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    Clinical Trial Results:
    Phase II, open label, international, multicentre clinical trial to investigate safety and efficacy of oral ITF 2357 in patients with active systemic onset juvenile idiopathic arthritis SOJIA

    Summary
    EudraCT number
    		 2006-000089-35
    Trial protocol
    		 IT  
    Global end of trial date
    25 Aug 2008

    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 description should be changed.

    Trial information

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    Trial identification
    Sponsor protocol code
    DSC/05/2357/19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00570661
    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
    25 Aug 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Aug 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety and tolerability of oral ITF2357 in patients with active SOJIA with inadequate response or intolerance to standard therapy with oral steroids and methotrexate, with or without previously used biologic agents.
    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
    12 Sep 2006
    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: 5
    Country: Number of subjects enrolled
    Serbia: 12
    Worldwide total number of subjects
    17
    EEA total number of subjects
    5
    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)
    8
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Seventeen patients were screened and enrolled in the study.

    Pre-assignment
    Screening details
    		 Patients with SOJIA according to the International League against Rheumatism criteria, established before the age of 16 y and for at least 6 mo before the study entry, having active disease for at least 1 mo while receiving more than 0.2 mg/kg/day prednisolone or equivalent steroid with/without concurrent methotrexate therapy (≥ 10 mg/m2 weekly).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable. The study was open label.

    Arms
    Arm title
    		 ITF2357
    Arm description
    		 ITF2357 hard gelatine capsules were administered orally, in fed conditions, at the cumulative daily dose of 1.5 mg/kg achieved by administration of 0.75 mg/kg at 12-hour interval for 4 weeks initially. The doses of 1.5 mg/kg/day were achieved by administration of an appropriate number of capsules of definite strength. Treatment was further prolonged up to 12 weeks in total if so suggested by the observed benefits and the lack of treatment-limiting toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ITF2357
    Investigational medicinal product code
    Other name
    Givinostat, histone deacetylase inhibitor
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    ITF2357 hard gelatine capsule for oral administration supplied at the dose strengths of 7.5, 10, 12.5, 15, 20 mg and 50 mg. The investigational product was administered orally, in fed conditions, at the cumulative daily dose of 1.5 mg/kg achieved by administration of 0.75 mg/kg at 12-hour interval. Each patient received the same daily dose for the whole treatment period. ITF2357 was initially administered for 4 weeks. Treatment was further prolonged up to 12 weeks in total if so suggested by the observed benefits and the lack of treatment-limiting toxicity.

    Number of subjects in period 1
    		ITF2357
    Started
    17
    Completed
    10
    Not completed
    7
         Unmet crtierion of sufficient therapeutic response
    1
         Adverse event, non-fatal
    1
         Disease worsening
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 17 17
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.18 ( 5.39 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 11 11
    Subject analysis sets

    Subject analysis set title
    ITF2357 - ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All recruited patients who received study medication and for whom at least one safety or efficacy measurement was available.

    Subject analysis set title
    ITF2357 - PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who completed the study without any major deviations from the protocol procedures.

    Subject analysis sets values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects
    17
    9
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11.18 ( 5.39 )
    ( )
    Gender categorical
    Units: Subjects
        Female
    6
    1
        Male
    11
    8

    End points

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    End points reporting groups
    Reporting group title
    ITF2357
    Reporting group description
    		 ITF2357 hard gelatine capsules were administered orally, in fed conditions, at the cumulative daily dose of 1.5 mg/kg achieved by administration of 0.75 mg/kg at 12-hour interval for 4 weeks initially. The doses of 1.5 mg/kg/day were achieved by administration of an appropriate number of capsules of definite strength. Treatment was further prolonged up to 12 weeks in total if so suggested by the observed benefits and the lack of treatment-limiting toxicity.

    Subject analysis set title
    ITF2357 - ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All recruited patients who received study medication and for whom at least one safety or efficacy measurement was available.

    Subject analysis set title
    ITF2357 - PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who completed the study without any major deviations from the protocol procedures.

    Primary: Number of patients completing week 12 of treatment

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    End point title
    		 Number of patients completing week 12 of treatment [1]
    End point description
    All patients in the study PP population (N=9) completed 12 weeks of treatment with ITF2357 according to the specifications of the protocol and thus reached the primary end-point of the study. The asnalysis was repeated on the ITT population: 10 out of the 17 patients in the ITT population completed 12 weeks of treatment and reached the primary end-point of the study.
    End point type
    Primary
    End point timeframe
    At week 12.
    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
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17
    9
    Units: number of patients
        Completers
    10
    9
        Non completers
    7
    0
    No statistical analyses for this end point

    Secondary: JIA Outcome Core Set Variables - Patient global assessment

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    End point title
    		 JIA Outcome Core Set Variables - Patient global assessment
    End point description
    Patient/parent global Visual Analogue Scale (VAS) (VAS) is from 0 to 100.
    End point type
    Secondary
    End point timeframe
    At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17 [2]
    9
    Units: score
    arithmetic mean (standard deviation)
        pre-treatment
    47.71 ( 21.45 )
    48.00 ( 22.50 )
        week 2
    42.47 ( 21.30 )
    43.33 ( 21.15 )
        week 4
    28.88 ( 22.48 )
    21.22 ( 14.00 )
        week 6
    22.36 ( 18.33 )
    19.11 ( 15.00 )
        week 8
    18.00 ( 13.99 )
    17.22 ( 14.59 )
        week 10
    22.33 ( 19.58 )
    17.44 ( 13.28 )
        week 12
    24.21 ( 20.89 )
    19.11 ( 14.57 )
        FU1
    26.56 ( 18.02 )
    18.11 ( 15.53 )
        FU3
    22.71 ( 17.85 )
    15.38 ( 15.32 )
    Notes
    [2] - n=16 at week 4 and FU1 n=14 at week 6, week 12 and FU3 n=12 at week 8 and week 10
    No statistical analyses for this end point

    Secondary: JIA Outcome Core Set Variables - Physician global assessment

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    End point title
    		 JIA Outcome Core Set Variables - Physician global assessment
    End point description
    Physician's global c (VAS) is from 0 to 100.
    End point type
    Secondary
    End point timeframe
    At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17 [3]
    9
    Units: score
    arithmetic mean (standard deviation)
        pre-treatment
    56.12 ( 12.99 )
    50.44 ( 8.43 )
        week 2
    46.35 ( 22.08 )
    39.44 ( 22.72 )
        week 4
    37.19 ( 22.59 )
    37.67 ( 14.39 )
        week 6
    32.86 ( 22.94 )
    24.89 ( 18.45 )
        week 8
    25.50 ( 16.59 )
    22.44 ( 15.53 )
        week 10
    29.08 ( 22.58 )
    22.11 ( 16.99 )
        week 12
    31.64 ( 23.95 )
    21.22 ( 17.40 )
        FU1
    31.38 ( 22.36 )
    19.44 ( 19.02 )
        FU3
    29.87 ( 19.89 )
    23.44 ( 21.41 )
    Notes
    [3] - n=16 at week 4 and FU1 n=15 at FU3 n=14 at week 6 and week 12 n=12 at week and week 10
    No statistical analyses for this end point

    Secondary: JIA Outcome Core Set Variables - Number of joints with active arthritis

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    End point title
    		 JIA Outcome Core Set Variables - Number of joints with active arthritis
    End point description
    Number of active joints is from 0 to 75.
    End point type
    Secondary
    End point timeframe
    At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17 [4]
    9
    Units: number
    arithmetic mean (standard deviation)
        pre-treatment
    9.82 ( 9.11 )
    9.33 ( 8.70 )
        week 2
    8.41 ( 9.49 )
    7.11 ( 8.62 )
        week 4
    6.38 ( 9.26 )
    3.78 ( 5.47 )
        week 6
    3.57 ( 4.33 )
    3.44 ( 5.29 )
        week 8
    3.42 ( 4.29 )
    3.67 ( 4.85 )
        week 10
    2.75 ( 4.03 )
    2.89 ( 4.54 )
        week 12
    4.86 ( 4.74 )
    3.44 ( 4.59 )
        FU1
    3.88 ( 4.49 )
    3.00 ( 4.50 )
        FU3
    5.00 ( 6.05 )
    3.33 ( 4.58 )
    Notes
    [4] - n=16 at week 4 and FU1 n=15 at FU3 n=14 at week 6 and week 12 n=12 at week and week 10
    No statistical analyses for this end point

    Secondary: JIA Outcome Core Set Variables - Number of joints with limitation

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    End point title
    		 JIA Outcome Core Set Variables - Number of joints with limitation
    End point description
    Number of joints with limited range of motion is from 0 to 75.
    End point type
    Secondary
    End point timeframe
    At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17 [5]
    9
    Units: number
    arithmetic mean (standard deviation)
        pre-treatment
    11.59 ( 14.00 )
    10.00 ( 9.53 )
        week 2
    10.41 ( 14.42 )
    8.56 ( 9.76 )
        week 4
    7.44 ( 11.56 )
    6.44 ( 7.20 )
        week 6
    7.86 ( 11.91 )
    5.78 ( 7.17 )
        week 8
    4.67 ( 6.08 )
    5.78 ( 6.63 )
        week 10
    4.42 ( 5.65 )
    5.22 ( 6.32 )
        week 12
    8.79 ( 12.27 )
    4.78 ( 5.65 )
        FU1
    7.94 ( 12.22 )
    5.00 ( 5.92 )
        FU3
    7.20 ( 8.79 )
    5.22 ( 5.70 )
    Notes
    [5] - n=16 at week 4 and FU1 n=15 at FU3 n=14 at week 6 and week 12 n=12 at week and week 10
    No statistical analyses for this end point

    Secondary: JIA Outcome Core Set Variables - CHAQ

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    End point title
    		 JIA Outcome Core Set Variables - CHAQ
    End point description
    The Childhood Health Assessment Questionnaire (CHAQ) is from 0 to 3
    End point type
    Secondary
    End point timeframe
    At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17 [6]
    9 [7]
    Units: score
    arithmetic mean (standard deviation)
        pre-treatment
    1.75 ( 0.74 )
    1.55 ( 0.54 )
        week 2
    1.39 ( 0.87 )
    1.13 ( 0.57 )
        week 4
    1.23 ( 0.88 )
    0.93 ( 0.55 )
        week 6
    1.02 ( 0.82 )
    0.75 ( 0.56 )
        week 8
    0.85 ( 0.82 )
    0.58 ( 0.50 )
        week 10
    0.85 ( 0.87 )
    0.55 ( 0.50 )
        week 12
    0.95 ( 0.82 )
    0.58 ( 0.41 )
        FU1
    1.02 ( 0.93 )
    0.56 ( 0.39 )
        FU3
    0.85 ( 0.78 )
    0.58 ( 0.51 )
    Notes
    [6] - n=16 at week 4 and FU1 n=14 at week 6, week 12 and FU3 n=12 at week 8 and week 10
    [7] - n=8 at FU3
    No statistical analyses for this end point

    Secondary: JIA Outcome Core Set Variables - ESR

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    End point title
    		 JIA Outcome Core Set Variables - ESR
    End point description
    Measurements of erythrocyte sedimentation rate (ESR) were performed at the local laboratory cooperating with each study site.
    End point type
    Secondary
    End point timeframe
    At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17 [8]
    9 [9]
    Units: mm/h
    arithmetic mean (standard deviation)
        pre-treatment
    62.71 ( 31.76 )
    65.22 ( 23.05 )
        week 2
    59.12 ( 30.90 )
    53.44 ( 26.54 )
        week 4
    59.50 ( 34.71 )
    52.67 ( 22.66 )
        week 6
    53.90 ( 22.35 )
    57.67 ( 20.66 )
        week 8
    49.92 ( 31.20 )
    49.33 ( 33.78 )
        week 10
    59.25 ( 23.35 )
    58.33 ( 23.40 )
        week 12
    54.14 ( 37.07 )
    56.44 ( 40.76 )
        FU1
    46.31 ( 28.30 )
    39.89 ( 28.32 )
        FU3
    41.00 ( 25.02 )
    44.57 ( 25.00 )
    Notes
    [8] - n=16 at week 4 and FU1 n=14 at week 12 n=13 at FU3 n=12 at week 8 n=10 at week 6 n=8 at week 10
    [9] - n=7 at FU3 n=6 at week 6 and week 10
    No statistical analyses for this end point

    Secondary: Overall SFS results - Sum of first five variables and sum of last five variables

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    End point title
    		 Overall SFS results - Sum of first five variables and sum of last five variables
    End point description
    Modified Systemic Feature Score (SFS) variables included: - temperature, rash, lymph nodes, liver and spleen size, and clinical evidence of serositis (clinical variables) - ESR, CRP, leukocyte count, haemoglobin, thrombocyte count (laboratory variables). Items in both sets of variables were scored as present (1) or not present (0) based on predefined criteria, described in the attached chart. SFS data were presented as the sum of the first 5 items and the sum of the last 5 items. Each sum could range from a minimum of 0 to a maximum of 5.
    End point type
    Secondary
    End point timeframe
    At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17 [10]
    9
    Units: score
    arithmetic mean (standard deviation)
        sum of clinical variables - pre-treatment
    0.94 ( 0.75 )
    1.33 ( 0.71 )
        sum of clinical variables - week 2
    0.35 ( 0.61 )
    0.44 ( 0.73 )
        sum of clinical variables - week 4
    0.31 ( 0.48 )
    0.11 ( 0.33 )
        sum of clinical variables - week 6
    0.14 ( 0.36 )
    0.11 ( 0.33 )
        sum of clinical variables - week 8
    0.17 ( 0.39 )
    0.11 ( 0.33 )
        sum of clinical variables - week 10
    0.33 ( 0.65 )
    0.11 ( 0.33 )
        sum of clinical variables - week 12
    0.29 ( 0.47 )
    0.22 ( 0.44 )
        sum of clinical variables - FU1
    0.20 ( 0.41 )
    0.22 ( 0.44 )
        sum of laboratory variables - pre-treatment
    4.24 ( 1.15 )
    4.33 ( 1.00 )
        sum of laboratory variables - week 2
    2.65 ( 1.17 )
    2.44 ( 1.42 )
        sum of laboratory variables - week 4
    2.25 ( 1.18 )
    2.11 ( 0.93 )
        sum of laboratory variables - week 6
    1.93 ( 1.21 )
    1.56 ( 1.33 )
        sum of laboratory variables - week 8
    1.92 ( 1.44 )
    2.00 ( 1.66 )
        sum of laboratory variables - week 10
    2.08 ( 1.38 )
    2.00 ( 1.58 )
        sum of laboratory variables - week 12
    2.07 ( 1.27 )
    1.89 ( 1.45 )
        sum of laboratory variables - FU1
    2.56 ( 1.67 )
    2.22 ( 1.92 )
    Attachments
    		 Overall SFS_PP and ITT populations
    Description
    Notes
    [10] - n=16 at wk 4 (clin) & FU1 (lab) n=14 at wk 6 & wk 12 n=12 at wk 8 & wk 10 n=15 at FU1 (clin)
    No statistical analyses for this end point

    Secondary: N. and % of pts with presence or absence of each item for SFS

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    End point title
    		 N. and % of pts with presence or absence of each item for SFS
    End point description
    Description of criteria for SFS results is attached.
    End point type
    Secondary
    End point timeframe
    At pretreatment visit, at weeks 4, 8, 12 (End of treatment) and 1 month follow up (FU1) in the ITT and PP respectively. See the two tables attached.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17
    9
    Units: number and % of patients
    0
    0
    Attachments
    		 ITT population
    PP population
    Description
    No statistical analyses for this end point

    Secondary: N. and % of pts with sufficient therapeutic response at week 4 to continue treatment

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    End point title
    		 N. and % of pts with sufficient therapeutic response at week 4 to continue treatment
    End point description
    Therapeutic response at week 4 was considered sufficient by the Investigator if a decrease in Systemic Feature Score of 2 (at least one of the first five variables) and/or JIA30 response (or above: 50 or 70) was obtained. Number of patients are reported here. For number and percentage of patients, see attached tables.
    End point type
    Secondary
    End point timeframe
    At week 4.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17
    9
    Units: number of patients
        Therapeutic response
    11
    8
        Absence of therapeutic response
    6
    1
    Attachments
    		 ITT population
    PP population
    No statistical analyses for this end point

    Secondary: N. and % of pts with JIA plus SFS clinical improvement

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    End point title
    		 N. and % of pts with JIA plus SFS clinical improvement
    End point description
    Clinical improvement at week 2, 4, 6, 8, 10 and 12 was evaluated on the basis of JIA30, JIA50 and JIA70 plus SFS (two points decrease in SFS) as per protocol. Patients were considered as improved and with positive therapeutic response if 3 or more JIA Core Set Variables improved by 30% and no more than one worsened by 30%. JIA50 and JIA70 were defined as an improvement of 3 or more JIA Core Set Variables by 50% and 70%, respectively, and no more than 1 worsened by 30%. Additionally two points decrease in Systemic Feature Score were considered as disease improvement. Number of patients at week 12 are reported here. For number and percentage of patients at all timepoints, see attached tables.
    End point type
    Secondary
    End point timeframe
    At weeks 2, 4, 6, 8, 10 and 12.
    End point values
    		 ITF2357 - ITT population ITF2357 - PP population
    Number of subjects analysed
    17
    9
    Units: number of patients
        JIA30 plus SFS - Clinical improvement
    10
    8
        JIA30 plus SFS - Absence of clinical improvement
    7
    1
        JIA50 plus SFS - Clinical improvement
    9
    8
        JIA50 plus SFS - Absence of clinical improvement
    8
    1
        JIA70 plus SFS - Clinical improvement
    9
    8
        JIA70 plus SFS - Absence of clinical improvement
    8
    1
    Attachments
    		 ITT population
    PP population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At weeks 1, 2, 4, 6, 8, 10, 12 (end of treatment) and FU1 and FU3
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    IT2357 - safety population
    Reporting group description
    		 Safety population: all recruited patients who received at least one dose of the study medication.

    Serious adverse events
    		 IT2357 - safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 17 (11.76%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Varicella
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IT2357 - safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 17 (82.35%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Enteritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    6
    Vomiting
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nephrolithiasis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Arthritis
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Joint swelling
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Otitis media acute
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2007
    Reason for the amendment was that some protocol changes were necessary following the occurrence of two SUSARs during treatment with ITF2357 in patients affected by onco haematological malignancies. The two SUSARs were: - A fatal liver failure - QTc prolongation (QTc > 500 msec) with concomitant sinus bradycardia, low serum K and Mg. The following protocol changes were introduced:  more restrictive inclusion/exclusion criteria related to virological aspects, excluding patients with on-going clinically relevant viral infections or with risk of developing severe viral infections  treatment discontinuation in case of occurrence of severe viral or bacterial infections  more restrictive inclusion/exclusion criteria related to cardiovascular aspects, excluding patients with additional risk factors for Torsade de Pointes and excluding use of concomitant medications with potential risk of Torsade de Pointes  calculation of QTc interval as for Bazett’s formula at each ECG recording and measurements of serum concentration of Mg and K  treatment discontinuation in case of QTc prolongation and/or serum levels of Mg and K falling below the Lower Limit of Normal Laboratory Ranges during the treatment with ITF2357. In addition the following inclusion criteria were modified: basal Hb below 11 mg/dL and previous treatment with methotrexate not required any longer as inclusion criteria  check for sufficient therapeutic response restricted to week 4 and 8, based on either SFS reduction of 2 points and/or JIA30 achievement  calculation of items 5 to 10 of the SFS to be done in comparison vs. pre-treatment values instead of values measured in the previous visit.

    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 results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/21538322
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