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    Clinical Trial Results:
    A rollover study to provide continued treatment with GSK1120212 to subjects with solid tumors or leukemia

    Summary
    EudraCT number
    		 2010-023015-33
    Trial protocol
    		 GB   BE   SE   IT   DE   FR  
    Global end of trial date
    18 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Feb 2019
    First version publication date
    03 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    114375
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01376310
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    18 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To provide continued treatment with trametinib (GSK1120212) for subjects who had previously participated in a trametinib study and who continued to receive clinical benefit as well as have an acceptable safety profile with trametinib.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    United States: 150
    Worldwide total number of subjects
    159
    EEA total number of subjects
    4
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    92
    From 65 to 84 years
    66
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 159 subjects received treatment with GSK1120212 and were included in the safety set.

    Pre-assignment
    Screening details
    		 Continued treatment with GSK1120212 was provided for subjects who had previously participated in a GSK1120212 study and who continued to receive clinical benefit as well as have an acceptable safety profile with GSK1120212.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A
    Arm description
    		 Subjects on GSK1120212 Monotherapy and have been treated less than 24 weeks in their parent study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK1120212
    Investigational medicinal product code
    GSK1120212
    Other name
    Trametinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose of study treatment administered to subjects were individualized based upon the dose/regimen received during their participation in the parent study at the time of transition to the rollover study.

    Arm title
    		 Cohort B
    Arm description
    		 Subjects on GSK1120212 monotherapy who have been treated for 24 weeks or greater in their parent study. Also, subjects entering this study from any GSK1120212 combo trial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK1120212
    Investigational medicinal product code
    GSK1120212
    Other name
    Trametinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose of study treatment administered to subjects were individualized based upon the dose/regimen received during their participation in the parent study at the time of transition to the rollover study.

    Number of subjects in period 1
    		Cohort A Cohort B
    Started
    126
    33
    Completed
    90
    22
    Not completed
    36
    11
         Study closed/terminated
    1
    2
         Consent withdrawn by subject
    8
    2
         Physician decision
    26
    7
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Subjects on GSK1120212 Monotherapy and have been treated less than 24 weeks in their parent study.

    Reporting group title
    Cohort B
    Reporting group description
    		 Subjects on GSK1120212 monotherapy who have been treated for 24 weeks or greater in their parent study. Also, subjects entering this study from any GSK1120212 combo trial.

    Reporting group values
    		 Cohort A Cohort B Total
    Number of subjects
    		 126 33 159
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 74 18 92
        From 65-84 years
    		 51 15 66
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.0 ± 12.34 61.7 ± 11.30 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 66 17 83
        Male
    		 60 16 76
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 116 28 144
        Black
    		 6 3 9
        Asian
    		 2 2 4
        Native American/Pacific Islander
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Subjects on GSK1120212 Monotherapy and have been treated less than 24 weeks in their parent study.

    Reporting group title
    Cohort B
    Reporting group description
    		 Subjects on GSK1120212 monotherapy who have been treated for 24 weeks or greater in their parent study. Also, subjects entering this study from any GSK1120212 combo trial.

    Primary: Number of participants with adverse events

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    End point title
    		 Number of participants with adverse events [1]
    End point description
    Number of participants with adverse events as a measure of safety and tolerability
    End point type
    Primary
    End point timeframe
    Until 30 days after the last dose of study treatment. Subjects may have continued to receive study treatment until disease progression, death, unacceptable toxicity or until locally commercially available. The maximum duration of exposure was 76 months.
    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 analyses were performed.
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    126
    33
    Units: Participants
        Adverse Events
    119
    30
        Treatment-Related Adverse Events
    101
    26
        Serious Adverse Events
    26
    13
        Treatment-Related Serious Adverse Events
    8
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Subjects on GSK1120212 Monotherapy and have been treated less than 24 weeks in their parent study.

    Reporting group title
    Cohort B
    Reporting group description
    		 Subjects on GSK1120212 monotherapy who have been treated for 24 weeks or greater in their parent study. Also, subjects entering this study from any GSK1120212 combo trial.

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Serious adverse events
    		 Cohort A Cohort B All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 126 (20.63%)
    13 / 33 (39.39%)
    39 / 159 (24.53%)
         number of deaths (all causes)
    13
    3
    16
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 33 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 33 (6.06%)
    4 / 159 (2.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    2 / 126 (1.59%)
    1 / 33 (3.03%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 33 (3.03%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 33 (3.03%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal fluid collection
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 33 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 33 (3.03%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 33 (3.03%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 33 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Moraxella infection
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 126 (1.59%)
    3 / 33 (9.09%)
    5 / 159 (3.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 33 (3.03%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 33 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         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
    		 Cohort A Cohort B All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    115 / 126 (91.27%)
    28 / 33 (84.85%)
    143 / 159 (89.94%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 33 (6.06%)
    4 / 159 (2.52%)
         occurrences all number
    2
    2
    4
    Hypertension
         subjects affected / exposed
    7 / 126 (5.56%)
    0 / 33 (0.00%)
    7 / 159 (4.40%)
         occurrences all number
    7
    0
    7
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    10 / 126 (7.94%)
    2 / 33 (6.06%)
    12 / 159 (7.55%)
         occurrences all number
    13
    2
    15
    Fatigue
         subjects affected / exposed
    43 / 126 (34.13%)
    3 / 33 (9.09%)
    46 / 159 (28.93%)
         occurrences all number
    47
    3
    50
    Mucosal inflammation
         subjects affected / exposed
    7 / 126 (5.56%)
    4 / 33 (12.12%)
    11 / 159 (6.92%)
         occurrences all number
    10
    7
    17
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 126 (3.17%)
    2 / 33 (6.06%)
    6 / 159 (3.77%)
         occurrences all number
    4
    2
    6
    Oedema
         subjects affected / exposed
    5 / 126 (3.97%)
    2 / 33 (6.06%)
    7 / 159 (4.40%)
         occurrences all number
    5
    2
    7
    Oedema peripheral
         subjects affected / exposed
    27 / 126 (21.43%)
    6 / 33 (18.18%)
    33 / 159 (20.75%)
         occurrences all number
    33
    7
    40
    Pyrexia
         subjects affected / exposed
    10 / 126 (7.94%)
    3 / 33 (9.09%)
    13 / 159 (8.18%)
         occurrences all number
    12
    4
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 126 (9.52%)
    3 / 33 (9.09%)
    15 / 159 (9.43%)
         occurrences all number
    13
    3
    16
    Dyspnoea
         subjects affected / exposed
    17 / 126 (13.49%)
    5 / 33 (15.15%)
    22 / 159 (13.84%)
         occurrences all number
    18
    5
    23
    Dyspnoea exertional
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 33 (6.06%)
    4 / 159 (2.52%)
         occurrences all number
    2
    2
    4
    Epistaxis
         subjects affected / exposed
    5 / 126 (3.97%)
    2 / 33 (6.06%)
    7 / 159 (4.40%)
         occurrences all number
    6
    2
    8
    Nasal congestion
         subjects affected / exposed
    8 / 126 (6.35%)
    0 / 33 (0.00%)
    8 / 159 (5.03%)
         occurrences all number
    10
    0
    10
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 126 (6.35%)
    1 / 33 (3.03%)
    9 / 159 (5.66%)
         occurrences all number
    8
    1
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 126 (5.56%)
    1 / 33 (3.03%)
    8 / 159 (5.03%)
         occurrences all number
    8
    1
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 126 (7.14%)
    1 / 33 (3.03%)
    10 / 159 (6.29%)
         occurrences all number
    9
    1
    10
    Blood creatinine increased
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 33 (6.06%)
    4 / 159 (2.52%)
         occurrences all number
    2
    2
    4
    Weight decreased
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 33 (6.06%)
    4 / 159 (2.52%)
         occurrences all number
    2
    3
    5
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 33 (6.06%)
    4 / 159 (2.52%)
         occurrences all number
    2
    2
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 126 (9.52%)
    3 / 33 (9.09%)
    15 / 159 (9.43%)
         occurrences all number
    15
    3
    18
    Dysgeusia
         subjects affected / exposed
    8 / 126 (6.35%)
    1 / 33 (3.03%)
    9 / 159 (5.66%)
         occurrences all number
    8
    1
    9
    Headache
         subjects affected / exposed
    9 / 126 (7.14%)
    3 / 33 (9.09%)
    12 / 159 (7.55%)
         occurrences all number
    11
    3
    14
    Migraine
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    2
    Paraesthesia
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    2
    Sciatica
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 126 (11.90%)
    3 / 33 (9.09%)
    18 / 159 (11.32%)
         occurrences all number
    15
    3
    18
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 126 (4.76%)
    5 / 33 (15.15%)
    11 / 159 (6.92%)
         occurrences all number
    6
    8
    14
    Ascites
         subjects affected / exposed
    5 / 126 (3.97%)
    2 / 33 (6.06%)
    7 / 159 (4.40%)
         occurrences all number
    5
    2
    7
    Constipation
         subjects affected / exposed
    14 / 126 (11.11%)
    7 / 33 (21.21%)
    21 / 159 (13.21%)
         occurrences all number
    16
    7
    23
    Diarrhoea
         subjects affected / exposed
    36 / 126 (28.57%)
    12 / 33 (36.36%)
    48 / 159 (30.19%)
         occurrences all number
    44
    19
    63
    Dry mouth
         subjects affected / exposed
    13 / 126 (10.32%)
    1 / 33 (3.03%)
    14 / 159 (8.81%)
         occurrences all number
    13
    1
    14
    Dysphagia
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 33 (6.06%)
    3 / 159 (1.89%)
         occurrences all number
    1
    2
    3
    Nausea
         subjects affected / exposed
    33 / 126 (26.19%)
    7 / 33 (21.21%)
    40 / 159 (25.16%)
         occurrences all number
    38
    11
    49
    Stomatitis
         subjects affected / exposed
    10 / 126 (7.94%)
    2 / 33 (6.06%)
    12 / 159 (7.55%)
         occurrences all number
    10
    2
    12
    Vomiting
         subjects affected / exposed
    28 / 126 (22.22%)
    6 / 33 (18.18%)
    34 / 159 (21.38%)
         occurrences all number
    30
    11
    41
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    35 / 126 (27.78%)
    1 / 33 (3.03%)
    36 / 159 (22.64%)
         occurrences all number
    45
    1
    46
    Dry skin
         subjects affected / exposed
    15 / 126 (11.90%)
    2 / 33 (6.06%)
    17 / 159 (10.69%)
         occurrences all number
    20
    2
    22
    Nail disorder
         subjects affected / exposed
    1 / 126 (0.79%)
    3 / 33 (9.09%)
    4 / 159 (2.52%)
         occurrences all number
    1
    3
    4
    Pruritus
         subjects affected / exposed
    12 / 126 (9.52%)
    4 / 33 (12.12%)
    16 / 159 (10.06%)
         occurrences all number
    12
    5
    17
    Rash
         subjects affected / exposed
    28 / 126 (22.22%)
    7 / 33 (21.21%)
    35 / 159 (22.01%)
         occurrences all number
    37
    10
    47
    Rash maculo-papular
         subjects affected / exposed
    23 / 126 (18.25%)
    5 / 33 (15.15%)
    28 / 159 (17.61%)
         occurrences all number
    25
    6
    31
    Skin fissures
         subjects affected / exposed
    5 / 126 (3.97%)
    4 / 33 (12.12%)
    9 / 159 (5.66%)
         occurrences all number
    7
    9
    16
    Skin ulcer
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 126 (0.79%)
    3 / 33 (9.09%)
    4 / 159 (2.52%)
         occurrences all number
    1
    3
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 126 (3.97%)
    2 / 33 (6.06%)
    7 / 159 (4.40%)
         occurrences all number
    5
    2
    7
    Back pain
         subjects affected / exposed
    8 / 126 (6.35%)
    1 / 33 (3.03%)
    9 / 159 (5.66%)
         occurrences all number
    8
    2
    10
    Arthritis
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    2
    Flank pain
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    2
    Muscle spasms
         subjects affected / exposed
    2 / 126 (1.59%)
    3 / 33 (9.09%)
    5 / 159 (3.14%)
         occurrences all number
    4
    3
    7
    Muscular weakness
         subjects affected / exposed
    6 / 126 (4.76%)
    2 / 33 (6.06%)
    8 / 159 (5.03%)
         occurrences all number
    7
    4
    11
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    3 / 126 (2.38%)
    2 / 33 (6.06%)
    5 / 159 (3.14%)
         occurrences all number
    3
    2
    5
    Folliculitis
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    4
    4
    Conjunctivitis
         subjects affected / exposed
    3 / 126 (2.38%)
    2 / 33 (6.06%)
    5 / 159 (3.14%)
         occurrences all number
    4
    2
    6
    Furuncle
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 33 (6.06%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    2
    Nail infection
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 33 (6.06%)
    4 / 159 (2.52%)
         occurrences all number
    3
    2
    5
    Paronychia
         subjects affected / exposed
    2 / 126 (1.59%)
    5 / 33 (15.15%)
    7 / 159 (4.40%)
         occurrences all number
    3
    6
    9
    Oral herpes
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 33 (6.06%)
    3 / 159 (1.89%)
         occurrences all number
    1
    3
    4
    Pharyngitis
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 33 (6.06%)
    4 / 159 (2.52%)
         occurrences all number
    2
    2
    4
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 126 (2.38%)
    4 / 33 (12.12%)
    7 / 159 (4.40%)
         occurrences all number
    3
    4
    7
    Urinary tract infection
         subjects affected / exposed
    6 / 126 (4.76%)
    2 / 33 (6.06%)
    8 / 159 (5.03%)
         occurrences all number
    6
    2
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 126 (14.29%)
    2 / 33 (6.06%)
    20 / 159 (12.58%)
         occurrences all number
    19
    2
    21
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 126 (5.56%)
    3 / 33 (9.09%)
    10 / 159 (6.29%)
         occurrences all number
    7
    3
    10
    Dehydration
         subjects affected / exposed
    14 / 126 (11.11%)
    2 / 33 (6.06%)
    16 / 159 (10.06%)
         occurrences all number
    15
    2
    17
    Hypokalaemia
         subjects affected / exposed
    6 / 126 (4.76%)
    2 / 33 (6.06%)
    8 / 159 (5.03%)
         occurrences all number
    6
    3
    9

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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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