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    Clinical Trial Results:
    A Phase I Study of Ridaforolimus in Paediatric Patients with Advanced Solid Tumours

    Summary
    EudraCT number
    		 2011-000729-55
    Trial protocol
    		 GB   FR   Outside EU/EEA  
    Global end of trial date
    25 May 2018

    Results information
    Results version number
    		 v3(current)
    This version publication date
    15 Nov 2018
    First version publication date
    19 Jul 2015
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    8669-056
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01431534
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000458-PIP01-08
    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
    30 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Aug 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial are to determine the recommended dose of ridaforolimus for pediatric participants with advanced solid tumors by measuring the number of participants experiencing dose-limiting toxicities (DLTs) while on different doses of ridaforolimus, and to characterize the pharmacokinetics of ridaforolimus in these participants. Study-related visits concluded in August 2013. Participants who did not have disease progression, adequately tolerated therapy, and continued to meet eligibility criteria for 6 months after the enrollment period had been completed could continue treatment in an extension phase until they met discontinuation criteria or voluntarily withdrew.
    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
    30 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    20
    EEA total number of subjects
    16
    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)
    7
    Adolescents (12-17 years)
    13
    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
    		 This study enrolled children from the ages of 6 to <18 years with advanced solid tumors including lymphoma and tumors of the central nervous system who met the study inclusion/exclusion criteria

    Period 1
    Period 1 title
    Treatment Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ridaforolimus 22 mg/m^2
    Arm description
    		 Participants received 22 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.
    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
    Oral administration of 10 mg enteric-coated tablets at doses of 22 mg/m^2, 28 mg/m^2, or 33 mg/m^2 based on body surface area (BSA), once daily for 5 consecutive days each week in consecutive 28-day cycles.

    Arm title
    		 Ridaforolimus 28mg/m^2
    Arm description
    		 Participants received 28 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.
    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
    Oral administration of 10 mg enteric-coated tablets at doses of 22 mg/m^2, 28 mg/m^2, or 33 mg/m^2 based on body surface area (BSA), once daily for 5 consecutive days each week in consecutive 28-day cycles.

    Arm title
    		 Ridaforolimus 33 mg/m^2
    Arm description
    		 Participants received 33 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.
    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
    Oral administration of 10 mg enteric-coated tablets at doses of 22 mg/m^2, 28 mg/m^2, or 33 mg/m^2 based on body surface area (BSA), once daily for 5 consecutive days each week in consecutive 28-day cycles.

    Number of subjects in period 1
    		Ridaforolimus 22 mg/m^2 Ridaforolimus 28mg/m^2 Ridaforolimus 33 mg/m^2
    Started
    4
    3
    13
    Completed
    0
    0
    2
    Not completed
    4
    3
    11
         Adverse event, non-fatal
    -
    -
    1
         Progressive Disease
    4
    3
    10
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Ridaforolimus 33 mg/m^2
    Arm description
    		 Participants receive ridaforolimus 33 mg/m^2, orally, 10 mg enteric-coated tablet QD x 5/week, in 28-day cycles; this population comprises all participants who did not have disease progression, adequately tolerated therapy, and continued to meet study eligibility criteria for 6 months after the trial's enrollment period was complete.
    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
    Oral administration of 10 mg enteric-coated tablets at doses of 22 mg/m^2, 28 mg/m^2, or 33 mg/m^2 based on body surface area (BSA), once daily for 5 consecutive days each week in consecutive 28-day cycles.

    Number of subjects in period 2
    		Ridaforolimus 33 mg/m^2
    Started
    2
    Completed
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ridaforolimus 22 mg/m^2
    Reporting group description
    		 Participants received 22 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.

    Reporting group title
    Ridaforolimus 28mg/m^2
    Reporting group description
    		 Participants received 28 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.

    Reporting group title
    Ridaforolimus 33 mg/m^2
    Reporting group description
    		 Participants received 33 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.

    Reporting group values
    		 Ridaforolimus 22 mg/m^2 Ridaforolimus 28mg/m^2 Ridaforolimus 33 mg/m^2 Total
    Number of subjects
    		 4 3 13 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 1 0 6 7
        Adolescents (12-17 years)
    		 3 3 7 13
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.0 ( 3.7 ) 14.7 ( 2.5 ) 12.2 ( 3.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2 8 12
        Male
    		 2 1 5 8

    End points

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    End points reporting groups
    Reporting group title
    Ridaforolimus 22 mg/m^2
    Reporting group description
    		 Participants received 22 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.

    Reporting group title
    Ridaforolimus 28mg/m^2
    Reporting group description
    		 Participants received 28 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.

    Reporting group title
    Ridaforolimus 33 mg/m^2
    Reporting group description
    		 Participants received 33 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study.
    Reporting group title
    Ridaforolimus 33 mg/m^2
    Reporting group description
    		 Participants receive ridaforolimus 33 mg/m^2, orally, 10 mg enteric-coated tablet QD x 5/week, in 28-day cycles; this population comprises all participants who did not have disease progression, adequately tolerated therapy, and continued to meet study eligibility criteria for 6 months after the trial's enrollment period was complete.

    Primary: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0)

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    End point title
    		 Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) [1]
    End point description
    DLT defined using NCI-CTCAE v.4.0 as any of the following events occurring during the first 28-day cycle that were possibly, probably, or definitely study drug-related: Grade 4 neutropenia for ≥5 days; Grade 3-4 neutropenia associated with fever, antibiotics, or hospitalization for infection; Grade 4 thrombocytopenia for ≥5 days or requiring platelet transfusion; ≥Grade 3 hyperglycemia for ≥5 days despite management; ≥Grade 3 diarrhea for >24 hours despite management; ≥Grade 3 nausea or vomiting despite management; any other Grade ≥3 non-hematological toxicity persisting despite management (except alopecia, transient electrolyte abnormalities, transient Grade 3 liver function test elevations, and Grade 3 neurotoxicity for participants with baseline Grade 3 neurotoxicity); inability to complete DLT assessment period, interruption in dosing for >10 dosing days during DLT assessment period, or any delay in the initiation of the next cycle for >10 dosing days due to any related toxicity.
    End point type
    Primary
    End point timeframe
    Cycle 1 (cycle = 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: No statistical analysis was planned for this endpoint.
    End point values
    		 Ridaforolimus 22 mg/m^2 Ridaforolimus 28mg/m^2 Ridaforolimus 33 mg/m^2
    Number of subjects analysed
    4 [2]
    3 [3]
    13 [4]
    Units: Participants
    0
    0
    1
    Notes
    [2] - Participants who completed Cycle 1 and received >75% of drug, or who discontinued due to related DLT
    [3] - Participants who completed Cycle 1 and received >75% of drug, or who discontinued due to related DLT
    [4] - Participants who completed Cycle 1 and received >75% of drug, or who discontinued due to related DLT
    No statistical analyses for this end point

    Primary: Area Under the Concentration-Time Curve of Ridaforolimus From Time 0 to 24 Hours (AUC0-24 hr)

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    End point title
    		 Area Under the Concentration-Time Curve of Ridaforolimus From Time 0 to 24 Hours (AUC0-24 hr) [5]
    End point description
    AUC is a measure of the amount of drug in the blood over time. Whole blood samples were collected pre-dose (within 5 minutes of ridaforolimus administration) and post-dose at specified time points on Day 5 of the first week of Cycle 1 to determine AUC0-24 hr. Participants who received all 5 ridaforolimus doses in the first week of 28-day Cycle 1 were analyzed.
    End point type
    Primary
    End point timeframe
    Day 5 of Cycle 1 [28-day cycle]: pre-dose (0.0 hours) and 0.5, 1.0, 2.0, 4.0, 8.0, 24.0, and 72.0 hours after administration of ridaforolimus
    Notes
    [5] - 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
    		 Ridaforolimus 22 mg/m^2 Ridaforolimus 28mg/m^2 Ridaforolimus 33 mg/m^2
    Number of subjects analysed
    4
    3
    11
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    1340 ( 31.7 )
    2330 ( 36.2 )
    2280 ( 29.8 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to the 17-Dec-2013 database lock (up to ~56 weeks)
    Adverse event reporting additional description
    All participants who received at least one dose of study treatment on the base study. Per protocol, safety data from the extension period were not included in the study database and did not contribute to the primary safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Ridaforolimus 22 mg/m^2
    Reporting group description
    		 Participants receive ridaforolimus 22 mg/m^2, orally, 10 mg enteric-coated tablet QD x 5/week, in 28-day cycles

    Reporting group title
    Ridaforolimus 33 mg/m^2
    Reporting group description
    		 Participants receive ridaforolimus 33 mg/m^2, orally, 10 mg enteric-coated tablet QD x 5/week, in 28-day cycles

    Reporting group title
    Ridaforolimus 28mg/m^2
    Reporting group description
    		 Participants receive ridaforolimus 28mg/m^2, orally, 10 mg enteric-coated tablet QD x 5/week, in 28-day cycles

    Serious adverse events
    		 Ridaforolimus 22 mg/m^2 Ridaforolimus 33 mg/m^2 Ridaforolimus 28mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    7 / 13 (53.85%)
    2 / 3 (66.67%)
         number of deaths (all causes)
    1
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Partial seizure
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric perforation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related sepsis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ridaforolimus 22 mg/m^2 Ridaforolimus 33 mg/m^2 Ridaforolimus 28mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    13 / 13 (100.00%)
    3 / 3 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    2
    Chills
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Fatigue
         subjects affected / exposed
    4 / 4 (100.00%)
    7 / 13 (53.85%)
    3 / 3 (100.00%)
         occurrences all number
    4
    8
    3
    Gait disturbance
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Local swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Pyrexia
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 13 (30.77%)
    1 / 3 (33.33%)
         occurrences all number
    3
    4
    2
    Thrombus in device
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 4 (25.00%)
    6 / 13 (46.15%)
    1 / 3 (33.33%)
         occurrences all number
    2
    8
    1
    Dysphonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 13 (23.08%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    1
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Haemoptysis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hiccups
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Increased upper airway secretion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal dryness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    0
    5
    0
    Pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory distress
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Sputum discoloured
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 13 (15.38%)
    0 / 3 (0.00%)
         occurrences all number
    1
    2
    0
    Confusional state
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Depression
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    9 / 13 (69.23%)
    1 / 3 (33.33%)
         occurrences all number
    4
    15
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    8 / 13 (61.54%)
    2 / 3 (66.67%)
         occurrences all number
    2
    15
    2
    Blood albumin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 13 (15.38%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 13 (30.77%)
    0 / 3 (0.00%)
         occurrences all number
    1
    5
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    Blood chloride decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 4 (0.00%)
    5 / 13 (38.46%)
    0 / 3 (0.00%)
         occurrences all number
    0
    8
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 4 (0.00%)
    6 / 13 (46.15%)
    0 / 3 (0.00%)
         occurrences all number
    0
    6
    0
    Blood glucose decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Blood magnesium increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 13 (30.77%)
    0 / 3 (0.00%)
         occurrences all number
    1
    8
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
    1 / 3 (33.33%)
         occurrences all number
    6
    3
    1
    Blood selenium increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 13 (30.77%)
    1 / 3 (33.33%)
         occurrences all number
    2
    5
    2
    C-reactive protein increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 13 (38.46%)
    2 / 3 (66.67%)
         occurrences all number
    1
    6
    2
    Haemoglobin decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 13 (15.38%)
    1 / 3 (33.33%)
         occurrences all number
    4
    6
    2
    International normalised ratio decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 13 (30.77%)
    0 / 3 (0.00%)
         occurrences all number
    5
    5
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 13 (15.38%)
    0 / 3 (0.00%)
         occurrences all number
    4
    2
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    10 / 13 (76.92%)
    0 / 3 (0.00%)
         occurrences all number
    3
    17
    0
    Reticulocyte count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 13 (30.77%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 13 (30.77%)
    2 / 3 (66.67%)
         occurrences all number
    5
    9
    3
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Animal bite
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Ataxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Extrapyramidal disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    3 / 4 (75.00%)
    6 / 13 (46.15%)
    1 / 3 (33.33%)
         occurrences all number
    6
    11
    2
    Hyporeflexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Paraparesis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Tremor
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    V11th nerve paralysis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Dizziness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    2
    6
    0
    Leukopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Neutropenia
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 13 (23.08%)
    1 / 3 (33.33%)
         occurrences all number
    4
    6
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid ptosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Mydriasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Photophobia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 13 (15.38%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 13 (15.38%)
    1 / 3 (33.33%)
         occurrences all number
    4
    2
    1
    Aphthous stomatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 4 (25.00%)
    6 / 13 (46.15%)
    2 / 3 (66.67%)
         occurrences all number
    1
    7
    2
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    6 / 13 (46.15%)
    0 / 3 (0.00%)
         occurrences all number
    2
    11
    0
    Dry mouth
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    3
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Lip dry
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Lip Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    4 / 4 (100.00%)
    8 / 13 (61.54%)
    2 / 3 (66.67%)
         occurrences all number
    6
    11
    2
    Odynophagia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Oral dysaesthesia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Oral pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Stomatitis
         subjects affected / exposed
    2 / 4 (50.00%)
    10 / 13 (76.92%)
    3 / 3 (100.00%)
         occurrences all number
    3
    18
    4
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 13 (15.38%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Vomiting
         subjects affected / exposed
    2 / 4 (50.00%)
    7 / 13 (53.85%)
    1 / 3 (33.33%)
         occurrences all number
    12
    10
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Eczema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Hair texture abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 13 (15.38%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 13 (15.38%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Skin lesion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Skin striae
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Enuresis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Haematuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhage urinary tract
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 13 (15.38%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Pollakiuria
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 13 (15.38%)
    3 / 3 (100.00%)
         occurrences all number
    1
    2
    3
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 13 (15.38%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    1
    Bone pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Joint swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    0
    2
    Muscle spasms
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 13 (23.08%)
    2 / 3 (66.67%)
         occurrences all number
    5
    3
    2
    Myalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Myopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Osteonecrosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 13 (30.77%)
    0 / 3 (0.00%)
         occurrences all number
    4
    6
    0
    Pain in jaw
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Genital herpes
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Impetigo
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Otitis media
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 13 (15.38%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Skin infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Tracheitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Varicella
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Vulvitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Wound infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 4 (50.00%)
    6 / 13 (46.15%)
    2 / 3 (66.67%)
         occurrences all number
    2
    7
    2
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hypercholesterolemia
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 13 (7.69%)
    1 / 3 (33.33%)
         occurrences all number
    3
    1
    2
    Fluid retention
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 13 (30.77%)
    0 / 3 (0.00%)
         occurrences all number
    1
    7
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 13 (30.77%)
    0 / 3 (0.00%)
         occurrences all number
    1
    4
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 13 (15.38%)
    0 / 3 (0.00%)
         occurrences all number
    1
    4
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    1
    6
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 13 (23.08%)
    0 / 3 (0.00%)
         occurrences all number
    2
    9
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    5
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 13 (7.69%)
    1 / 3 (33.33%)
         occurrences all number
    3
    6
    2
    Iron deficiency
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    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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