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED -OTHER, CYST
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    TUMOR PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Vascular disorders
    HOT FLASHES
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    FLUSHING
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HEMATOMA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HYPERTENSION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    12 / 50 (24.00%)
         occurrences all number
    73
    HYPOTENSION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    VASCULAR DISORDERS - OTHER, VARICOSE VEIN PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    THROMBOEMBOLIC EVENT
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    7
    VASCULAR DISORDERS - OTHER, CIRCULATORY DISORDER
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PHLEBITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    General disorders and administration site conditions
    INFUSION RELATED REACTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CHILLS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    DISEASE PROGRESSION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    EDEMA FACE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    EDEMA LIMBS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    20 / 50 (40.00%)
         occurrences all number
    24
    FATIGUE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    35 / 50 (70.00%)
         occurrences all number
    93
    FEVER
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    11 / 50 (22.00%)
         occurrences all number
    15
    FLU LIKE SYMPTOMS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    GAIT DISTURBANCE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    5
    INFUSION SITE EXTRAVASATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    LOCALIZED EDEMA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    MALAISE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    NON-CARDIAC CHEST PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    7
    Immune system disorders
    IMMUNE SYSTEM DISORDERS - OTHER, HAYFEVER
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    POSTNASAL DRIP
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ALLERGIC RHINITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    COUGH
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    9 / 50 (18.00%)
         occurrences all number
    11
    DYSPNEA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    10 / 50 (20.00%)
         occurrences all number
    16
    EPISTAXIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    3
    HICCUPS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HOARSENESS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    HYPOXIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    LARYNGEAL INFLAMMATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    LUNG INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    NASAL CONGESTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PRODUCTIVE COUGH
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDER, OTHER EMBOLI
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER LRTI
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, PFO
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER,LRTI
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RESPIRATORY, THORACIC,MEDIASTINAL DISORDER-OTHER,HAEMOPTYSIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SORE THROAT
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    PULMONARY HYPERTENSION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Psychiatric disorders
    AGITATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ANXIETY
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DEPRESSION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    HALLUCINATIONS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INSOMNIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RESTLESSNESS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    27
    ALKALINE PHOSPHATASE INCREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    ASPARTATE AMINOTRANSFERASE INCREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    11
    BLOOD BILIRUBIN INCREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    8
    CREATININE INCREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    GGT INCREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    INVESTIGATIONS - OTHER, CREATININE CLEARANCE DECREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INVESTIGATIONS - OTHER, DECREASED GFR
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    INVESTIGATIONS - OTHER, INCREASED D-DIMER
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INVESTIGATIONS - OTHER, THROMBOCYTOSIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    LYMPHOCYTE COUNT DECREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    NEUTROPHIL COUNT DECREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    24 / 50 (48.00%)
         occurrences all number
    141
    PLATELET COUNT DECREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    16 / 50 (32.00%)
         occurrences all number
    86
    THYROID STIMULATING HORMONE INCREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    WEIGHT GAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    12
    WEIGHT LOSS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    6
    WHITE BLOOD CELL DECREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    FRACTURE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    SYNCOPE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    FALL
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Cardiac disorders
    ATRIAL FIBRILLATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CARDIAC DISORDERS - OTHER, SPECIFY PATENT FORAMEN OVALE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CARDIAC DISORDERS - OTHER, DYSPNEA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CHEST PAIN - CARDIAC
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    MYOCARDIAL INFARCTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PAROXYSMAL ATRIAL TACHYCARDIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PERICARDITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SINUS TACHYCARDIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    3
    SUPRAVENTRICULAR TACHYCARDIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Nervous system disorders
    PRESYNCOPE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DIZZINESS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    DYSGEUSIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    9
    HEADACHE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    9 / 50 (18.00%)
         occurrences all number
    15
    LETHARGY
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    MEMORY IMPAIRMENT
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    NERVOUS SYSTEM DISORDERS - OTHER , SCIATICA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    NERVOUS SYSTEM DISORDERS, OTHER - PERIPHERAL NEUROPATHY
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    PARESTHESIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    PERIPHERAL SENSORY NEUROPATHY
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    14 / 50 (28.00%)
         occurrences all number
    23
    SOMNOLENCE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SYNCOPE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    ANEMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    29 / 50 (58.00%)
         occurrences all number
    144
    FEBRILE NEUTROPENIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    Ear and labyrinth disorders
    EAR AND LABYRINTH DISORDERS - OTHER, INTERMITTENT PRESSURE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    EAR PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    HEARING IMPAIRED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    8
    TINNITUS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    9 / 50 (18.00%)
         occurrences all number
    12
    Eye disorders
    DRY EYE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    EYE DISORDERS - OTHER, RED EYE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    EYE DISORDERS - OTHER, SUBCONJUNCTIVAL HAEMORRHAGE (LEFT)
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    EYE DISORDERS, OTHER - SCRATCH TO THE LEFT EYE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, INDIGESTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    GASTROINTESTINAL DISORDERS - OTHER, HYPER SALIVATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, MELENAS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, ODYNOPHAGIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, RECTAL MASS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, REDUCED APPETITE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, STEATORHEA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, TENESMUS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS-OTHER, STOMATITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    4
    GASTROINTESTINAL PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HEMORRHOIDS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    MUCOSITIS ORAL
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    9
    NAUSEA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    27 / 50 (54.00%)
         occurrences all number
    42
    RECTAL PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SMALL INTESTINAL OBSTRUCTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ABDOMINAL PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    18 / 50 (36.00%)
         occurrences all number
    29
    ASCITES
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    8
    BLOATING
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    COLONIC HEMORRHAGE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CONSTIPATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    22 / 50 (44.00%)
         occurrences all number
    32
    DIARRHEA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    14 / 50 (28.00%)
         occurrences all number
    23
    DRY MOUTH
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    DYSPEPSIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    ESOPHAGEAL VARICES HEMORRHAGE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    FLATULENCE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    GASTROESOPHAGEAL REFLUX DISEASE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    6
    GASTROINTESTINAL DISORDERS - OTHER, ABDOMINAL DISTENTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, FRACTURED TOOTH
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GASTROINTESTINAL DISORDERS - OTHER, MELAENA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    STOMACH PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    4
    TOOTHACHE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    UPPER GASTROINTESTINAL HEMORRHAGE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    VOMITING
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    15 / 50 (30.00%)
         occurrences all number
    21
    SMALL INTESTINAL PERFORATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Hepatobiliary disorders
    HEPATOBILIARY DISORDERS - OTHER, GRAM NEGATIVE INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    CHOLECYSTITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    GALLBLADDER OBSTRUCTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    GALLBLADDER PERFORATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    HEPATOBILIARY DISORDERS - OTHER, BILIARY OBSTRUCTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HEPATOBILIARY DISORDERS - OTHER, CHOLESTASIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    4
    HEPATOBILIARY DISORDERS - OTHER, HEPATIC ABSCESS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    HEPATOBILIARY DISORDERS - OTHER, JAUNDICE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    ALOPECIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    10 / 50 (20.00%)
         occurrences all number
    12
    BULLOUS DERMATITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    DRY SKIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    4
    ERYTHEMA MULTIFORME
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HYPERHIDROSIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    NAIL CHANGES
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    PRURITUS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    8 / 50 (16.00%)
         occurrences all number
    12
    RASH ACNEIFORM
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    RASH MACULO-PAPULAR
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    3
    SCALP PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, ITCHING
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, ROSACEA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SKIN RASH
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS, OTHER
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    URTICARIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    3
    CHRONIC KIDNEY DISEASE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    CYSTITIS NONINFECTIVE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RENAL AND URINARY DISORDERS - OTHER, ACUTE RENAL FAILURE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RENAL AND URINARY DISORDERS - OTHER, MALIGNANT CHOLESTASIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RENAL AND URINARY DISORDERS - OTHER, SPECIFY
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RENAL AND URINARY DISORDERS - OTHER, TUBULOINT. NEPHRITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    URINARY RETENTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Endocrine disorders
    ADRENAL INSUFFICIENCY
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    ENDOCRINE DISORDERS - OTHER, TSH DECREASED
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HYPERTHYROIDISM
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    HYPOTHYROIDISM
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    6
    BACK PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    7 / 50 (14.00%)
         occurrences all number
    10
    BONE PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    FLANK PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    GENERALIZED MUSCLE WEAKNESS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    JOINT EFFUSION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    MUSCLE CRAMP
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER,
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, ACHE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    MUSCULOSKELETAL CONNECTIVE TISSUE DISORDER- OTHER, HYPOTONIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    MYALGIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    NECK PAIN
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    PAIN IN EXTREMITY
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    Infections and infestations
    BILIARY TRACT INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    4
    INFECTIONS AND INFESTATIONS - OTHER, INFECTION OF UK SOURCE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, BACTERIAL PERITONITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, C.DIFFICILE INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    INFECTIONS AND INFESTATIONS - OTHER, CHOLANGITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, ERYSIPEL
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, INFECTION OF UK SOURCE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, NKNOWN SOURCE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, NON-NEUTROPENIC INF
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, NON-NEUTROPENIC INFECTI
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, SKIN INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER, VIRAL INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    INFECTIONS AND INFESTATIONS - OTHER,INFECTION UNKNOWN SOURCE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    LUNG INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    9
    PARONYCHIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    RHINITIS INFECTIVE
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    SEPSIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    10
    SINUSITIS
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    2
    SKIN INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    THRUSH
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    TOOTH INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    UPPER RESPIRATORY INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    5 / 50 (10.00%)
         occurrences all number
    6
    UPPER RESPIRATORY INFECTION - OTHER, NOSE INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    URINARY TRACT INFECTION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    6 / 50 (12.00%)
         occurrences all number
    12
    Metabolism and nutrition disorders
    HYPOKALEMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    3
    ANOREXIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    11 / 50 (22.00%)
         occurrences all number
    14
    DEHYDRATION
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    HYPERCALCEMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    7
    HYPERGLYCEMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    HYPOALBUMINEMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    2 / 50 (4.00%)
         occurrences all number
    2
    HYPOCALCEMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HYPOMAGNESEMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    3 / 50 (6.00%)
         occurrences all number
    5
    HYPOPHOSPHATEMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    1 / 50 (2.00%)
         occurrences all number
    1
    HYPONATREMIA
    alternative dictionary used: AECTC 5.0
         subjects affected / exposed
    4 / 50 (8.00%)
         occurrences all number
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Sep 2019
    AMENDMENT 1 -Patients selection criteria were modified to clearly specify that highly effective birth control measures according to the standard national guidelines should be used for patients (male or female) of childbearing / reproductive potential. -The request to renew/repeat pregnancy testing in women of childbearing potential up to 6 months after last dose of trial medication was added. -Appendix G for recommendation based on Clinical Trial Facilitation Group (CTFG) guidelines for sites and countries where applicable (e.g. Germany, Austria, …) was added. -Systemic corticosteroids were allowed for supportive care and should use the lowest dose and duration feasible as per international and intuitional guidelines to align with MSD approach. -The guideline that pembrolizumab should be permanently discontinued in case of: • recurrent colitis grade 3 • liver metastasis with baseline Grade 2 elevation of AST or ALT, hepatitis with AST or ALT ≥ 50% and lasts ≥ 1 week was added.
    17 Jul 2020
    AMENDMENT 2 -Update of background section regarding pembrolizumab (pharmacokinetic, selected dosing, efficacy and safety data) -Guidance provided for administration of pembrolizumab, cisplatin and gemcitabine -Update safety guidance of pembrolizumab -Update about the drug-drug interactions for cisplatin and gemcitabine.
    10 Dec 2020
    AMENDMENT 3 -Eligibility: the C-reactive protein (CRP) has been removed from the eligibility. CRP is raised in advanced/metastatic setting of a cancer and therefore not relevant for the studied patient population. -Update of safety guidelines for gemcitabine and cisplatin -Update of concomitant treatments -Miscellaneous: clarifications implemented in the protocol in different sections.
    24 Jun 2021
    AMENDMENT 4 -Following the update of reference documents for pembrolizumab (SmPC-Merck, dated 26 May 2021) and for cisplatin (SmPC-Hospira-dated 29/07/2020) a new addendum to the patient information sheet (PISIC) has been prepared for patients already enrolled.
    15 Oct 2021
    AMENDMENT 5 -Following the update of reference documents for pembrolizumab (SmPC-Merck, dated 15 September 2021), a new addendum to the patient information sheet (PISIC) has been prepared for patients already enrolled.
    13 Jan 2022
    AMENDMENT 6 -The Translational research has been now described in the protocol, for submission of the project to regulatory bodies.
    18 Jul 2022
    AMENDMENT 7 -Following the update of reference document for pembrolizumab (IB version 22, dated 13 May 2022), a new addendum to the patient information sheet (PISIC) has been prepared for patients already enrolled to update the safety language.
    16 Dec 2022
    AMENDMENT 8 -Following the update of reference documents for pembrolizumab IB version 23, dated 26 October 2022 and the SmPC dated 17 November 2022, a new addendum to PISIC has been prepared to update the risk language. -The translational research section of the protocol has been revised to include the change with regards to the new lab that will perform the analyses of the collected samples.

    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.
    This study was not randomized. No internal control arm is available which limits the interpretation of these results. PFS is an endpoint which could be influenced by the prognosis of the enrolled study population.
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