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    Clinical Trial Results:
    A phase I/II multicenter, open-label study of CLR457 administered orally in adult patients with advanced solid malignancies

    Summary
    EudraCT number
    		 2014-000316-34
    Trial protocol
    		 FR   IT  
    Global end of trial date
    12 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2016
    First version publication date
    30 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCLR457X2101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02189174
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    12 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    1. To determine the maximum tolerated dose (MTD) or recommended dose (RP2D) of CLR457 (dose escalation phase I) 2. To investigate the anti-tumor activity of CLR457 (Phase II)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 2014
    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
    Canada: 4
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Spain: 3
    Worldwide total number of subjects
    31
    EEA total number of subjects
    3
    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)
    19
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This was a Phase 1/2, multi-center open-label study. Phase 1 was the dose escalation part to determine the maximum tolerated dose (MTD) or recommended dose for phase 2 (RP2D). Due to poor tolerability and lack of efficacy, the study was terminated and phase 2 was not conducted.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CLR457 5 mg
    Arm description
    		 Patients received CLR457 5 mg orally once daily until they met the criteria for study discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR457
    Investigational medicinal product code
    CLR457
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    5mg CLR457 orally once daily

    Arm title
    		 CLR457 10 mg
    Arm description
    		 Patients received CLR457 10 mg orally once daily until they met the criteria for study discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR457
    Investigational medicinal product code
    CLR457
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10mg CLR457 orally once daily

    Arm title
    		 CLR457 20 mg
    Arm description
    		 Patients received CLR457 20 mg orally once daily until they met the criteria for study discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR457
    Investigational medicinal product code
    CLR457
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20mg CLR457 orally once daily

    Arm title
    		 CLR457 40 mg
    Arm description
    		 Patients received CLR457 40 mg orally once daily until they met the criteria for study discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR457
    Investigational medicinal product code
    CLR457
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    40mg CLR457 orally once daily

    Arm title
    		 CLR457 70 mg
    Arm description
    		 Patients received CLR457 70 mg orally once daily until they met the criteria for study discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR457
    Investigational medicinal product code
    CLR457
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    70mg CLR457 orally once daily

    Arm title
    		 CLR457 100 mg
    Arm description
    		 Patients received CLR457 100 mg orally once daily until they met the criteria for study discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLR457
    Investigational medicinal product code
    CLR457
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100mg CLR457 orally once daily

    Number of subjects in period 1
    		CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Started
    2
    3
    4
    5
    6
    11
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    2
    3
    4
    5
    6
    11
         Consent withdrawn by subject
    -
    -
    -
    1
    -
    2
         Physician decision
    -
    -
    -
    -
    -
    2
         Adverse event, non-fatal
    -
    -
    -
    1
    -
    4
         Progressive disease
    2
    3
    4
    3
    6
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CLR457 5 mg
    Reporting group description
    		 Patients received CLR457 5 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 10 mg
    Reporting group description
    		 Patients received CLR457 10 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 20 mg
    Reporting group description
    		 Patients received CLR457 20 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 40 mg
    Reporting group description
    		 Patients received CLR457 40 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 70 mg
    Reporting group description
    		 Patients received CLR457 70 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 100 mg
    Reporting group description
    		 Patients received CLR457 100 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg Total
    Number of subjects
    		 2 3 4 5 6 11 31
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 1 1 1 4 5 7 19
        From 65-84 years
    		 1 2 3 1 1 4 12
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57 ± 14.14 62.7 ± 8.5 68.5 ± 10.12 60 ± 8.09 59.8 ± 10.42 59.9 ± 9.65 -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 2 5 5 8 23
        Male
    		 1 1 2 0 1 3 8

    End points

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    End points reporting groups
    Reporting group title
    CLR457 5 mg
    Reporting group description
    		 Patients received CLR457 5 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 10 mg
    Reporting group description
    		 Patients received CLR457 10 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 20 mg
    Reporting group description
    		 Patients received CLR457 20 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 40 mg
    Reporting group description
    		 Patients received CLR457 40 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 70 mg
    Reporting group description
    		 Patients received CLR457 70 mg orally once daily until they met the criteria for study discontinuation.

    Reporting group title
    CLR457 100 mg
    Reporting group description
    		 Patients received CLR457 100 mg orally once daily until they met the criteria for study discontinuation.

    Primary: Best Overall Response - Phase 1

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    End point title
    		 Best Overall Response - Phase 1 [1]
    End point description
    Tumor response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Categories assessed were complete response (CR), partial response (PR), non-CR/non-progressive disease, stable disease (SD1), progressive disease, unknown, overall response rate (ORR: CR+PR) and disease control rate (DCR: CR+PR+SD1+Non-CR/non-progressive disease).
    End point type
    Primary
    End point timeframe
    28 days
    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: Statistical analysis does not apply to this end point.
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    6
    11
    Units: Patients
        CR
    0
    0
    0
    0
    0
    0
        PR
    0
    0
    0
    0
    0
    0
        Non-CR/non-progressive disease
    0
    0
    0
    1
    0
    1
        SD1
    0
    0
    0
    2
    2
    4
        Progressive disease
    2
    3
    4
    2
    3
    3
        Unknown
    0
    0
    0
    0
    1
    3
        ORR
    0
    0
    0
    0
    0
    0
        DCR
    0
    0
    0
    3
    2
    5
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: area under the plasma concentration-time curve from time 0 to 24 hours (AUC0_24h)

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    End point title
    		 Pharmacokinetic (PK) parameter: area under the plasma concentration-time curve from time 0 to 24 hours (AUC0_24h)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    6
    10
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    1182 ± 40.8
    2241 ± 7.5
    6718 ± 41.6
    9567 ± 34.9
    10537 ± 47.6
    18390 ± 25.8
    No statistical analyses for this end point

    Secondary: PK parameter: observed maximum plasma concentration following administration (Cmax)

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    End point title
    		 PK parameter: observed maximum plasma concentration following administration (Cmax)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    6
    11
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    100 ± 0.4
    230 ± 24.5
    475 ± 24.2
    687 ± 47.2
    732 ± 44.8
    1449 ± 28.7
    No statistical analyses for this end point

    Secondary: PK parameter: time to reach the maximum concentration after drug administration (Tmax)

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    End point title
    		 PK parameter: time to reach the maximum concentration after drug administration (Tmax)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    6
    11
    Units: hour
        median (full range (min-max))
    2.5 (1 to 4)
    1 (0.917 to 2)
    2.51 (2.05 to 3.95)
    2.07 (0.983 to 6)
    3.5 (0.717 to 24.1)
    2.93 (0.5 to 7.53)
    No statistical analyses for this end point

    Secondary: PK parameter: area under the plasma concentration-time curve from time zero to the end of dosing interval tau at steady state (AUCtau)

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    End point title
    		 PK parameter: area under the plasma concentration-time curve from time zero to the end of dosing interval tau at steady state (AUCtau)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    4
    4
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    1665 ± 81.7
    2846 ± 25.5
    7662 ± 45.3
    11727 ± 39
    14762 ± 37.1
    23754 ± 40.4
    No statistical analyses for this end point

    Secondary: PK parameter: lowest plasma concentration observed during a dosing interval at steady state (Cmin)

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    End point title
    		 PK parameter: lowest plasma concentration observed during a dosing interval at steady state (Cmin)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    5
    4
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    18 ± 291.6
    48 ± 48.2
    148 ± 56.3
    270 ± 84.8
    257 ± 31.4
    148 ± 726
    No statistical analyses for this end point

    Secondary: PK parameter: apparent systemic clearance from plasma following extravascular administration (CL/F)

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    End point title
    		 PK parameter: apparent systemic clearance from plasma following extravascular administration (CL/F)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    4
    4
    Units: mL/h
        geometric mean (geometric coefficient of variation)
    3003 ± 81.7
    3514 ± 25.5
    2610 ± 45.3
    3411 ± 39
    4742 ± 37.1
    4210 ± 40.4
    No statistical analyses for this end point

    Secondary: PK parameter: apparent volume of distribution using the terminal elimination phase following extravascular administration (V/F)

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    End point title
    		 PK parameter: apparent volume of distribution using the terminal elimination phase following extravascular administration (V/F)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    4
    4
    Units: mL
        geometric mean (geometric coefficient of variation)
    43139 ± 6.6
    66520 ± 11.5
    55193 ± 32.1
    115503 ± 109.2
    72822 ± 49.9
    67311 ± 38.2
    No statistical analyses for this end point

    Secondary: PK parameter: accumulation ration (Racc)

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    End point title
    		 PK parameter: accumulation ration (Racc)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    4
    5
    4
    4
    Units: ratio
        geometric mean (geometric coefficient of variation)
    1.4 ± 33.4
    1.3 ± 24.3
    1.1 ± 28.4
    1.3 ± 38.4
    1.4 ± 29.5
    1.3 ± 37
    No statistical analyses for this end point

    Secondary: PK parameter: effective half-life based on drug accumulation at steady state (T1/2, acc)

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    End point title
    		 PK parameter: effective half-life based on drug accumulation at steady state (T1/2, acc)
    End point description
    Plasma samples were collected and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose at 0 hour (h), post dose at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h
    End point values
    		 CLR457 5 mg CLR457 10 mg CLR457 20 mg CLR457 40 mg CLR457 70 mg CLR457 100 mg
    Number of subjects analysed
    2
    3
    3
    4
    4
    3
    Units: hour
        median (full range (min-max))
    13.9 (7.58 to 20.2)
    7.92 (6.53 to 18.4)
    11.8 (5.71 to 15.3)
    11 (4.13 to 27.9)
    16.8 (11.9 to 23.7)
    12.1 (5.04 to 27)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    CLR457 5 mg
    Reporting group description
    		 CLR457 5 mg

    Reporting group title
    CLR457 10 mg
    Reporting group description
    		 CLR457 10 mg

    Reporting group title
    CLR457 100 mg
    Reporting group description
    		 CLR457 100 mg

    Reporting group title
    CLR457 40 mg
    Reporting group description
    		 CLR457 40 mg

    Reporting group title
    CLR457 70 mg
    Reporting group description
    		 CLR457 70 mg

    Reporting group title
    CLR457 20 mg
    Reporting group description
    		 CLR457 20 mg

    Serious adverse events
    		 CLR457 5 mg CLR457 10 mg CLR457 100 mg CLR457 40 mg CLR457 70 mg CLR457 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    7 / 11 (63.64%)
    2 / 5 (40.00%)
    5 / 6 (83.33%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    1
    0
    1
    0
    2
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    LYMPHANGIOSIS CARCINOMATOSA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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 / 1
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    MULTI-ORGAN FAILURE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOLITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    LARGE INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    PANCREATITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    VOMITING
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    PNEUMONITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    LUNG INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    PARAINFLUENZAE VIRUS INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    WOUND INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    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
    		 CLR457 5 mg CLR457 10 mg CLR457 100 mg CLR457 40 mg CLR457 70 mg CLR457 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    3 / 3 (100.00%)
    11 / 11 (100.00%)
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    EMBOLISM
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    HYPERTENSION
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    3
    1
    1
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    2
    1
    0
    2
    FACE OEDEMA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    CHILLS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    FATIGUE
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
    6 / 11 (54.55%)
    3 / 5 (60.00%)
    5 / 6 (83.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    1
    6
    3
    6
    2
    FEELING ABNORMAL
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    LOCALISED OEDEMA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    0
    2
    1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    MALAISE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    PYREXIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    8 / 11 (72.73%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    13
    0
    1
    0
    THIRST
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Immune system disorders
    SEASONAL ALLERGY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Reproductive system and breast disorders
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    VAGINAL DISCHARGE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    PELVIC PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    4 / 11 (36.36%)
    4 / 5 (80.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    4
    4
    1
    0
    DYSPHONIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    DYSPNOEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    1
    2
    1
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    EPISTAXIS
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    HICCUPS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    HYPOXIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    NASAL INFLAMMATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    RHINORRHOEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    UPPER-AIRWAY COUGH SYNDROME
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    AGITATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    DELIRIUM
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    ANXIETY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    DEPRESSION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    DISORIENTATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    INSOMNIA
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    Investigations
    ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    AMYLASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    BLOOD CHOLESTEROL INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    2
    2
    1
    BLOOD GLUCOSE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    LIPASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    4
    0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    5
    1
    2
    0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    FALL
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    PALPITATIONS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    DYSKINESIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    DYSGEUSIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    0
    HEADACHE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    SYNCOPE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    SCIATICA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    HYPERSOMNIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    LYMPHOPENIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    NEUTROPENIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    ANAEMIA
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    0
    1
    3
    1
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Eye disorders
    VISION BLURRED
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    VITREOUS FLOATERS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    2
    1
    2
    2
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    CHEILITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    DRY MOUTH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    2
    1
    0
    DIARRHOEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    5 / 11 (45.45%)
    4 / 5 (80.00%)
    4 / 6 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    9
    4
    8
    0
    CONSTIPATION
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    2 / 11 (18.18%)
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    2
    3
    2
    1
    DYSPEPSIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    DYSPHAGIA
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    GASTRIC ULCER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    GLOSSITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    LIP SWELLING
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    NAUSEA
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
    4 / 11 (36.36%)
    3 / 5 (60.00%)
    4 / 6 (66.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    4
    3
    6
    1
    OBSTRUCTION GASTRIC
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    STOMATITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    10 / 11 (90.91%)
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    12
    3
    2
    0
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    VOMITING
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    3
    2
    4
    2
    Skin and subcutaneous tissue disorders
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    DECUBITUS ULCER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    DRY SKIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    ERYTHEMA
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    NAIL DISORDER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    ONYCHALGIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    PRURITUS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    1
    3
    0
    RASH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 11 (27.27%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    3
    0
    5
    1
    RASH MACULAR
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    7 / 11 (63.64%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    8
    2
    3
    0
    RASH PRURITIC
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    SWELLING FACE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    POLLAKIURIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    PROTEINURIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    BACK PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    2
    2
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    MUSCULOSKELETAL DISORDER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    MYALGIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    NECK PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    CELLULITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    CANDIDA INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    KLEBSIELLA BACTERAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    MUCOSAL INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    LUNG INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    PNEUMONIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    SKIN INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    WOUND INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    4 / 11 (36.36%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    4
    3
    3
    3
    DEHYDRATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    HYPOCALCAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    5 / 11 (45.45%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    7
    2
    1
    1
    HYPERCALCAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    GOUT
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    1
    0
    1
    2
    HYPOMAGNESAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 11 (9.09%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    3
    3
    2
    3
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2014
    This amendment addressed the following revisions requested by Heath Authorities. The main objective was to increase patient safety mainly based on potential toxicities related to CLR457 and patient medical history: Change in dose limiting toxicity criteria for hematologic and hepatic toxicities and corresponding dose modification criteria; change in exclusion criteria; and clarification that Japanese patients are required to be hospitalized during Cycle 1 of Phase I.
    13 Nov 2014
    The rational for this amendment was to comply with Health Authority request to include the following: change in exclusion criteria to exclude patient with current or past history of interstitial lung disease/pneumonitis; clarification regarding dose limiting toxicity criteria for hematologic toxicity in case of use of hematopoietic colony-stimulating growth factors; clarity on the definition of “women of childbearing potential”; and increase in the period for contraceptive measures for female participants to 1 month and 3 months for male participants after study drug discontinuation. FOR JAPAN ONLY: For patients under the age of 20 years additional written consent was needed from his/her legal representative and an Appendix 9 was provided to Protocol to add guidance for management of hepatitis B virus infection to raise awareness of the Investigators on this topic.
    16 Dec 2014
    Because laboratory assessments for pancreatic enzymes were not included in the laboratory parameters collection plan, lipase and amylase laboratory tests were now added to allow monitoring of pancreatic function. In addition sodium measurements were added to the laboratory collection plan to complete the electrolyte panel. QT prolonging agents were clarified to be prohibited throughout the study to align with the exclusion criteria. Clarification was provided regarding the operational aspects of the Novartis optional companion sample collection protocol studying treatment resistance. Integrated Response Technology was not used for Phase II due to system set -up limitations. The assignment of a patient to a particular group was coordinated by Novartis both in Phase I and Phase II. The duration of the follow-up period of the newborn and mother in case of pregnancy was missing and was added in this amendment.

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

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

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