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    Clinical Trial Results:
    A Phase I Study of Monotherapy Dalotuzumab and Ridaforolimus-Dalotuzumab Combination Treatment in Paediatric Patients with Advanced Solid Tumours

    Summary
    EudraCT number
    		 2011-003407-38
    Trial protocol
    		 GB   FR  
    Global end of trial date
    25 Sep 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Mar 2016
    First version publication date
    13 Jun 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    8669-062
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01431547
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill RD, Kenilworth NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    25 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This is a study of dalotuzumab given as monotherapy and in combination with ridaforolimus for pediatric participants with advanced solid tumors. This study will find the maximum tolerated dose (MTD) and collect pharmacokinetic (PK) data for dalotuzumab alone and in combination with ridaforolimus.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Feb 2013
    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
    United States: 7
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    France: 11
    Worldwide total number of subjects
    24
    EEA total number of subjects
    17
    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)
    12
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants from age 3 to <18 years were enrolled in the dalotuzumab dose-finding cohorts; subjects of age 6 to <18 years could receive dalotuzumab-ridaforolimus combination therapy.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dalotuzumab 900 mg/m^2
    Arm description
    		 Participants receive dalotuzumab 900 mg/m^2, intravenously (IV) every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    dalotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dalotuzumab at assigned dose (based on body surface area), intravenously

    Arm title
    		 Dalotuzumab 1200 mg/m^2
    Arm description
    		 Participants receive dalotuzumab 1200 mg/m^2, IV, every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    dalotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dalotuzumab at assigned dose (based on body surface area), intravenously

    Arm title
    		 Dalotuzumab 1500 mg/m^2
    Arm description
    		 Participants receive dalotuzumab 1500 mg/m^2, IV, every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    dalotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dalotuzumab at assigned dose (based on body surface area), intravenously

    Arm title
    		 Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Arm description
    		 Participants receive dalotuzumab 900 mg/m^2, IV, every 3 weeks, plus ridaforolimus 28 mg/m^2 enteric-coated tablets, orally, once per day for 5 days each week
    Arm type
    		 Experimental

    Investigational medicinal product name
    ridaforolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ridaforolimus, enteric coated tablets. orally, once a day for 5 days per week

    Investigational medicinal product name
    dalotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dalotuzumab at assigned dose (based on body surface area), intravenously

    Number of subjects in period 1
    		Dalotuzumab 900 mg/m^2 Dalotuzumab 1200 mg/m^2 Dalotuzumab 1500 mg/m^2 Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Started
    11
    3
    6
    4
    Completed
    0
    0
    0
    0
    Not completed
    11
    3
    6
    4
         Physician decision
    -
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    -
    1
         Adverse event, non-fatal
    1
    -
    -
    -
         Lack of efficacy
    10
    3
    6
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dalotuzumab 900 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 900 mg/m^2, intravenously (IV) every 3 weeks

    Reporting group title
    Dalotuzumab 1200 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 1200 mg/m^2, IV, every 3 weeks

    Reporting group title
    Dalotuzumab 1500 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 1500 mg/m^2, IV, every 3 weeks

    Reporting group title
    Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 900 mg/m^2, IV, every 3 weeks, plus ridaforolimus 28 mg/m^2 enteric-coated tablets, orally, once per day for 5 days each week

    Reporting group values
    		 Dalotuzumab 900 mg/m^2 Dalotuzumab 1200 mg/m^2 Dalotuzumab 1500 mg/m^2 Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2 Total
    Number of subjects
    		 11 3 6 4 24
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 6 1 4 1 12
        Adolescents (12-17 years)
    		 5 2 2 3 12
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 5 1 4 2 12
        Male
    		 6 2 2 2 12

    End points

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    End points reporting groups
    Reporting group title
    Dalotuzumab 900 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 900 mg/m^2, intravenously (IV) every 3 weeks

    Reporting group title
    Dalotuzumab 1200 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 1200 mg/m^2, IV, every 3 weeks

    Reporting group title
    Dalotuzumab 1500 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 1500 mg/m^2, IV, every 3 weeks

    Reporting group title
    Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 900 mg/m^2, IV, every 3 weeks, plus ridaforolimus 28 mg/m^2 enteric-coated tablets, orally, once per day for 5 days each week

    Primary: Number of Participants with Dose-limiting Toxicities (DLTs)

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    End point title
    		 Number of Participants with Dose-limiting Toxicities (DLTs) [1]
    End point description
    A dose-limiting toxicity is an event (medical or clinical) that results in a change in the study drug dose.
    End point type
    Primary
    End point timeframe
    Up to 21 days (Cycle 1)
    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: No statistical analysis was planned for this endpoint.
    End point values
    		 Dalotuzumab 900 mg/m^2 Dalotuzumab 1200 mg/m^2 Dalotuzumab 1500 mg/m^2 Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Number of subjects analysed
    11
    3
    6
    4
    Units: Participants
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Area Under the Concentration-Time Curve from Hour 0 to Infinity (AUC0-inf) for Dalotuzumab Alone or in Combination with Ridaforolimus

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    End point title
    		 Area Under the Concentration-Time Curve from Hour 0 to Infinity (AUC0-inf) for Dalotuzumab Alone or in Combination with Ridaforolimus [2]
    End point description
    AUC is a measure of the amount of drug in the body over time. The geometric mean provides the typical value of this set of numbers by using the product of their values; the coefficient of variation provides the percent of the geometric means represented by the standard deviation and is used to compensate for the inherent differences among participants in the study.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 1, 24, 48, 168 (Day 8), and 336 hours (Day 15) post first infusion; pre-dose at Week 4 (Day 22), Week 7 (Day 43), and Weeks 13 and 19.
    Notes
    [2] - 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: No statistical analysis was planned for this endpoint.
    End point values
    		 Dalotuzumab 900 mg/m^2 Dalotuzumab 1200 mg/m^2 Dalotuzumab 1500 mg/m^2 Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Number of subjects analysed
    10 [3]
    3 [4]
    6 [5]
    4 [6]
    Units: hr*ug/mL
        geometric mean (geometric coefficient of variation)
    87900 ± 61.2
    164000 ± 106
    186000 ± 79.2
    80300 ± 24.5
    Notes
    [3] - All participants taking >=1 dose of study drug(s) having required samples taken and analyzed
    [4] - All participants taking >=1 dose of study drug(s) having required samples taken and analyzed
    [5] - All participants taking >=1 dose of study drug(s) having required samples taken and analyzed
    [6] - All participants taking >=1 dose of study drug(s) having required samples taken and analyzed
    No statistical analyses for this end point

    Primary: Area Under the Concentration-Time Curve from Hour 0 to Hour 24 (AUC0-24) for Ridaforolimus in Combination with Dalotuzumab

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    End point title
    		 Area Under the Concentration-Time Curve from Hour 0 to Hour 24 (AUC0-24) for Ridaforolimus in Combination with Dalotuzumab [7] [8]
    End point description
    AUC 0-24 is a measure of the amount of drug in the body over 24 hours after the dose The geometric mean provides the typical value for the group by using the product of the AUC0-24 values; the coefficient of variation provides the percent of the geometric mean represented by the standard deviation and is used to compensate for the inherent differences among participants in the group.
    End point type
    Primary
    End point timeframe
    Pre-dose on Days 1-5 in the first cycle of therapy and post-dose on Day 5 at 0.5, 1, 2, 4, 8, 24, and 72 hours.
    Notes
    [7] - 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: No statistical analysis was planned for this endpoint.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    		 Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Number of subjects analysed
    3 [9]
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    2350 ± 38.5
    Notes
    [9] - One participant was excluded from the analysis due to limited samples
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected for 30 days after the last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Dalotuzumab 900 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 900 mg/m^2, intravenously (IV) every 3 weeks

    Reporting group title
    Dalotuzumab 1200 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 1200 mg/m^2, IV, every 3 weeks

    Reporting group title
    Dalotuzumab 1500 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 1500 mg/m^2, IV, every 3 weeks

    Reporting group title
    Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Reporting group description
    		 Participants receive dalotuzumab 900 mg/m^2, IV, every 3 weeks, plus ridaforolimus 28 mg/m^2 enteric-coated tablets, orally, once per day for 5 days each week

    Serious adverse events
    		 Dalotuzumab 900 mg/m^2 Dalotuzumab 1200 mg/m^2 Dalotuzumab 1500 mg/m^2 Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 11 (63.64%)
    1 / 3 (33.33%)
    4 / 6 (66.67%)
    1 / 4 (25.00%)
         number of deaths (all causes)
    3
    1
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Neurological decompensation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dalotuzumab 900 mg/m^2 Dalotuzumab 1200 mg/m^2 Dalotuzumab 1500 mg/m^2 Dalotuzumab 900 mg/m^2 + ridaforolimus 28 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour associated fever
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Tumour pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hot flush
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pallor
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Vena cava thrombosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Catheter site pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    3
    Chills
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Fatigue
         subjects affected / exposed
    4 / 11 (36.36%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    4
    1
    4
    2
    General physical health deterioration
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    3
    Pyrexia
         subjects affected / exposed
    4 / 11 (36.36%)
    2 / 3 (66.67%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    6
    3
    3
    3
    Soft tissue inflammation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Scrotal oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 4 (75.00%)
         occurrences all number
    1
    0
    0
    4
    Nasal congestion
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Orthopnoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Sneezing
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tachypnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    0
    0
    2
    Insomnia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    4
    0
    2
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    2
    0
    3
    3
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Blood albumin decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    3
    0
    0
    5
    Blood calcium decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Blood cholesterol increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    1
    2
    Blood creatinine increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    0
    1
    Blood glucose decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    2
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    0
    0
    2
    Blood potassium decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 4 (75.00%)
         occurrences all number
    1
    0
    0
    4
    Blood sodium decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    1
    4
    Blood triglycerides increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    3
    2
    Blood uric acid increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    5
    0
    1
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    0
    4
    Haemoglobin increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    High density lipoprotein increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    3
    0
    0
    6
    Neutrophil count decreased
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    1
    1
    Platelet count decreased
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    4 / 4 (100.00%)
         occurrences all number
    3
    0
    0
    8
    Protein total decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    1
    2
    Weight increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    10
    1
    1
    3
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Head injury
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Scratch
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    2
    Nervous system disorders
    Cerebellar syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    4 / 11 (36.36%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    13
    1
    4
    6
    Hyperaesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Hyporeflexia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Slow speech
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    5
    1
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear swelling
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Otorrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema of eyelid
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Photophobia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    2
    Vision blurred
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    4
    1
    1
    4
    Abdominal pain upper
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Anal fissure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    Ascites
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Chapped lips
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    4 / 11 (36.36%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    4 / 4 (100.00%)
         occurrences all number
    5
    1
    3
    8
    Diarrhoea
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    4
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    2
    Flatulence
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Hyoaesthesia oral
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    3 / 4 (75.00%)
         occurrences all number
    5
    1
    2
    3
    Oral pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Proctalgia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    4 / 4 (100.00%)
         occurrences all number
    1
    0
    0
    6
    Toothache
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 11 (27.27%)
    2 / 3 (66.67%)
    3 / 6 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    8
    2
    5
    6
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    1
    1
    Erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Palmar erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    0
    2
    Pruritus
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    0
    0
    1
    Rash
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash macular
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Rash papular
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Swelling face
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    2
    Dysuria
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Incontinence
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    0
    0
    5
    Back pain
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 4 (75.00%)
         occurrences all number
    4
    0
    0
    4
    Bone pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    0
    3
    Musculoskeletal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    1
    5
    Myalgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    1
    Pain in extremity
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 3 (66.67%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    0
    4
    Infections and infestations
    Ear infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lung infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    1
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Sphingomonas paucimobilis infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    3
    1
    3
    2
    Dehydration
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    7
    0
    4
    0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypernatraemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    10
    0
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hyponatraemia
         subjects affected / exposed
    4 / 11 (36.36%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    7
    1
    4
    0
    Hypophosphataemia
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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