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    Clinical Trial Results:
    A multicenter, open label, dose finding study to evaluate efficacy and safety of Givinostat administered in two different doses in patients with polyarticular course Juvenile Idiopathic Arthritis (poly JIA) not adequately responding to the standard treatment

    Summary
    EudraCT number
    		 2010-019094-15
    Trial protocol
    		 CZ   BE   ES   IT   SI  
    Global end of trial date
    01 Jun 2012

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Jul 2019
    First version publication date
    25 May 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Friendly name should be changed.

    Trial information

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    Trial identification
    Sponsor protocol code
    DSC/08/2357/36
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01261624
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Italfarmaco S.p.A.
    Sponsor organisation address
    Via dei Lavoratori 54, Milan, Italy, 20092
    Public contact
    Clinical Trial Transparency Manager, Italfarmaco S.p.A., Italfarmaco S.p.A., +39 02 66041503, info@italfarmaco.com
    Scientific contact
    Clinical Trial Transparency Manager, Italfarmaco S.p.A., Italfarmaco S.p.A., +39 02 66041503, info@italfarmaco.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000551-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jun 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jun 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2012
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety profile of Givinostat administered in two different doses in patients with polyarticular course JIA not adequately responding to the standard treatment, to the purpose of selecting the best dose to be tested on a larger scale in a following phase III clinical trial.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki and in accordance with the International Conference on Harmonization (ICH) Consolidated Guideline on Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 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
    Romania: 3
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    16
    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)
    9
    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
    		 A total of 21 patients were screened and 16 patients were enrolled in the study. The enrolment was discontinued at 16 patients due to poor enrolment rate. The first 10 enrolled patients were assigned to the Low Dose treatment cohort (0.50 mg/kg BID) and the following six patients were assigned to the High Dose treatment cohort (0.75 mg/kg BID).

    Pre-assignment
    Screening details
    		 A total of 21 patients were screened and 16 patients were enrolled in the study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Low Dose Cohort (0.50 mg/kg BID)
    Arm description
    		 Patients received the dose of 0.50 mg/kg BID for 12 weeks. Responders (defined as achieving at least an ACR Pediatric Criteria level 30 of response) continued receiving the assigned dose for a further 12 weeks. Non-responders were allowed to increase the dose to 0.75 mg/kg BID for a further 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Other name
    ITF2357, histone deacetylase inhibitor
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Givinostat, oral suspension, was administered at the doses of 0.5 mg/kg BID, in fed conditions, during 12 consecutive weeks. Responders (achieving at least an ACR Pediatric 30 level of response) continued receiving the assigned dose for a further 12 weeks. Non-responders to 0.50 mg/kg BID were allowed to increase the dosage to 0.75 mg/kg BID for a further 12 weeks.

    Arm title
    		 High Dose Cohort (0.75 mg/kg BID)
    Arm description
    		 Patients received the dose of 0.75 mg/kg BID for 12 weeks. Responders (defined as achieving at least an ACR Pediatric Criteria level 30 of response) continued receiving the assigned dose for a further 12 weeks. Non-responders after 12 weeks discontinued the study treatment permanently.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Histone deacetylase inhibitor
    Other name
    ITF2357
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Givinostat, oral suspension, was administered at the doses of 0.75 mg/kg BID, in fed conditions, during 12 consecutive weeks. Responders (achieving at least an ACR Pediatric 30 level of response) continued receiving the assigned dose for a further 12 weeks. Non-responders to the initial dose of 0.75 mg/kg BID were permanently discontinued from the study.

    Number of subjects in period 1
    		Low Dose Cohort (0.50 mg/kg BID) High Dose Cohort (0.75 mg/kg BID)
    Started
    10
    6
    Completed
    8
    2
    Not completed
    2
    4
         Disease progression
    2
    1
         Insufficient response
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Low Dose Cohort (0.50 mg/kg BID)
    Reporting group description
    		 Patients received the dose of 0.50 mg/kg BID for 12 weeks. Responders (defined as achieving at least an ACR Pediatric Criteria level 30 of response) continued receiving the assigned dose for a further 12 weeks. Non-responders were allowed to increase the dose to 0.75 mg/kg BID for a further 12 weeks

    Reporting group title
    High Dose Cohort (0.75 mg/kg BID)
    Reporting group description
    		 Patients received the dose of 0.75 mg/kg BID for 12 weeks. Responders (defined as achieving at least an ACR Pediatric Criteria level 30 of response) continued receiving the assigned dose for a further 12 weeks. Non-responders after 12 weeks discontinued the study treatment permanently.

    Reporting group values
    		 Low Dose Cohort (0.50 mg/kg BID) High Dose Cohort (0.75 mg/kg BID) Total
    Number of subjects
    		 10 6 16
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 4 3 7
        Adolescents (12-17 years)
    		 6 3 9
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.7 ( 5.5 ) 9.7 ( 5.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 6 14
        Male
    		 2 0 2
    Subject analysis sets

    Subject analysis set title
    Low dose discontinued
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis set title
    Low dose throughout
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis set title
    Switched dose
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis set title
    High dose throughout
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis set title
    High dose discontinued
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis sets values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects
    1
    1
    8
    2
    4
    Age categorical
    Units: Subjects
        Children (2-11 years)
    1
    1
    2
    1
    2
        Adolescents (12-17 years)
    0
    0
    6
    1
    2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    1
    1
    6
    2
    4
        Male
    0
    0
    2
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Low Dose Cohort (0.50 mg/kg BID)
    Reporting group description
    		 Patients received the dose of 0.50 mg/kg BID for 12 weeks. Responders (defined as achieving at least an ACR Pediatric Criteria level 30 of response) continued receiving the assigned dose for a further 12 weeks. Non-responders were allowed to increase the dose to 0.75 mg/kg BID for a further 12 weeks

    Reporting group title
    High Dose Cohort (0.75 mg/kg BID)
    Reporting group description
    		 Patients received the dose of 0.75 mg/kg BID for 12 weeks. Responders (defined as achieving at least an ACR Pediatric Criteria level 30 of response) continued receiving the assigned dose for a further 12 weeks. Non-responders after 12 weeks discontinued the study treatment permanently.

    Subject analysis set title
    Low dose discontinued
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis set title
    Low dose throughout
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis set title
    Switched dose
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis set title
    High dose throughout
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Subject analysis set title
    High dose discontinued
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set comprised all enrolled patients who received at least one dose of investigational medicinal product and from whom at least one measurement of the ACR Pediatric variables after Day 1 was obtained.

    Primary: ACR Pediatric 30 response level after 12 weeks of treatment

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    End point title
    		 ACR Pediatric 30 response level after 12 weeks of treatment [1]
    End point description
    ACR Pediatric variables include: Physician's Global Assessment of disease activity on a 0-100 mm visual analogue scale from 0 mm = no disease activity to 100 mm = very severe disease activity; Parent's or patient's Global Assessment of Patient's overall well-being on a 100 mm VAS from 0 mm = very well to 100 mm = very poor; Functional ability: Childhood Health Assessment Questionnaire; Number of joints with active arthritis using the ACR definition (any joint with swelling, or in the absence of swelling, limitation of motion accompanied by pain/tenderness not due to bone deformity); Number of joints with limitation of motion; Laboratory measure of inflammation: C-reactive protein (mg/L) Patients were considered as responders if they achieve at least an ACR Pediatric Criteria level 30 of response, defined as a 30% improvement as compared to baseline in at least 3 of the 6 variables listed above, with no more than 1 variable worsening by > than 30%.
    End point type
    Primary
    End point timeframe
    At 12 weeks of treatment.
    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 data available
    End point values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects analysed
    1
    1
    8
    2
    4
    Units: number of patients
    0
    1
    3
    2
    1
    No statistical analyses for this end point

    Secondary: ACR pediatric response level (ACR 50, 70, 90 and 100) at week 12 of treatment

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    End point title
    		 ACR pediatric response level (ACR 50, 70, 90 and 100) at week 12 of treatment
    End point description
    ACR Pediatric variables include: Physician's Global Assessment of disease activity on a 0- 100 mm visual analogue scale from 0 mm = no disease activity to 100 mm = very severe disease activity; Parent's or patient's Global Assessment of Patient's overall well-being on a 100 mm VAS from 0 mm = very well to 100 mm = very poor; Functional ability: Childhood Health Assessment Questionnaire; Number of joints with active arthritis using the ACR definition (any joint with swelling, or in the absence of swelling, limitation of motion accompanied by pain/tenderness not due to bone deformity); Number of joints with limitation of motion; Laboratory measure of inflammation: C-reactive protein (mg/L) Patients were considered as responders if they achieve at least an ACR Pediatric Criteria level 50, 70, 90 and 100 of response, defined as a 50%, 70%, 90% and 100% improvement as compared to baseline in at least 3 of the 6 variables listed above, with no more than 1 variable worsening by > than 30%.
    End point type
    Secondary
    End point timeframe
    At week 12 of treatment.
    End point values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects analysed
    1
    1
    8
    2
    4
    Units: number of patients
        Level 50
    0
    1
    1
    2
    1
        Level 70
    0
    1
    0
    1
    0
        Level 90
    0
    0
    0
    0
    0
        Level 100
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Changes Over Time of Physician’s Global Assessment of Disease Activity

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    End point title
    		 Mean Changes Over Time of Physician’s Global Assessment of Disease Activity
    End point description
    Only values at 12 and 24 weeks of treatment, expressed as percentage change from baseline, are reported here.
    End point type
    Secondary
    End point timeframe
    At 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 weeks of treatment.
    End point values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects analysed
    0 [2]
    1
    8 [3]
    2
    2 [4]
    Units: percentage
    arithmetic mean (standard deviation)
        12 weeks
    ( )
    81.36 ( 000 )
    10.56 ( 27.93 )
    83.57 ( 16.66 )
    0.00 ( 28.28 )
        24 weeks
    ( )
    32.20 ( 000 )
    33.40 ( 41.96 )
    74.48 ( 32.80 )
    000 ( 000 )
    Notes
    [2] - The only patient in this cohort discontinued the study before week 12.
    [3] - 7 patients are part of this ITT cohort at 24 weeks
    [4] - 2 and 0 patients are part of this ITT cohort at weeks 12 and 24 respectively.
    No statistical analyses for this end point

    Secondary: Mean Changes Over Time of Parent’s or Patient’s Global Assessment of Patient’s Overall Well-being

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    End point title
    		 Mean Changes Over Time of Parent’s or Patient’s Global Assessment of Patient’s Overall Well-being
    End point description
    Only values at 12 and 24 weeks of treatment, expressed as percentage change from baseline, are reported here.
    End point type
    Secondary
    End point timeframe
    At 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 weeks of treatment.
    End point values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects analysed
    0 [5]
    1
    8 [6]
    2
    2 [7]
    Units: percentage
    arithmetic mean (standard deviation)
        12 weeks
    ( )
    80.85 ( 000 )
    13.46 ( 40.17 )
    88.37 ( 16.44 )
    -0.67 ( 46.20 )
        24 weeks
    ( )
    48.94 ( 000 )
    -6.59 ( 100.07 )
    94.38 ( 1.92 )
    000 ( 000 )
    Notes
    [5] - The only patient in this cohort discontinued the study before week 12
    [6] - 7 patients are part of this ITT cohort at 24 weeks
    [7] - 2 and 0 patients are part of this ITT cohort at weeks 12 and 24 respectively.
    No statistical analyses for this end point

    Secondary: Mean Changes Over Time of Functional Ability – Childhood Health Assessment Questionnaire (CHAQ)

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    End point title
    		 Mean Changes Over Time of Functional Ability – Childhood Health Assessment Questionnaire (CHAQ)
    End point description
    Only values at 12 and 24 weeks of treatment, expressed as percentage change from baseline, are reported here.
    End point type
    Secondary
    End point timeframe
    At 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 weeks of treatment.
    End point values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects analysed
    0 [8]
    1
    8 [9]
    2
    2 [10]
    Units: percentage
    arithmetic mean (standard deviation)
        week 12
    ( )
    28.5714 ( 000 )
    -13.8671 ( 85.6095 )
    79.1667 ( 29.4628 )
    50.0000 ( 000 )
        week 24
    ( )
    14.2857 ( 000 )
    31.5018 ( 65.5471 )
    100.0000 ( 0.0000 )
    000 ( 000 )
    Notes
    [8] - The only patient in this cohort discontinued the study before week 12
    [9] - 7 patients are part of this ITT cohort at 24 weeks
    [10] - 2 and 0 patients are part of this ITT cohort at weeks 12 and 24 respectively.
    No statistical analyses for this end point

    Secondary: Mean change over time of Number of Joints with Active Arthritis

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    End point title
    		 Mean change over time of Number of Joints with Active Arthritis
    End point description
    Only values from weeks 12 and 24 weeks of treatment, expressed as percentage change from baseline, are reported here.
    End point type
    Secondary
    End point timeframe
    At weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 weeks of treatment.
    End point values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects analysed
    0 [11]
    1
    8 [12]
    2
    2 [13]
    Units: percentage
    arithmetic mean (standard deviation)
        week 12
    ( )
    100.00 ( 000 )
    40.46 ( 38.36 )
    62.72 ( 29.15 )
    1.90 ( 78.12 )
        week 24
    ( )
    85.00 ( 000 )
    53.36 ( 37.16 )
    63.16 ( 52.10 )
    000 ( 000 )
    Notes
    [11] - The only patient in this cohort discontinued the study before week 12
    [12] - 7 patients are part of this ITT cohort at 24 weeks
    [13] - 2 and 0 patients are part of this ITT cohort at weeks 12 and 24 respectively.
    No statistical analyses for this end point

    Secondary: Mean Change over time of Number of Joints with Limitation of Motion

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    End point title
    		 Mean Change over time of Number of Joints with Limitation of Motion
    End point description
    Only values from weeks 12 and 24 weeks of treatment, expressed as percentage change from baseline, are reported here.
    End point type
    Secondary
    End point timeframe
    At weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 weeks of treatment.
    End point values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects analysed
    0 [14]
    1
    8 [15]
    2
    2 [16]
    Units: percentage
    arithmetic mean (standard deviation)
        week 12
    ( )
    -3.85 ( 000 )
    13.41 ( 31.38 )
    -87.50 ( 229.81 )
    1.67 ( 68.35 )
        week 24
    ( )
    7.69 ( 000 )
    24.79 ( 13.07 )
    -262.50 ( 477.30 )
    000 ( 000 )
    Notes
    [14] - The only patient in this cohort discontinued the study before week 12
    [15] - 7 patients are part of this ITT cohort at 24 weeks
    [16] - 2 and 0 patients are part of this ITT cohort at weeks 12 and 24 respectively
    No statistical analyses for this end point

    Secondary: Mean change over time of Laboratory Measure of Inflammation – C-reactive Protein

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    End point title
    		 Mean change over time of Laboratory Measure of Inflammation – C-reactive Protein
    End point description
    Only values from weeks 12 and 24 weeks of treatment, expressed as percentage change from baseline, are reported here.
    End point type
    Secondary
    End point timeframe
    At weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 weeks of treatment.
    End point values
    		 Low dose discontinued Low dose throughout Switched dose High dose throughout High dose discontinued
    Number of subjects analysed
    0 [17]
    1
    8 [18]
    2
    2 [19]
    Units: Percentage
    arithmetic mean (standard deviation)
        week 12
    ( )
    68.027 ( 000 )
    -147.124 ( 253.627 )
    19.415 ( 62.812 )
    -19.121 ( 51.285 )
        week 24
    ( )
    9.184 ( 000 )
    -10.402 ( 149.724 )
    -39.096 ( 19.934 )
    000 ( 000 )
    Notes
    [17] - The only patient in this cohort discontinued the study before week 12
    [18] - 7 patients are part of this ITT cohort at 24 weeks
    [19] - 2 and 0 patients are part of this ITT cohort at weeks 12 and 24 respectively.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded at days 1, 8, 15, 29, 43, 57, 71, 85 (Week 12), 99, 113, 127, 141, 155, 169 (Week 24 - End of study) and at post-study checks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Low dose discontinued - Safety set
    Reporting group description
    		 The safety set comprised all enrolled patients who received at least one dose of investigational medicinal product.

    Reporting group title
    Low dose throughout - Safety set
    Reporting group description
    		 The safety set comprised all enrolled patients who received at least one dose of investigational medicinal product.

    Reporting group title
    Switched dose - Safety set
    Reporting group description
    		 The safety set comprised all enrolled patients who received at least one dose of investigational medicinal product.

    Reporting group title
    High dose throughout - Safety set
    Reporting group description
    		 The safety set comprised all enrolled patients who received at least one dose of investigational medicinal product.

    Reporting group title
    High dose discontinued - Safety set
    Reporting group description
    		 The safety set comprised all enrolled patients who received at least one dose of investigational medicinal product.

    Serious adverse events
    		 Low dose discontinued - Safety set Low dose throughout - Safety set Switched dose - Safety set High dose throughout - Safety set High dose discontinued - Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Low dose discontinued - Safety set Low dose throughout - Safety set Switched dose - Safety set High dose throughout - Safety set High dose discontinued - Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    8 / 8 (100.00%)
    2 / 2 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Psychiatric disorders
    Nightmare
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Investigations
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Erythropenia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    1 / 2 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Coxsackie viral infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Otitis media acute
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Rhinitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Hypercholesterolemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypoalbuminemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Hypophosphatemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    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.
    No limitations or caveats are applicable to this summary of the results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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