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    Clinical Trial Results:
    A first-in-human, open-label, dose escalation followed by dose expansion phase I/IIa trial to evaluate the safety, preliminary efficacy and pharmacokinetics of intratumoral CyPep-1 monotherapy and in combination with pembrolizumab in patients with advanced solid cancers.

    Summary
    EudraCT number
    		 2019-003317-33
    Trial protocol
    		 NL   FR   ES  
    Global end of trial date
    05 Jul 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jul 2025
    First version publication date
    02 Jul 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CyPep-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cytovation ASA
    Sponsor organisation address
    5058 Bergen, Bergen, Norway,
    Public contact
    General contact, Cytovation ASA, contact@cytovation.com
    Scientific contact
    General contact, Cytovation ASA, contact@cytovation.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
    05 Dec 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jul 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of IT administration of CyPep-1 as monotherapy and in combination with pembrolizumab. To identify the recommended phase II dose (RP2D) of CyPep-1 as monotherapy and in combination with pembrolizumab.
    Protection of trial subjects
    The Dose Escalation Committee (DEC) was comprised of all the Investigators or designees, medical monitor, and representatives of the Sponsor. The decisions on dose escalation and CyPep 1 maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) were taken by the DEC after reviewing safety data (including dose-limiting toxicities [DLTs] from all patients who entered Phase I of the study and completed the DLT observation period). The DEC was responsible for the review of all data after all patients in the highest dose cohort completed the DLT observation period and before enrolment of patients in the expansion cohort at RP2D in monotherapy and combination with pembrolizumab cohort was initiated. The decision to de escalate the dose of CyPep-1 based on the observed severity and relatedness of safety events (DLT/treatment limiting toxicity [TLT] criteria for CyPep-1) and to what dose (either dose level of the next lowest dose level from Phase I or 50-70% of current dose level), was also made by the DEC after reviewing available safety data (including TLTs). Based on the review of this data, recommendations were made regarding the further conduct and the scientific and ethical integrity of the study. The final decision to act upon these recommendations was the responsibility of the Sponsor
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Apr 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 42
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    France: 14
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    20
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 7 investigational sites in 3 countries (France, Spain, and The Netherlands). A total of 87 patients were screened for eligibility, with 27 excluded (25 due to screening failures, and 2 not assigned). Of the original 87 patients screened, 60 were eligible and were allocated into corresponding Phase I and II treatment arms

    Pre-assignment
    Screening details
    		 The study consisted of 2 phases and 4 arms. For both phases and all study arms, patients signed the ICF and completed the Screening visit to determine eligibility to participate in the study. Patients stayed in the study until end of study or until confirmed disease progression, unacceptable toxicity, death or discontinuation for any other reason.

    Period 1
    Period 1 title
    Phase 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study, blinding not applicable.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Cohort 1
    Arm description
    		 Cohort 1: dose escalation at 0.5 mg/mL, n=3
    Arm type
    		 Experimental

    Investigational medicinal product name
    CyPep-1 0.5 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution and suspension for suspension for injection in pre-filled syringe
    Routes of administration
    Intratumoral use
    Dosage and administration details
    0.5 mL via intratumoral administration

    Arm title
    		 Cohort 2
    Arm description
    		 Cohort 2: 2 mg/mL, n=5
    Arm type
    		 Experimental

    Investigational medicinal product name
    CyPep-1 2.0 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution and suspension for suspension for injection in pre-filled syringe
    Routes of administration
    Intratumoral use
    Dosage and administration details
    CyPep-1 2.0 mg/mL intratumoral

    Arm title
    		 Cohort 3
    Arm description
    		 Cohort 3: 5 mg/mL, n=6
    Arm type
    		 Experimental

    Investigational medicinal product name
    CyPep-1 5.0 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intratumoral use
    Dosage and administration details
    5.0 mg/mL via intratumoral

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3
    Started
    3
    5
    6
    Completed
    0
    0
    0
    Not completed
    3
    5
    6
         Consent withdrawn by subject
    -
    1
    -
         Death
    3
    4
    6
    Period 2
    Period 2 title
    Phase 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study, blinding not applicable.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm B
    Arm description
    		 The safety and tolerability of CyPep-1 in combination with pembrolizumab was evaluated in a cohort of 15 patients in total, using a staggered approach. Initially, 3 patients received CyPep-1 at RP2D in combination with pembrolizumab once every 6 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    CyPep-1 5.0 mg/mL + IV pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution and suspension for suspension for injection in pre-filled syringe
    Routes of administration
    Intratumoral use
    Dosage and administration details
    5.0mg/mL via intratumoral administration

    Arm title
    		 Arm C (Cohort 4)
    Arm description
    		 the safety and tolerability of at least 2 dose levels of CyPep-1, the RP2D and the dose immediately below that, were evaluated when CyPep-1 was administered IT using ultrasound guidance to one metastatic lesion in the liver (Cohort 4: 2 mg/mL, n=6)
    Arm type
    		 Experimental

    Investigational medicinal product name
    CyPep-1 2.0 mg/mL for liver metastases
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution and suspension for suspension for injection in pre-filled syringe
    Routes of administration
    Intratumoral use
    Dosage and administration details
    2.0mg/mL via intratumoral administration

    Arm title
    		 Arm C (Cohort 5)
    Arm description
    		 The safety and tolerability of at least 2 dose levels of CyPep-1, the RP2D and the dose immediately below that, were evaluated when CyPep-1 was administered IT using ultrasound guidance to one metastatic lesion in the liver. The RP2D (Cohort 5: 5 mg/mL, n=6)
    Arm type
    		 Experimental

    Investigational medicinal product name
    CyPep-1 5.0 mg/mL for liver metastases
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Intratumoral use
    Dosage and administration details
    5.0mg/mL via intratumoral administration

    Arm title
    		 Arm D
    Arm description
    		 The safety and tolerability of CyPep-1 at RP2D was planned to be further evaluated with focus on assessing efficacy signals of CyPep-1 monotherapy in 30 patients with cutaneous melanoma
    Arm type
    		 Experimental

    Investigational medicinal product name
    CyPep-1 5.0 mg/mL for melanoma
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution and suspension for suspension for injection in pre-filled syringe
    Routes of administration
    Intratumoral use
    Dosage and administration details
    5.0mg/mL via intratumoral administration

    Arm title
    		 Arm A
    Arm description
    		 CyPep-1 5.0mg/mL Monotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    CyPep-1 5.0 mg/mL Monotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution and suspension for suspension for injection in pre-filled syringe
    Routes of administration
    Intratumoral use
    Dosage and administration details
    5.0 mg/mL via intratumoral

    Number of subjects in period 2
    		Arm B Arm C (Cohort 4) Arm C (Cohort 5) Arm D Arm A
    Started
    15
    6
    6
    1
    18
    Completed
    1
    1
    0
    0
    2
    Not completed
    14
    5
    6
    1
    16
         Consent withdrawn by subject
    -
    -
    -
    1
    2
         Death
    14
    5
    5
    -
    13
         Termination of the study
    -
    -
    -
    -
    1
         Sponsor terminated
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Cohort 1
    Reporting group description
    		 Cohort 1: dose escalation at 0.5 mg/mL, n=3

    Reporting group title
    Cohort 2
    Reporting group description
    		 Cohort 2: 2 mg/mL, n=5

    Reporting group title
    Cohort 3
    Reporting group description
    		 Cohort 3: 5 mg/mL, n=6

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects in both the phases are different because the arms are not mutually exclusive. The subjects in Phase 1 (dose escalation) did not roll over into Phase 2 (dose expansion).
    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 Total
    Number of subjects
    		 3 5 6 14
    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)
    		 0 2 2 4
        From 65-84 years
    		 3 3 4 10
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 53 ( 11.2 ) 64 ( 10.8 ) 57.0 ( 5.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 2 5
        Male
    		 2 3 4 9

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Cohort 1: dose escalation at 0.5 mg/mL, n=3

    Reporting group title
    Cohort 2
    Reporting group description
    		 Cohort 2: 2 mg/mL, n=5

    Reporting group title
    Cohort 3
    Reporting group description
    		 Cohort 3: 5 mg/mL, n=6
    Reporting group title
    Arm B
    Reporting group description
    		 The safety and tolerability of CyPep-1 in combination with pembrolizumab was evaluated in a cohort of 15 patients in total, using a staggered approach. Initially, 3 patients received CyPep-1 at RP2D in combination with pembrolizumab once every 6 weeks

    Reporting group title
    Arm C (Cohort 4)
    Reporting group description
    		 the safety and tolerability of at least 2 dose levels of CyPep-1, the RP2D and the dose immediately below that, were evaluated when CyPep-1 was administered IT using ultrasound guidance to one metastatic lesion in the liver (Cohort 4: 2 mg/mL, n=6)

    Reporting group title
    Arm C (Cohort 5)
    Reporting group description
    		 The safety and tolerability of at least 2 dose levels of CyPep-1, the RP2D and the dose immediately below that, were evaluated when CyPep-1 was administered IT using ultrasound guidance to one metastatic lesion in the liver. The RP2D (Cohort 5: 5 mg/mL, n=6)

    Reporting group title
    Arm D
    Reporting group description
    		 The safety and tolerability of CyPep-1 at RP2D was planned to be further evaluated with focus on assessing efficacy signals of CyPep-1 monotherapy in 30 patients with cutaneous melanoma

    Reporting group title
    Arm A
    Reporting group description
    		 CyPep-1 5.0mg/mL Monotherapy

    Primary: Type and number of adverse events

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    End point title
    		 Type and number of adverse events [1]
    End point description
    End point type
    Primary
    End point timeframe
    From the time of ICF signing until Follow up visit (or until EoT, if it occurred >30 days after the last CyPep-1 administration for Phase I and Arms A, C, and D; for Arm B. After the FU visit, only ongoing AEs or SAEs related to CyPep-1 were collected.
    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: Descriptive statistics was used. The total number/incidence of TEAEs was summarized, including the number of patients with at least one TEAE and the number of TEAEs per cohort and overall. The number of TEAEs per intensity (CTCAE) and relation to study drug was also included and summarized per cohort and overall.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Arm B Arm C (Cohort 4) Arm C (Cohort 5) Arm D Arm A
    Number of subjects analysed
    3
    5
    6
    15
    6
    6
    1
    18
    Units: Number of events
        TEAE
    24
    37
    62
    262
    91
    91
    4
    143
        TESAE
    1
    0
    0
    7
    1
    3
    0
    3
        CTCAE Grade ≥3
    9
    4
    5
    12
    4
    12
    0
    8
        TEAE Leading to Study Treatment Discontinuation
    0
    0
    1
    0
    0
    0
    0
    1
        Dose-Limiting Toxicity
    0
    0
    0
    0
    0
    2
    0
    0
        Treatment-Limiting Toxicity
    0
    0
    0
    0
    0
    0
    0
    0
        Fatal TEAE
    0
    0
    0
    0
    0
    1
    0
    0
        TEAE Leading to CyPep-1 Interruption
    1
    1
    1
    8
    1
    2
    0
    10
        TEAE Leading to Pembrolizumab Interruption
    0
    0
    0
    5
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    End point type
    Secondary
    End point timeframe
    28 days after the date of the initial response
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Arm B Arm C (Cohort 4) Arm C (Cohort 5) Arm D Arm A
    Number of subjects analysed
    3
    5
    6
    15
    6
    6
    1
    18
    Units: percentage
    number (not applicable)
        Overall Response Rate
    0
    0
    0
    0
    16.7
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Other pre-specified
    End point timeframe
    from start of study treatment to the date of death
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Arm B Arm C (Cohort 4) Arm C (Cohort 5) Arm D Arm A
    Number of subjects analysed
    3
    5
    6
    15
    6
    6
    1
    18
    Units: Months
        median (full range (min-max))
    5.2 (2.1 to 21.9)
    5.5 (0.6 to 16.6)
    13.2 (5.3 to 19.8)
    5.8 (1.5 to 26.7)
    8.3 (3.3 to 26.3)
    4.2 (3.3 to 26.3)
    0 (0 to 0)
    7.7 (1.0 to 26.2)
    No statistical analyses for this end point

    Other pre-specified: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Other pre-specified
    End point timeframe
    time from treatment start until disease relapse or disease progression (based on all lesions, using iRECIST) or death due to any cause, whichever occurred earliest
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Arm B Arm C (Cohort 4) Arm C (Cohort 5) Arm D Arm A
    Number of subjects analysed
    3
    5
    6
    15
    6
    6
    1
    18
    Units: Months
        median (full range (min-max))
    1.6 (1.2 to 1.9)
    0.9 (0.0 to 9.3)
    2.8 (1.6 to 12.3)
    1.8 (0.0 to 5.4)
    2.1 (1.4 to 5.7)
    1.9 (1.8 to 16.6)
    1.9 (1.8 to 16.6)
    1.8 (0.0 to 5.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of ICF signing until Follow up visit (or until EoT, if it occurred >30 days after the last CyPep-1 administration for Phase I and Arms A, C, and D; for Arm B. After the FU visit, only ongoing AEs or SAEs related to CyPep-1 were collected.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 CyPep-1 5.0 mg/mL Monotherapy

    Reporting group title
    Cohort 2
    Reporting group description
    		 CyPep-1 2.0 mg/mL

    Reporting group title
    Cohort 3
    Reporting group description
    		 CyPep-1 5.0 mg/mL

    Reporting group title
    Arm A
    Reporting group description
    		 CyPep-1 5.0 mg/mL Monotherapy

    Reporting group title
    Arm B
    Reporting group description
    		 CyPep-1 5.0 mg/mL + IV pembrolizumab

    Reporting group title
    Arm C (Cohort 4)
    Reporting group description
    		 CyPep-1 2.0 mg/mL for liver metastases

    Reporting group title
    Arm C (Cohort 5)
    Reporting group description
    		 CyPep-1 5.0 mg/mL for liver metastases

    Reporting group title
    Arm D
    Reporting group description
    		 CyPep-1 5.0 mg/mL for melanoma

    Serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Arm A Arm B Arm C (Cohort 4) Arm C (Cohort 5) Arm D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    3
    4
    6
    13
    14
    5
    5
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Brachiocephalic vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Injection site hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Arm A Arm B Arm C (Cohort 4) Arm C (Cohort 5) Arm D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    18 / 18 (100.00%)
    15 / 15 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    1 / 1 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    5 / 18 (27.78%)
    7 / 15 (46.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    14
    8
    11
    0
    0
    0
    Metastases to bone
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    Tumour thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    1
    0
    Brachiocephalic vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 5 (60.00%)
    3 / 6 (50.00%)
    9 / 18 (50.00%)
    8 / 15 (53.33%)
    2 / 6 (33.33%)
    5 / 6 (83.33%)
    1 / 1 (100.00%)
         occurrences all number
    0
    3
    5
    13
    16
    5
    6
    2
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    1 / 15 (6.67%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    4
    4
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    2
    0
    Influenza like illness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    4
    1
    1
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Injection site reaction
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 5 (80.00%)
    6 / 6 (100.00%)
    15 / 18 (83.33%)
    12 / 15 (80.00%)
    5 / 6 (83.33%)
    5 / 6 (83.33%)
    1 / 1 (100.00%)
         occurrences all number
    2
    6
    23
    60
    72
    15
    26
    2
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    Face oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Injection site injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Reproductive system and breast disorders
    Breast tenderness
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    1
    1
    5
    2
    5
    0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    0
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    4
    0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Laryngeal oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Pneumothorax
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Delirium
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    5
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    5
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Amylase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Urine output decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    1
    0
    Drain site complication
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Post procedural erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Post procedural fever
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Post procedural haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Stoma site erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    1
    0
    0
    Aphasia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Brachial plexopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    5 / 18 (27.78%)
    5 / 15 (33.33%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    3
    5
    6
    2
    3
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Hypoacusis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Chalazion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    5 / 15 (33.33%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    4
    1
    7
    6
    1
    0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    5 / 15 (33.33%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    2
    9
    8
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    3
    1
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    4 / 15 (26.67%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    1
    5
    8
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    0
    0
    Ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Oesophageal obstruction
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    4
    1
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Breath odour
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Eructation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Oedema mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Retching
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Vitiligo
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Psoriasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Scar pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Skin wound
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Hyperthyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    3
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    6 / 15 (40.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    1
    3
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Mobility decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Pain in jaw
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    1
    1
    0
    0
    0
    Pyelonephritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    2
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    3 / 15 (20.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    4 / 18 (22.22%)
    4 / 15 (26.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    5
    7
    4
    2
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    3
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    3
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Malnutrition
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Nov 2019
    • Removal Day 2 from Schedule of Events • Clarification prophylactic hydration requirement • Update non-clinical data • Clarification of risks and benefits • Clarification SUSAR definition • Clarification safety analysis will be performed for RP2D selection

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Apr 2020
    Temporary halt of recruitment due to the COVID-19 pandemic Apr2020- May2020
    01 Jun 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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